Saunders, C.N.
Kinnersley, B.
Culliford, R.
Cornish, A.J.
Law, P.J.
Houlston, R.S.
(2022). Relationship between genetically determined telomere length and glioma risk. Neuro oncol,
Vol.24
(2),
pp. 171-181.
show abstract
BACKGROUND: Telomere maintenance is increasingly recognized as being fundamental to glioma oncogenesis with longer leukocyte telomere length (LTL) reported to increase risk of glioma. To gain further insight into the relationship between telomere genetics and risk of glioma, we conducted several complementary analyses, using genome-wide association studies data on LTL (78 592 individuals) and glioma (12 488 cases and 18 169 controls). METHODS: We performed both classical and summary Mendelian randomization (SMR), coupled with heterogeneity in dependent instruments tests, at genome-wide significant LTL loci to examine if an association was mediated by the same causal variant in glioma. To prioritize genes underscoring glioma-LTL associations, we analyzed gene expression and DNA methylation data. RESULTS: Genetically increased LTL was significantly associated with increased glioma risk, random-effects inverse variance weighted ORs per 1 SD unit increase in the putative risk factor (odds ratio [OR]SD) 4.79 (95% confidence interval: 2.11-10.85; P = 1.76 × 10-4). SMR confirmed the previously reported LTL associations at 3q26.2 (TERC; PSMR = 1.33 × 10-5), 5p15.33 (TERT; PSMR = 9.80 × 10-27), 10q24.33 (STN1 alias OBFC1; PSMR = 4.31 × 10-5), and 20q13.3 (STMN3/RTEL1; PSMR = 2.47 × 10-4) glioma risk loci. Our analysis implicates variation at 1q42.12 (PSMR = 1.55 × 10-2), 6p21.3 (PSMR = 9.76 × 10-3), 6p22.2 (PSMR = 5.45 × 10-3), 7q31.33 (PSMR = 6.52 × 10-3), and 11q22.3 (PSMR = 8.89 × 10-4) as risk factors for glioma risk. While complicated by patterns of linkage disequilibrium, genetic variation involving PARP1, PRRC2A, CARMIL1, POT1, and ATM-NPAT1 was implicated in the etiology of glioma. CONCLUSIONS: These observations extend the role of telomere-related genes in the development of glioma..
Palles, C.
West, H.D.
Chew, E.
Galavotti, S.
Flensburg, C.
Grolleman, J.E.
Jansen, E.A.
Curley, H.
Chegwidden, L.
Arbe-Barnes, E.H.
Lander, N.
Truscott, R.
Pagan, J.
Bajel, A.
Sherwood, K.
Martin, L.
Thomas, H.
Georgiou, D.
Fostira, F.
Goldberg, Y.
Adams, D.J.
van der Biezen, S.A.
Christie, M.
Clendenning, M.
Thomas, L.E.
Deltas, C.
Dimovski, A.J.
Dymerska, D.
Lubinski, J.
Mahmood, K.
van der Post, R.S.
Sanders, M.
Weitz, J.
Taylor, J.C.
Turnbull, C.
Vreede, L.
van Wezel, T.
Whalley, C.
Arnedo-Pac, C.
Caravagna, G.
Cross, W.
Chubb, D.
Frangou, A.
Gruber, A.J.
Kinnersley, B.
Noyvert, B.
Church, D.
Graham, T.
Houlston, R.
Lopez-Bigas, N.
Sottoriva, A.
Wedge, D.
Jenkins, M.A.
Kuiper, R.P.
Roberts, A.W.
Cheadle, J.P.
Ligtenberg, M.J.
Hoogerbrugge, N.
Koelzer, V.H.
Rivas, A.D.
Winship, I.M.
Ponte, C.R.
Buchanan, D.D.
Power, D.G.
Green, A.
Tomlinson, I.P.
Sampson, J.R.
Majewski, I.J.
de Voer, R.M.
(2022). Germline MBD4 deficiency causes a multi-tumor predisposition syndrome. The american journal of human genetics,
Vol.109
(5),
pp. 953-960.
Reijns, M.A.
Parry, D.A.
Williams, T.C.
Nadeu, F.
Hindshaw, R.L.
Rios Szwed, D.O.
Nicholson, M.D.
Carroll, P.
Boyle, S.
Royo, R.
Cornish, A.J.
Xiang, H.
Ridout, K.
Genomics England Research Consortium,
Colorectal Cancer Domain UK 100,
Schuh, A.
Aden, K.
Palles, C.
Campo, E.
Stankovic, T.
Taylor, M.S.
Jackson, A.P.
(2022). Signatures of TOP1 transcription-associated mutagenesis in cancer and germline. Nature,
.
show abstract
The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair1. In microorganisms, transcription has been demonstrated to be mutagenic2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes4. Here we show that ID4-a cancer insertion-deletion (indel) mutation signature of unknown aetiology5 characterized by short (2 to 5 base pair) deletions -is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress6, their activity may also be an important source of mutations in the human genome..
Ajore, R.
Niroula, A.
Pertesi, M.
Cafaro, C.
Thodberg, M.
Went, M.
Bao, E.L.
Duran-Lozano, L.
Lopez de Lapuente Portilla, A.
Olafsdottir, T.
Ugidos-Damboriena, N.
Magnusson, O.
Samur, M.
Lareau, C.A.
Halldorsson, G.H.
Thorleifsson, G.
Norddahl, G.L.
Gunnarsdottir, K.
Försti, A.
Goldschmidt, H.
Hemminki, K.
van Rhee, F.
Kimber, S.
Sperling, A.S.
Kaiser, M.
Anderson, K.
Jonsdottir, I.
Munshi, N.
Rafnar, T.
Waage, A.
Weinhold, N.
Thorsteinsdottir, U.
Sankaran, V.G.
Stefansson, K.
Houlston, R.
Nilsson, B.
(2022). Functional dissection of inherited non-coding variation influencing multiple myeloma risk. Nature communications,
Vol.13
(1),
pp. 151-?.
show abstract
Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy..
Clay-Gilmour, A.
Chattopadhyay, S.
Hildebrandt, M.A.
Thomsen, H.
Weinhold, N.
Vodicka, P.
Vodickova, L.
Hoffmann, P.
Nöthen, M.M.
Jöckel, K.-.
Schmidt, B.
Langer, C.
Hajek, R.
Hallmans, G.
Pettersson-Kymmer, U.
Ohlsson, C.
Späth, F.
Houlston, R.
Goldschmidt, H.
Manasanch, E.E.
Norman, A.
Kumar, S.
Rajkumar, S.V.
Slager, S.
Försti, A.
Vachon, C.M.
Hemminki, K.
(2022). Genome-wide meta-analysis of monoclonal gammopathy of undetermined significance (MGUS) identifies risk loci impacting IRF-6. ,
Vol.12
(4),
p. 60.
Yngvadottir, B.
Andreou, A.
Bassaganyas, L.
Larionov, A.
Cornish, A.J.
Chubb, D.
Saunders, C.N.
Smith, P.
Zhang, H.
Cole, Y.
Consortium, G.E.
Larkin, J.
Browning, L.
Turajlic, S.
Litchfield, K.
Houlston, R.S.
Maher, E.R.
(2022). Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases. ,
,
p. ddac089.
show abstract
BACKGROUND: Renal cell carcinoma (RCC) occurs in a number of cancer predisposition syndromes but the genetic architecture of susceptibility to RCC is not well defined. We investigated the frequency of pathogenic germline variants in cancer susceptibility genes (CSGs) within a large series of unselected RCC participants. METHODS: Whole genome sequencing data on 1336 RCC participants and 5834 controls recruited to the UK 100000 Genomes Project, a nationwide multicentre study, was analysed to identify rare pathogenic or likely pathogenic (P/LP) short variants (SNVs and INDELs) and structural variants in 121 CSGs. RESULTS: Among 1336 RCC participants (mean 61.3 years [±12SD], range 13-88 years; 64% male), 85 participants (6.4%; 95% CI [5.1, 7.8]) had one or more P/LP germline variant in a wider range of CSGs than previously recognised. A further 64 intragenic variants in CSGs previously associated with RCC were classified as a variant of uncertain significance (VUS) (24 'hot VUSs') and were considered to be of potential clinical relevance as further evaluation might result in their reclassification. Most patients with pathogenic variants in well-established RCC-CSGs were aged < 50 years. Burden test analysis for filtered variants in CSGs demonstrated a significant excess of CHEK2 variants RCC European participants compared to the healthy European controls (P = 0.0019). CONCLUSIONS: Approximately 6% of patients with RCC unselected for family history have a germline variant requiring additional follow-up analysis. To improve diagnostic yield we suggest expanding the panel of RCC-CSGs tested to include CHEK2 and all SDHx subunits and raising the eligibility criteria for age-based testing..
Andreou, A.
Yngvadottir, B.
Bassaganyas, L.
Clarke, G.
Martin, E.
Whitworth, J.
Cornish, A.J.
Genomics England Research Consortium,
Houlston, R.S.
Rich, P.
Egan, C.
Hodgson, S.V.
Warren, A.Y.
Snape, K.
Maher, E.R.
(2022). Elongin C (ELOC/TCEB1) associated von Hippel-Lindau disease. Human molecular genetics,
,
pp. ddac066-?.
show abstract
Around 95% of patients with clinical features diagnostic of Von Hippel-Lindau disease (VHL) have a detectable inactivating germline variant in VHL. The VHL protein (pVHL) functions as part of the VCB-CR complex which plays a key role in oxygen sensing and degradation of hypoxia inducible factors. To date, only variants in VHL has been shown to cause VHL disease. We undertook trio analysis by Whole-exome sequencing (WES) in a proband with VHL disease but without a detectable VHL mutation. Molecular studies were also performed on paired DNA extracted from the proband's kidney tumour and blood and bioinformatics analysis of sporadic renal cell carcinoma data set was undertaken. A de novo pathogenic variant in ELOC (NM_005648.4:c.236A > G [p.Tyr79Cys]) gene was identified in the proband. ELOC encodes elongin C, a key component [C] of the VCB-CR complex. The p.Tyr79Cys substitution is a mutational hotspot in sporadic VHL-competent renal cell carcinoma (RCC) and has previously been shown to mimic the effects of pVHL deficiency on hypoxic signalling. Analysis of a RCC from the proband showed similar findings to that in somatically ELOC mutated RCC (expression of hypoxia responsive proteins, no somatic VHL variants and chromosome 8 loss). These findings are consistent with pathogenic ELOC variants being a novel cause for VHL disease and suggest that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease with no detectable VHL variant..
Vickers, A.J.
Sud, A.
Bernstein, J.
Houlston, R.
(2022). Polygenic risk scores to stratify cancer screening should predict mortality not incidence. ,
Vol.6
(1),
p. 32.
show abstract
Population-based cancer screening programs such as mammography or colonscopy generally directed at all healthy individuals in a given age stratum. It has recently been proposed that cancer screening could be restricted to a high-risk subgroup based on polygenic risk scores (PRSs) using panels of single-nucleotide polymorphisms (SNPs). These PRSs were, however, generated to predict cancer incidence rather than cancer mortality and will not necessarily address overdiagnosis, a major problem associated with cancer screening programs. We develop a simple net-benefit framework for evaluating screening approaches that incorporates overdiagnosis. We use this methodology to demonstrate that if a PRS does not differentially discriminate between incident and lethal cancer, restricting screening to a subgroup with high scores will only improve screening outcomes in a small number of scenarios. In contrast, restricting screening to a subgroup defined as high-risk based on a marker that is more strongly predictive of mortality than incidence will often afford greater net benefit than screening all eligible individuals. If PRS-based cancer screening is to be effective, research needs to focus on identifying PRSs associated with cancer mortality, an unchartered and clinically-relevant area of research, with a much higher potential to improve screening outcomes..
Saunders, C.N.
Cornish, A.J.
Kinnersley, B.
Law, P.J.
Houlston, R.S.
Collaborators,
(2021). Searching for causal relationships of glioma: a phenome-wide Mendelian randomisation study. British journal of cancer,
Vol.124
(2),
pp. 447-454.
show abstract
Background The aetiology of glioma is poorly understood. Summary data from genome-wide association studies (GWAS) can be used in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to search for glioma risk factors.Methods We performed an MR-PheWAS analysing 316 phenotypes, proxied by 8387 genetic variants, and summary genetic data from a GWAS of 12,488 glioma cases and 18,169 controls. Causal effects were estimated under a random-effects inverse-variance-weighted (IVW-RE) model, with robust adjusted profile score (MR-RAPS), weighted median and mode-based estimates computed to assess the robustness of findings. Odds ratios per one standard deviation increase in each phenotype were calculated for all glioma, glioblastoma (GBM) and non-GBM tumours.Results No significant associations (P < 1.58 × 10 -4 ) were observed between phenotypes and glioma under the IVW-RE model. Suggestive associations (1.58 × 10 -4 < P < 0.05) were observed between leukocyte telomere length (LTL) with all glioma (OR SD = 3.91, P = 9.24 × 10 -3 ) and GBM (OR SD = 4.86, P = 3.23 × 10 -2 ), but the association was primarily driven by the TERT variant rs2736100. Serum low-density lipoprotein cholesterol and plasma HbA1C showed suggestive associations with glioma (OR SD = 1.11, P = 1.39 × 10 -2 and OR SD = 1.28, P = 1.73 × 10 -2 , respectively), both associations being reliant on single genetic variants.Conclusions Our study provides further insight into the aetiological basis of glioma for which published data have been mixed..
Weinhold, N.
Salwender, H.J.
Cairns, D.A.
Raab, M.S.
Waldron, G.
Blau, I.W.
Bertsch, U.
Hielscher, T.
Morgan, G.J.
Jauch, A.
Davies, F.E.
Hänel, M.
Cook, G.
Scheid, C.
Houlston, R.
Goldschmidt, H.
Jackson, G.
Kaiser, M.F.
(2021). Chromosome 1q21 abnormalities refine outcome prediction in patients with multiple myeloma - a meta-analysis of 2,596 trial patients. Haematologica,
Vol.106
(10),
pp. 2754-2758.
Lesseur, C.
Ferreiro-Iglesias, A.
McKay, J.D.
Bossé, Y.
Johansson, M.
Gaborieau, V.
Landi, M.T.
Christiani, D.C.
Caporaso, N.C.
Bojesen, S.E.
Amos, C.I.
Shete, S.
Liu, G.
Rennert, G.
Albanes, D.
Aldrich, M.C.
Tardon, A.
Chen, C.
Triantafillos, L.
Field, J.K.
Teare, M.D.
Kiemeney, L.A.
Diergaarde, B.
Ferris, R.L.
Zienolddiny, S.
Lam, S.
Olshan, A.F.
Weissler, M.C.
Lacko, M.
Risch, A.
Bickeböller, H.
Ness, A.R.
Thomas, S.
Le Marchand, L.
Schabath, M.B.
Wünsch-Filho, V.
Tajara, E.H.
Andrew, A.S.
Clifford, G.M.
Lazarus, P.
Grankvist, K.
Johansson, M.
Arnold, S.
Melander, O.
Brunnström, H.
Boccia, S.
Cadoni, G.
Timens, W.
Obeidat, M.
Xiao, X.
Houlston, R.S.
Hung, R.J.
Brennan, P.
(2021). Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers. Plos genetics,
Vol.17
(3),
pp. e1009254-?.
show abstract
Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites..
Studd, J.B.
Cornish, A.J.
Hoang, P.H.
Law, P.
Kinnersley, B.
Houlston, R.
(2021). Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes. Blood cancer journal,
Vol.11
(11),
pp. 177-?.
show abstract
To obtain a comprehensive picture of composite genetic driver events and clonal dynamics in subtypes of paediatric acute lymphoblastic leukaemia (ALL) we analysed tumour-normal whole genome sequencing and expression data from 361 newly diagnosed patients. We report the identification of both structural drivers, as well as recurrent non-coding variation in promoters. Additionally we found the transcriptional profile of histone gene cluster 1 and CTCF altered tumours shared hallmarks of hyperdiploid ALL suggesting a 'hyperdiploid like' subtype. ALL subtypes are driven by distinct mutational processes with AID mutagenesis being confined to ETV6-RUNX1 tumours. Subclonality is a ubiquitous feature of ALL, consistent with Darwinian evolution driving selection and expansion of tumours. Driver mutations in B-cell developmental genes (IKZF1, PAX5, ZEB2) tend to be clonal and RAS/RTK mutations subclonal. In addition to identifying new avenues for therapeutic exploitation, this analysis highlights that targeted therapies should take into account composite mutational profile and clonality..
Wills, C.
He, Y.
Summers, M.G.
Lin, Y.
Phipps, A.I.
Watts, K.
Law, P.J.
Al-Tassan, N.A.
Maughan, T.S.
Kaplan, R.
Houlston, R.S.
Peters, U.
Newcomb, P.A.
Chan, A.T.
Buchanan, D.D.
Gallinger, S.
Marchand, L.L.
Pai, R.K.
Shi, Q.
Alberts, S.R.
Gray, V.
West, H.D.
Escott-Price, V.
Dunlop, M.G.
Cheadle, J.P.
(2021). A genome-wide search for determinants of survival in 1926 patients with advanced colorectal cancer with follow-up in over 22,000 patients. European journal of cancer,
Vol.159,
pp. 247-258.
Zhang, X.
Li, X.
He, Y.
Law, P.J.
Farrington, S.M.
Campbell, H.
Tomlinson, I.P.
Houlston, R.S.
Dunlop, M.G.
Timofeeva, M.
Theodoratou, E.
(2021). Phenome-wide association study (PheWAS) of colorectal cancer risk SNP effects on health outcomes in UK Biobank. British journal of cancer,
.
show abstract
BACKGROUND:Associations between colorectal cancer (CRC) and other health outcomes have been reported, but these may be subject to biases, or due to limitations of observational studies. METHODS:We set out to determine whether genetic predisposition to CRC is also associated with the risk of other phenotypes. Under the phenome-wide association study (PheWAS) and tree-structured phenotypic model (TreeWAS), we studied 334,385 unrelated White British individuals (excluding CRC patients) from the UK Biobank cohort. We generated a polygenic risk score (PRS) from CRC genome-wide association studies as a measure of CRC risk. We performed sensitivity analyses to test the robustness of the results and searched the Danish Disease Trajectory Browser (DTB) to replicate the observed associations. RESULTS:Eight PheWAS phenotypes and 21 TreeWAS nodes were associated with CRC genetic predisposition by PheWAS and TreeWAS, respectively. The PheWAS detected associations were from neoplasms and digestive system disease group (e.g. benign neoplasm of colon, anal and rectal polyp and diverticular disease). The results from the TreeWAS corroborated the results from the PheWAS. These results were replicated in the observational data within the DTB. CONCLUSIONS:We show that benign colorectal neoplasms share genetic aetiology with CRC using PheWAS and TreeWAS methods. Additionally, CRC genetic predisposition is associated with diverticular disease..
Duran-Lozano, L.
Thorleifsson, G.
Lopez de Lapuente Portilla, A.
Niroula, A.
Went, M.
Thodberg, M.
Pertesi, M.
Ajore, R.
Cafaro, C.
Olason, P.I.
Stefansdottir, L.
Bragi Walters, G.
Halldorsson, G.H.
Turesson, I.
Kaiser, M.F.
Weinhold, N.
Abildgaard, N.
Andersen, N.F.
Mellqvist, U.-.
Waage, A.
Juul-Vangsted, A.
Thorsteinsdottir, U.
Hansson, M.
Houlston, R.
Rafnar, T.
Stefansson, K.
Nilsson, B.
(2021). Germline variants at SOHLH2 influence multiple myeloma risk. Blood cancer journal,
Vol.11
(4),
pp. 76-?.
show abstract
Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10 -14 ). This gene encodes a transcription factor involved in gametogenesis that is normally only weakly expressed in plasma cells. The association is represented by 14 variants in linkage disequilibrium. Among these, rs75712673 maps to a genomic region with open chromatin in plasma cells, and upregulates SOHLH2 in this cell type. Moreover, rs75712673 influences transcriptional activity in luciferase assays, and shows a chromatin looping interaction with the SOHLH2 promoter. Our work provides novel insight into MM susceptibility..
Ostrom, Q.T.
Edelson, J.
Byun, J.
Han, Y.
Kinnersley, B.
Melin, B.
Houlston, R.S.
Monje, M.
Walsh, K.M.
Amos, C.I.
Bondy, M.L.
(2021). Partitioned glioma heritability shows subtype-specific enrichment in immune cells. Neuro-oncology,
.
show abstract
Background Epidemiological studies of adult glioma have identified genetic syndromes and 25 heritable risk loci that modify individual risk for glioma, as well increased risk in association with exposure to ionizing radiation and decreased risk in association with allergies. In this analysis we assess whether there is shared genome-wide genetic architecture between glioma and atopic/autoimmune diseases.Methods Using summary statistics from a glioma genome-wide association studies (GWAS) meta-analysis, we identified significant enrichment for risk variants associated with gene expression changes in immune cell populations. We also estimated genetic correlations between glioma and autoimmune, atopic, and hematologic traits using LDscore regression, which leverages genome-wide single nucleotide polymorphism (SNP) associations and patterns of linkage disequilibrium.Results Nominally significant negative correlations were observed for glioblastoma and primary biliary cirrhosis (rg=-0.26, p=0.0228), and for non-glioblastoma gliomas and celiac disease (rg=-0.32, p=0.0109). Our analyses implicate dendritic cells (GB pHM= 0.0306 and non-GB pHM=0.0186) in mediating both glioblastoma and non-glioblastoma genetic predisposition, with glioblastoma-specific associations identified in natural killer (NK) (pHM=0.0201) and stem cells (pHM=0.0265).Conclusions This analysis identifies putative new associations between glioma and autoimmune conditions with genomic architecture that is inversely correlated with that of glioma and that T cells, NK cells, and myeloid cells are involved in mediating glioma predisposition. This provides further evidence that increased activation of the acquired immune system may modify individual susceptibility to glioma..
Bartram, T.
Schütte, P.
Möricke, A.
Houlston, R.S.
Ellinghaus, E.
Zimmermann, M.
Bergmann, A.
Löscher, B.-.
Klein, N.
Hinze, L.
Junk, S.V.
Forster, M.
Bartram, C.R.
Köhler, R.
Franke, A.
Schrappe, M.
Kratz, C.P.
Cario, G.
Stanulla, M.
(2021). Genetic Variation in ABCC4 and CFTR and Acute Pancreatitis during Treatment of Pediatric Acute Lymphoblastic Leukemia. Journal of clinical medicine,
Vol.10
(21).
show abstract
Background Acute pancreatitis (AP) is a serious, mechanistically not entirely resolved side effect of L-asparaginase-containing treatment for acute lymphoblastic leukemia (ALL). To find new candidate variations for AP, we conducted a genome-wide association study (GWAS). Methods In all, 1,004,623 single-nucleotide variants (SNVs) were analyzed in 51 pediatric ALL patients with AP (cases) and 1388 patients without AP (controls). Replication used independent patients. Results The top-ranked SNV (rs4148513) was located within the ABCC4 gene (odds ratio (OR) 84.1; p = 1.04 × 10 -14 ). Independent replication of our 20 top SNVs was not supportive of initial results, partly because rare variants were neither present in cases nor present in controls. However, results of combined analysis (GWAS and replication cohorts) remained significant (e.g., rs4148513; OR = 47.2; p = 7.31 × 10 -9 ). Subsequently, we sequenced the entire ABCC4 gene and its close relative, the cystic fibrosis associated CFTR gene, a strong AP candidate gene, in 48 cases and 47 controls. Six AP-associated variants in ABCC4 and one variant in CFTR were detected. Replication confirmed the six ABCC4 variants but not the CFTR variant. Conclusions Genetic variation within the ABCC4 gene was associated with AP during the treatment of ALL. No association of AP with CFTR was observed. Larger international studies are necessary to more conclusively assess the risk of rare clinical phenotypes..
He, Y.
Zhang, X.
Timofeeva, M.
Farrington, S.M.
Li, X.
Xu, W.
Campbell, H.
Houlston, R.S.
Tomlinson, I.P.
Theodoratou, E.
Dunlop, M.G.
(2021). Bidirectional Mendelian randomisation analysis of the relationship between circulating vitamin D concentration and colorectal cancer risk. International journal of cancer,
.
show abstract
Epidemiological evidence is consistent with a protective effect of vitamin D against colorectal cancer (CRC), but the observed strong associations are open to confounders and potential reverse causation. Previous Mendelian randomisation (MR) studies were limited by poor genetic instruments and inadequate statistical power. Moreover, whether genetically higher CRC risk can influence vitamin D level, namely the reverse causation, still remains unknown. Herein, we report the first bidirectional MR study. We employed 110 newly identified genetic variants as proxies for vitamin D to obtain unconfounded effect estimates on CRC risk in 26 397 CRC cases and 41 481 controls of European ancestry. To test for reserve causation, we estimated effects of 115 CRC-risk variants on vitamin D level among 417 580 participants from the UK Biobank. The causal association was estimated using the random-effect inverse-variance weighted (IVW) method. We found no significant causal effect of vitamin D on CRC risk [IVW estimate odds ratio: 0.97, 95% confidence interval (CI) = 0.88-1.07, P = .565]. Similarly, no significant reverse causal association was identified between genetically increased CRC risk and vitamin D levels (IVW estimate β: -0.002, 95% CI = -0.008 to 0.004, P = .543). Stratified analysis by tumour sites did not identify significant causal associations in either direction between vitamin D and colon or rectal cancer. Despite the improved statistical power of this study, we found no evidence of causal association of either direction between circulating vitamin D and CRC risk. Significant associations reported by observational studies may be primarily driven by unidentified confounders..
Lin, W.-.
Fordham, S.E.
Sunter, N.
Elstob, C.
Rahman, T.
Willmore, E.
Shepherd, C.
Strathdee, G.
Mainou-Fowler, T.
Piddock, R.
Mearns, H.
Barrow, T.
Houlston, R.S.
Marr, H.
Wallis, J.
Summerfield, G.
Marshall, S.
Pettitt, A.
Pepper, C.
Fegan, C.
Forconi, F.
Dyer, M.J.
Jayne, S.
Sellors, A.
Schuh, A.
Robbe, P.
Oscier, D.
Bailey, J.
Rais, S.
Bentley, A.
Cawkwell, L.
Evans, P.
Hillmen, P.
Pratt, G.
Allsup, D.J.
Allan, J.M.
(2021). Genome-wide association study identifies risk loci for progressive chronic lymphocytic leukemia. Nature communications,
Vol.12
(1),
pp. 665-?.
show abstract
Prognostication in patients with chronic lymphocytic leukemia (CLL) is challenging due to heterogeneity in clinical course. We hypothesize that constitutional genetic variation affects disease progression and could aid prognostication. Pooling data from seven studies incorporating 842 cases identifies two genomic locations associated with time from diagnosis to treatment, including 10q26.13 (rs736456, hazard ratio (HR) = 1.78, 95% confidence interval (CI) = 1.47-2.15; P = 2.71 × 10 -9 ) and 6p (rs3778076, HR = 1.99, 95% CI = 1.55-2.55; P = 5.08 × 10 -8 ), which are particularly powerful prognostic markers in patients with early stage CLL otherwise characterized by low-risk features. Expression quantitative trait loci analysis identifies putative functional genes implicated in modulating B-cell receptor or innate immune responses, key pathways in CLL pathogenesis. In this work we identify rs736456 and rs3778076 as prognostic in CLL, demonstrating that disease progression is determined by constitutional genetic variation as well as known somatic drivers..
Lin, W.-.
Fordham, S.E.
Hungate, E.
Sunter, N.J.
Elstob, C.
Xu, Y.
Park, C.
Quante, A.
Strauch, K.
Gieger, C.
Skol, A.
Rahman, T.
Sucheston-Campbell, L.
Wang, J.
Hahn, T.
Clay-Gilmour, A.I.
Jones, G.L.
Marr, H.J.
Jackson, G.H.
Menne, T.
Collin, M.
Ivey, A.
Hills, R.K.
Burnett, A.K.
Russell, N.H.
Fitzgibbon, J.
Larson, R.A.
Le Beau, M.M.
Stock, W.
Heidenreich, O.
Alharbi, A.
Allsup, D.J.
Houlston, R.S.
Norden, J.
Dickinson, A.M.
Douglas, E.
Lendrem, C.
Daly, A.K.
Palm, L.
Piechocki, K.
Jeffries, S.
Bornhäuser, M.
Röllig, C.
Altmann, H.
Ruhnke, L.
Kunadt, D.
Wagenführ, L.
Cordell, H.J.
Darlay, R.
Andersen, M.K.
Fontana, M.C.
Martinelli, G.
Marconi, G.
Sanz, M.A.
Cervera, J.
Gómez-Seguí, I.
Cluzeau, T.
Moreilhon, C.
Raynaud, S.
Sill, H.
Voso, M.T.
Lo-Coco, F.
Dombret, H.
Cheok, M.
Preudhomme, C.
Gale, R.E.
Linch, D.
Gaal-Wesinger, J.
Masszi, A.
Nowak, D.
Hofmann, W.-.
Gilkes, A.
Porkka, K.
Milosevic Feenstra, J.D.
Kralovics, R.
Grimwade, D.
Meggendorfer, M.
Haferlach, T.
Krizsán, S.
Bödör, C.
Stölzel, F.
Onel, K.
Allan, J.M.
(2021). Genome-wide association study identifies susceptibility loci for acute myeloid leukemia. Nature communications,
Vol.12
(1),
pp. 6233-?.
show abstract
Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10-8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10-10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA)..
Cornish, A.J.
Law, P.J.
Timofeeva, M.
Palin, K.
Farrington, S.M.
Palles, C.
Jenkins, M.A.
Casey, G.
Brenner, H.
Chang-Claude, J.
Hoffmeister, M.
Kirac, I.
Maughan, T.
Brezina, S.
Gsur, A.
Cheadle, J.P.
Aaltonen, L.A.
Tomlinson, I.
Dunlop, M.G.
Houlston, R.S.
(2020). Modifiable pathways for colorectal cancer: a mendelian randomisation analysis. The lancet. gastroenterology & hepatology,
Vol.5
(1),
pp. 55-62.
show abstract
Background Epidemiological studies have linked lifestyle, cardiometabolic, reproductive, developmental, and inflammatory factors to the risk of colorectal cancer. However, which specific factors affect risk and the strength of these effects are unknown. We aimed to examine the relationship between potentially modifiable risk factors and colorectal cancer.Methods We used a random-effects model to examine the relationship between 39 potentially modifiable risk factors and colorectal cancer in 26 397 patients with colorectal cancer and 41 481 controls (ie, people without colorectal cancer). These population data came from a genome-wide association study of people of European ancestry, which was amended to exclude UK BioBank data. In the model, we used genetic variants as instruments via two-sample mendelian randomisation to limit bias from confounding and reverse causation. We calculated odds ratios per genetically predicted SD unit increase in each putative risk factor (OR SD ) for colorectal cancer risk. We did mendelian randomisation Egger regressions to identify evidence of potential violations of mendelian randomisation assumptions. A Bonferroni-corrected threshold of p=1·3 × 10 -3 was considered significant, and p values less than 0·05 were considered to be suggestive of an association.Findings No putative risk factors were significantly associated with colorectal cancer risk after correction for multiple testing. However, suggestive associations with increased risk were noted for genetically predicted body fat percentage (OR SD 1·14 [95% CI 1·03-1·25]; p=0·0086), body-mass index (1·09 [1·01-1·17]; p=0·023), waist circumference (1·13 [1·02-1·26]; p=0·018), basal metabolic rate (1·10 [1·03-1·18]; p=0·0079), and concentrations of LDL cholesterol (1·14 [1·04-1·25]; p=0·0056), total cholesterol (1·09 [1·01-1·18]; p=0·025), circulating serum iron (1·17 [1·00-1·36]; p=0·049), and serum vitamin B12 (1·21 [1·04-1·42]; p=0·016), although potential pleiotropy among genetic variants used as instruments for vitamin B12 constrains the finding. A suggestive association was also noted between adult height and increased risk of colorectal cancer (OR SD 1·04 [95% CI 1·00-1·08]; p=0·032). Low blood selenium concentration had a suggestive association with decreased risk of colorectal cancer (OR SD 0·85 [95% CI 0·75-0·96]; p=0·0078) based on a single variant, as did plasma concentrations of interleukin-6 receptor subunit α (also based on a single variant; 0·98 [0·96-1·00]; p=0·035). Risk of colorectal cancer was not associated with any sex hormone or reproductive factor, serum calcium, or circulating 25-hydroxyvitamin D concentrations.Interpretation This analysis identified several modifiable targets for primary prevention of colorectal cancer, including lifestyle, obesity, and cardiometabolic factors, that should inform public health policy.Funding Cancer Research UK, UK Medical Research Council Human Genetics Unit Centre, DJ Fielding Medical Research Trust, EU COST Action, and the US National Cancer Institute..
Summers, M.G.
Maughan, T.S.
Kaplan, R.
Law, P.J.
Houlston, R.S.
Escott-Price, V.
Cheadle, J.P.
(2020). Comprehensive analysis of colorectal cancer-risk loci and survival outcome: A prognostic role for CDH1 variants. European journal of cancer,
Vol.124,
pp. 56-63.
Ostrom, Q.T.
Egan, K.M.
Nabors, L.B.
Gerke, T.
Thompson, R.C.
Olson, J.J.
LaRocca, R.
Chowdhary, S.
Eckel-Passow, J.E.
Armstrong, G.
Wiencke, J.K.
Bernstein, J.L.
Claus, E.B.
Il'yasova, D.
Johansen, C.
Lachance, D.H.
Lai, R.K.
Merrell, R.T.
Olson, S.H.
Sadetzki, S.
Schildkraut, J.M.
Shete, S.
Houlston, R.S.
Jenkins, R.B.
Wrensch, M.R.
Melin, B.
Amos, C.I.
Huse, J.T.
Barnholtz-Sloan, J.S.
Bondy, M.L.
(2020). Glioma risk associated with extent of estimated European genetic ancestry in African Americans and Hispanics. International journal of cancer,
Vol.146
(3),
pp. 739-748.
show abstract
Glioma incidence is highest in non-Hispanic Whites, and to date, glioma genome-wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case-Control Study and GliomaSE Case-Control Study previously estimated to have <80% EA, or self-identify as non-White. We estimated global and local ancestry using fastStructure and RFMix, respectively, using 1,000 genomes project reference populations. Within groups with ≥40% AA (AFR ≥0.4 ), and ≥15% NAA (AMR ≥0.15 ), genome-wide association between local EA and glioma was evaluated using logistic regression conditioned on global EA for all gliomas. We identified two regions (7q21.11, p = 6.36 × 10 -4 ; 11p11.12, p = 7.0 × 10 -4 ) associated with increased EA, and one associated with decreased EA (20p12.13, p = 0.0026) in AFR ≥0.4 . In addition, we identified a peak at rs1620291 (p = 4.36 × 10 -6 ) in 7q21.3. Among AMR ≥0.15 , we found an association between increased EA in one region (12q24.21, p = 8.38 × 10 -4 ), and decreased EA in two regions (8q24.21, p = 0. 0010; 20q13.33, p = 6.36 × 10 -4 ). No other significant associations were identified. This analysis identified an association between glioma and two regions previously identified in EA populations (8q24.21, 20q13.33) and four novel regions (7q21.11, 11p11.12, 12q24.21 and 20p12.13). The identifications of novel association with EA suggest regions to target for future genetic association studies..
Chattopadhyay, S.
Zheng, G.
Sud, A.
Sundquist, K.
Sundquist, J.
Försti, A.
Houlston, R.
Hemminki, A.
Hemminki, K.
(2020). Second primary cancers in non-Hodgkin lymphoma: Family history and survival. International journal of cancer,
Vol.146
(4),
pp. 970-976.
show abstract
Second primary cancers (SPCs) account for an increasing proportion of all cancer diagnoses and family history of cancer may be a risk factor for SPCs. Using the Swedish Family-Cancer Database on non-Hodgkin lymphoma (NHL), we assessed the influence of family history on risk of SPCs and of SPCs on survival. NHL patients were identified from the years 1958 to 2015 and generalized Poisson models were used to calculate relative risks (RRs) for SPCs and familial SPCs. Among 14,393 NHL patients, a total of 1,866 (13.0%) were diagnosed with SPC. Familial risk of nine particular cancers was associated with risks of these cancers as SPCs, with twofold to fivefold increase in RRs. At the end of a 25-year follow-up period, the survival probability for persons with SPC was only 20% of that for patients without SPC; the hazard ratio for SPC was 1.59 (95% CI: 1.46-1.72). Survival could be predicted by the prognostic groups based on first cancers and HRs increase systematically with worse prognosis yielding a trend of p = 4.6 × 10-5 . SPCs had deleterious consequences for survival in NHL patients. Family history was associated with increasing numbers of SPCs. Prevention of SPCs and their early detection is an important target in the overall strategy to improve survival in NHL patients. Counseling for avoidance of risk factors and targeted screening based on family history are feasible steps in risk reduction..
Zhang, Y.D.
Hurson, A.N.
Zhang, H.
Choudhury, P.P.
Easton, D.F.
Milne, R.L.
Simard, J.
Hall, P.
Michailidou, K.
Dennis, J.
Schmidt, M.K.
Chang-Claude, J.
Gharahkhani, P.
Whiteman, D.
Campbell, P.T.
Hoffmeister, M.
Jenkins, M.
Peters, U.
Hsu, L.
Gruber, S.B.
Casey, G.
Schmit, S.L.
O'Mara, T.A.
Spurdle, A.B.
Thompson, D.J.
Tomlinson, I.
De Vivo, I.
Landi, M.T.
Law, M.H.
Iles, M.M.
Demenais, F.
Kumar, R.
MacGregor, S.
Bishop, D.T.
Ward, S.V.
Bondy, M.L.
Houlston, R.
Wiencke, J.K.
Melin, B.
Barnholtz-Sloan, J.
Kinnersley, B.
Wrensch, M.R.
Amos, C.I.
Hung, R.J.
Brennan, P.
McKay, J.
Caporaso, N.E.
Berndt, S.I.
Birmann, B.M.
Camp, N.J.
Kraft, P.
Rothman, N.
Slager, S.L.
Berchuck, A.
Pharoah, P.D.
Sellers, T.A.
Gayther, S.A.
Pearce, C.L.
Goode, E.L.
Schildkraut, J.M.
Moysich, K.B.
Amundadottir, L.T.
Jacobs, E.J.
Klein, A.P.
Petersen, G.M.
Risch, H.A.
Stolzenberg-Solomon, R.Z.
Wolpin, B.M.
Li, D.
Eeles, R.A.
Haiman, C.A.
Kote-Jarai, Z.
Schumacher, F.R.
Al Olama, A.A.
Purdue, M.P.
Scelo, G.
Dalgaard, M.D.
Greene, M.H.
Grotmol, T.
Kanetsky, P.A.
McGlynn, K.A.
Nathanson, K.L.
Turnbull, C.
Wiklund, F.
Breast Cancer Association Consortium (BCAC),
Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON),
Colon Cancer Family Registry (CCFR),
Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT),
Endometrial Cancer Association Consortium (ECAC),
Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO),
Melanoma Genetics Consortium (GenoMEL),
Glioma International Case-Control Study (GICC),
International Lung Cancer Consortium (ILCCO),
Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium,
International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph),
Ovarian Cancer Association Consortium (OCAC),
Oral Cancer GWAS,
Pancreatic Cancer Case-Control Consortium (PanC4),
Pancreatic Cancer Cohort Consortium (PanScan),
Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL),
Renal Cancer GWAS,
Testicular Cancer Consortium (TECAC),
Chanock, S.J.
Chatterjee, N.
Garcia-Closas, M.
(2020). Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers. Nature communications,
Vol.11
(1),
pp. 3353-?.
show abstract
Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence..
Pertesi, M.
Went, M.
Hansson, M.
Hemminki, K.
Houlston, R.S.
Nilsson, B.
(2020). Genetic predisposition for multiple myeloma. Leukemia,
Vol.34
(3),
pp. 697-708.
show abstract
Multiple myeloma (MM) is the second most common blood malignancy. Epidemiological family studies going back to the 1920s have provided evidence for familial aggregation, suggesting a subset of cases have an inherited genetic background. Recently, studies aimed at explaining this phenomenon have begun to provide direct evidence for genetic predisposition to MM. Genome-wide association studies have identified common risk alleles at 24 independent loci. Sequencing studies of familial cases and kindreds have begun to identify promising candidate genes where variants with strong effects on MM risk might reside. Finally, functional studies are starting to give insight into how identified risk alleles promote the development of MM. Here, we review recent findings in MM predisposition field, and highlight open questions and future directions..
Loveday, C.
Litchfield, K.
Proszek, P.Z.
Cornish, A.J.
Santo, F.
Levy, M.
Macintyre, G.
Holryod, A.
Broderick, P.
Dudakia, D.
Benton, B.
Bakir, M.A.
Hiley, C.
Grist, E.
Swanton, C.
Huddart, R.
Powles, T.
Chowdhury, S.
Shipley, J.
O'Connor, S.
Brenton, J.D.
Reid, A.
de Castro, D.G.
Houlston, R.S.
Turnbull, C.
(2020). Genomic landscape of platinum resistant and sensitive testicular cancers. Nature communications,
Vol.11
(1),
pp. 2189-?.
show abstract
While most testicular germ cell tumours (TGCTs) exhibit exquisite sensitivity to platinum chemotherapy, ~10% are platinum resistant. To gain insight into the underlying mechanisms, we undertake whole exome sequencing and copy number analysis in 40 tumours from 26 cases with platinum-resistant TGCT, and combine this with published genomic data on an additional 624 TGCTs. We integrate analyses for driver mutations, mutational burden, global, arm-level and focal copy number (CN) events, and SNV and CN signatures. Albeit preliminary and observational in nature, these analyses provide support for a possible mechanistic link between early driver mutations in RAS and KIT and the widespread copy number events by which TGCT is characterised..
Hoang, P.H.
Cornish, A.J.
Chubb, D.
Jackson, G.
Kaiser, M.
Houlston, R.S.
(2020). Impact of mitochondrial DNA mutations in multiple myeloma. Blood cancer journal,
Vol.10
(5),
pp. 46-?.
Went, M.
Cornish, A.J.
Law, P.J.
Kinnersley, B.
van Duin, M.
Weinhold, N.
Försti, A.
Hansson, M.
Sonneveld, P.
Goldschmidt, H.
Morgan, G.J.
Hemminki, K.
Nilsson, B.
Kaiser, M.
Houlston, R.S.
(2020). Search for multiple myeloma risk factors using Mendelian randomization. Blood advances,
Vol.4
(10),
pp. 2172-2179.
show abstract
The etiology of multiple myeloma (MM) is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited in a Mendelian randomization (MR) phenome-wide association study (PheWAS) to search for factors influencing MM risk. We performed an MR-PheWAS analyzing 249 phenotypes, proxied by 10 225 genetic variants, and summary genetic data from a GWAS of 7717 MM cases and 29 304 controls. Odds ratios (ORs) per 1 standard deviation increase in each phenotype were estimated under an inverse variance weighted random effects model. A Bonferroni-corrected threshold of P = 2 × 10-4 was considered significant, whereas P < .05 was considered suggestive of an association. Although no significant associations with MM risk were observed among the 249 phenotypes, 28 phenotypes showed evidence suggestive of association, including increased levels of serum vitamin B6 and blood carnitine (P = 1.1 × 10-3) with greater MM risk and ω-3 fatty acids (P = 5.4 × 10-4) with reduced MM risk. A suggestive association between increased telomere length and reduced MM risk was also noted; however, this association was primarily driven by the previously identified risk variant rs10936599 at 3q26 (TERC). Although not statistically significant, increased body mass index was associated with increased risk (OR, 1.10; 95% confidence interval, 0.99-1.22), supporting findings from a previous meta-analysis of prospective observational studies. Our study did not provide evidence supporting any modifiable factors examined as having a major influence on MM risk; however, it provides insight into factors for which the evidence has previously been mixed..
Sud, A.
Jones, M.E.
Broggio, J.
Loveday, C.
Torr, B.
Garrett, A.
Nicol, D.L.
Jhanji, S.
Boyce, S.A.
Gronthoud, F.
Ward, P.
Handy, J.M.
Yousaf, N.
Larkin, J.
Suh, Y.-.
Scott, S.
Pharoah, P.D.
Swanton, C.
Abbosh, C.
Williams, M.
Lyratzopoulos, G.
Houlston, R.
Turnbull, C.
(2020). Collateral damage: the impact on outcomes from cancer surgery of the COVID-19 pandemic. Annals of oncology : official journal of the european society for medical oncology,
Vol.31
(8),
pp. 1065-1074.
show abstract
Background Cancer diagnostics and surgery have been disrupted by the response of health care services to the coronavirus disease 2019 (COVID-19) pandemic. Progression of cancers during delay will impact on patients' long-term survival.Patients and methods We generated per-day hazard ratios of cancer progression from observational studies and applied these to age-specific, stage-specific cancer survival for England 2013-2017. We modelled per-patient delay of 3 and 6 months and periods of disruption of 1 and 2 years. Using health care resource costing, we contextualise attributable lives saved and life-years gained (LYGs) from cancer surgery to equivalent volumes of COVID-19 hospitalisations.Results Per year, 94 912 resections for major cancers result in 80 406 long-term survivors and 1 717 051 LYGs. Per-patient delay of 3/6 months would cause attributable death of 4755/10 760 of these individuals with loss of 92 214/208 275 life-years, respectively. For cancer surgery, average LYGs per patient are 18.1 under standard conditions and 17.1/15.9 with a delay of 3/6 months (an average loss of 0.97/2.19 LYGs per patient), respectively. Taking into account health care resource units (HCRUs), surgery results on average per patient in 2.25 resource-adjusted life-years gained (RALYGs) under standard conditions and 2.12/1.97 RALYGs following delay of 3/6 months. For 94 912 hospital COVID-19 admissions, there are 482 022 LYGs requiring 1 052 949 HCRUs. Hospitalisation of community-acquired COVID-19 patients yields on average per patient 5.08 LYG and 0.46 RALYGs.Conclusions Modest delays in surgery for cancer incur significant impact on survival. Delay of 3/6 months in surgery for incident cancers would mitigate 19%/43% of LYGs, respectively, by hospitalisation of an equivalent volume of admissions for community-acquired COVID-19. This rises to 26%/59%, respectively, when considering RALYGs. To avoid a downstream public health crisis of avoidable cancer deaths, cancer diagnostic and surgical pathways must be maintained at normal throughput, with rapid attention to any backlog already accrued..
Semmes, E.C.
Vijayakrishnan, J.
Zhang, C.
Hurst, J.H.
Houlston, R.S.
Walsh, K.M.
(2020). Leveraging Genome and Phenome-Wide Association Studies to Investigate Genetic Risk of Acute Lymphoblastic Leukemia. Cancer epidemiology, biomarkers & prevention : a publication of the american association for cancer research, cosponsored by the american society of preventive oncology,
Vol.29
(8),
pp. 1606-1614.
show abstract
BACKGROUND:Genome-wide association studies (GWAS) of childhood cancers remain limited, highlighting the need for novel analytic strategies. We describe a hybrid GWAS and phenome-wide association study (PheWAS) approach to uncover genotype-phenotype relationships and candidate risk loci, applying it to acute lymphoblastic leukemia (ALL). METHODS:PheWAS was performed for 12 ALL SNPs identified by prior GWAS and two control SNP-sets using UK Biobank data. PheWAS-traits significantly associated with ALL SNPs compared with control SNPs were assessed for association with ALL risk (959 cases, 2,624 controls) using polygenic score and Mendelian randomization analyses. Trait-associated SNPs were tested for association with ALL risk in single-SNP analyses, with replication in an independent case-control dataset (1,618 cases, 9,409 controls). RESULTS:Platelet count was the trait most enriched for association with known ALL risk loci. A polygenic score for platelet count (223 SNPs) was not associated with ALL risk (P = 0.82) and Mendelian randomization did not suggest a causal relationship. However, twelve platelet count-associated SNPs were nominally associated with ALL risk in COG data and three were replicated in UK data (rs10058074, rs210142, rs2836441). CONCLUSIONS:In our hybrid GWAS-PheWAS approach, we identify pleiotropic genetic variation contributing to ALL risk and platelet count. Three SNPs known to influence platelet count were reproducibly associated with ALL risk, implicating genomic regions containing IRF1, proapoptotic protein BAK1, and ERG in platelet production and leukemogenesis. IMPACT:Incorporating PheWAS data into association studies can leverage genetic pleiotropy to identify cancer risk loci, highlighting the utility of our novel approach..
Sud, A.
Torr, B.
Jones, M.E.
Broggio, J.
Scott, S.
Loveday, C.
Garrett, A.
Gronthoud, F.
Nicol, D.L.
Jhanji, S.
Boyce, S.A.
Williams, M.
Riboli, E.
Muller, D.C.
Kipps, E.
Larkin, J.
Navani, N.
Swanton, C.
Lyratzopoulos, G.
McFerran, E.
Lawler, M.
Houlston, R.
Turnbull, C.
(2020). Effect of delays in the 2-week-wait cancer referral pathway during the COVID-19 pandemic on cancer survival in the UK: a modelling study. The lancet. oncology,
Vol.21
(8),
pp. 1035-1044.
show abstract
Background During the COVID-19 lockdown, referrals via the 2-week-wait urgent pathway for suspected cancer in England, UK, are reported to have decreased by up to 84%. We aimed to examine the impact of different scenarios of lockdown-accumulated backlog in cancer referrals on cancer survival, and the impact on survival per referred patient due to delayed referral versus risk of death from nosocomial infection with severe acute respiratory syndrome coronavirus 2.Methods In this modelling study, we used age-stratified and stage-stratified 10-year cancer survival estimates for patients in England, UK, for 20 common tumour types diagnosed in 2008-17 at age 30 years and older from Public Health England. We also used data for cancer diagnoses made via the 2-week-wait referral pathway in 2013-16 from the Cancer Waiting Times system from NHS Digital. We applied per-day hazard ratios (HRs) for cancer progression that we generated from observational studies of delay to treatment. We quantified the annual numbers of cancers at stage I-III diagnosed via the 2-week-wait pathway using 2-week-wait age-specific and stage-specific breakdowns. From these numbers, we estimated the aggregate number of lives and life-years lost in England for per-patient delays of 1-6 months in presentation, diagnosis, or cancer treatment, or a combination of these. We assessed three scenarios of a 3-month period of lockdown during which 25%, 50%, and 75% of the normal monthly volumes of symptomatic patients delayed their presentation until after lockdown. Using referral-to-diagnosis conversion rates and COVID-19 case-fatality rates, we also estimated the survival increment per patient referred.Findings Across England in 2013-16, an average of 6281 patients with stage I-III cancer were diagnosed via the 2-week-wait pathway per month, of whom 1691 (27%) would be predicted to die within 10 years from their disease. Delays in presentation via the 2-week-wait pathway over a 3-month lockdown period (with an average presentational delay of 2 months per patient) would result in 181 additional lives and 3316 life-years lost as a result of a backlog of referrals of 25%, 361 additional lives and 6632 life-years lost for a 50% backlog of referrals, and 542 additional lives and 9948 life-years lost for a 75% backlog in referrals. Compared with all diagnostics for the backlog being done in month 1 after lockdown, additional capacity across months 1-3 would result in 90 additional lives and 1662 live-years lost due to diagnostic delays for the 25% backlog scenario, 183 additional lives and 3362 life-years lost under the 50% backlog scenario, and 276 additional lives and 5075 life-years lost under the 75% backlog scenario. However, a delay in additional diagnostic capacity with provision spread across months 3-8 after lockdown would result in 401 additional lives and 7332 life-years lost due to diagnostic delays under the 25% backlog scenario, 811 additional lives and 14 873 life-years lost under the 50% backlog scenario, and 1231 additional lives and 22 635 life-years lost under the 75% backlog scenario. A 2-month delay in 2-week-wait investigatory referrals results in an estimated loss of between 0·0 and 0·7 life-years per referred patient, depending on age and tumour type.Interpretation Prompt provision of additional capacity to address the backlog of diagnostics will minimise deaths as a result of diagnostic delays that could add to those predicted due to expected presentational delays. Prioritisation of patient groups for whom delay would result in most life-years lost warrants consideration as an option for mitigating the aggregate burden of mortality in patients with cancer.Funding None..
Purdue, M.P.
Song, L.
Scélo, G.
Houlston, R.S.
Wu, X.
Sakoda, L.C.
Thai, K.
Graff, R.E.
Rothman, N.
Brennan, P.
Chanock, S.J.
Yu, K.
(2020). Pathway Analysis of Renal Cell Carcinoma Genome-Wide Association Studies Identifies Novel Associations. Cancer epidemiology, biomarkers & prevention : a publication of the american association for cancer research, cosponsored by the american society of preventive oncology,
Vol.29
(10),
pp. 2065-2069.
show abstract
Background Much of the heritable risk of renal cell carcinoma (RCC) associated with common genetic variation is unexplained. New analytic approaches have been developed to increase the discovery of risk variants in genome-wide association studies (GWAS), including multi-locus testing through pathway analysis.Methods We conducted a pathway analysis using GWAS summary data from six previous scans (10,784 cases and 20,406 controls) and evaluated 3,678 pathways and gene sets drawn from the Molecular Signatures Database. To replicate findings, we analyzed GWAS summary data from the UK Biobank (903 cases and 451,361 controls) and the Genetic Epidemiology Research on Adult Health and Aging cohort (317 cases and 50,511 controls).Results We identified 14 pathways/gene sets associated with RCC in both the discovery ( P < 1.36 × 10 -5 , the Bonferroni correction threshold) and replication ( P < 0.05) sets, 10 of which include components of the PI3K/AKT pathway. In tests across 2,035 genes in these pathways, associations (Bonferroni corrected P < 2.46 × 10 -5 in discovery and replication sets combined) were observed for CASP9, TIPIN , and CDKN2C . The strongest SNP signal was for rs12124078 ( P Discovery = 2.6 × 10 -5 ; P Replication = 1.5 × 10 -4 ; P Combined = 6.9 × 10 -8 ), a CASP9 expression quantitative trait locus.Conclusions Our pathway analysis implicates genetic variation within the PI3K/AKT pathway as a source of RCC heritability and identifies several promising novel susceptibility genes, including CASP9 , which warrant further investigation.Impact Our findings illustrate the value of pathway analysis as a complementary approach to analyzing GWAS data..
Hoang, P.H.
Cornish, A.J.
Sherborne, A.L.
Chubb, D.
Kimber, S.
Jackson, G.
Morgan, G.J.
Cook, G.
Kinnersley, B.
Kaiser, M.
Houlston, R.S.
(2020). An enhanced genetic model of relapsed IGH-translocated multiple myeloma evolutionary dynamics. Blood cancer journal,
Vol.10
(10).
show abstract
Abstract
Most patients with multiple myeloma (MM) die from progressive disease after relapse. To advance our understanding of MM evolution mechanisms, we performed whole-genome sequencing of 80 IGH-translocated tumour-normal newly diagnosed pairs and 24 matched relapsed tumours from the Myeloma XI trial. We identify multiple events as potentially important for survival and therapy-resistance at relapse including driver point mutations (e.g., TET2), translocations (MAP3K14), lengthened telomeres, and increased genomic instability (e.g., 17p deletions). Despite heterogeneous mutational processes contributing to relapsed mutations across MM subtypes, increased AID/APOBEC activity is particularly associated with shorter progression time to relapse, and contributes to higher mutational burden at relapse. In addition, we identify three enhanced major clonal evolution patterns of MM relapse, independent of treatment strategies and molecular karyotypes, questioning the viability of “evolutionary herding” approach in treating drug-resistant MM. Our data show that MM relapse is associated with acquisition of new mutations and clonal selection, and suggest APOBEC enzymes among potential targets for therapy-resistant MM..
Ji, X.
Mukherjee, S.
Landi, M.T.
Bosse, Y.
Joubert, P.
Zhu, D.
Gorlov, I.
Xiao, X.
Han, Y.
Gorlova, O.
Hung, R.J.
Brhane, Y.
Carreras-Torres, R.
Christiani, D.C.
Caporaso, N.
Johansson, M.
Liu, G.
Bojesen, S.E.
Le Marchand, L.
Albanes, D.
Bickeböller, H.
Aldrich, M.C.
Bush, W.S.
Tardon, A.
Rennert, G.
Chen, C.
Byun, J.
Dragnev, K.H.
Field, J.K.
Kiemeney, L.F.
Lazarus, P.
Zienolddiny, S.
Lam, S.
Schabath, M.B.
Andrew, A.S.
Bertazzi, P.A.
Pesatori, A.C.
Diao, N.
Su, L.
Song, L.
Zhang, R.
Leighl, N.
Johansen, J.S.
Mellemgaard, A.
Saliba, W.
Haiman, C.
Wilkens, L.
Fernandez-Somoano, A.
Fernandez-Tardon, G.
Heijden, E.H.
Kim, J.H.
Davies, M.P.
Marcus, M.W.
Brunnström, H.
Manjer, J.
Melander, O.
Muller, D.C.
Overvad, K.
Trichopoulou, A.
Tumino, R.
Goodman, G.E.
Cox, A.
Taylor, F.
Woll, P.
Wichmann, E.
Muley, T.
Risch, A.
Rosenberger, A.
Grankvist, K.
Johansson, M.
Shepherd, F.
Tsao, M.-.
Arnold, S.M.
Haura, E.B.
Bolca, C.
Holcatova, I.
Janout, V.
Kontic, M.
Lissowska, J.
Mukeria, A.
Ognjanovic, S.
Orlowski, T.M.
Scelo, G.
Swiatkowska, B.
Zaridze, D.
Bakke, P.
Skaug, V.
Butler, L.M.
Offit, K.
Srinivasan, P.
Bandlamudi, C.
Hellmann, M.D.
Solit, D.B.
Robson, M.E.
Rudin, C.M.
Stadler, Z.K.
Taylor, B.S.
Berger, M.F.
Houlston, R.
McLaughlin, J.
Stevens, V.
Nickle, D.C.
Obeidat, M.
Timens, W.
Artigas, M.S.
Shete, S.
Brenner, H.
Chanock, S.
Brennan, P.
McKay, J.D.
Amos, C.I.
(2020). Protein-altering germline mutations implicate novel genes related to lung cancer development. Nature communications,
Vol.11
(1),
pp. 2220-?.
show abstract
Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10 -15 ) and replication (adjusted OR = 2.93, P = 2.22 × 10 -3 ) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10 -22 ) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk..
Shah, V.
Sherborne, A.L.
Johnson, D.C.
Ellis, S.
Price, A.
Chowdhury, F.
Kendall, J.
Jenner, M.W.
Drayson, M.T.
Owen, R.G.
Gregory, W.M.
Morgan, G.J.
Davies, F.E.
Cook, G.
Cairns, D.A.
Houlston, R.S.
Jackson, G.
Kaiser, M.F.
on behalf of NCRI Haematology Clinical Studies Group,
(2020). Predicting ultrahigh risk multiple myeloma by molecular profiling: an analysis of newly diagnosed transplant eligible myeloma XI trial patients. Leukemia,
Vol.34
(11),
pp. 3091-3096.
Yang, X.
Song, H.
Leslie, G.
Engel, C.
Hahnen, E.
Auber, B.
Horváth, J.
Kast, K.
Niederacher, D.
Turnbull, C.
Houlston, R.
Hanson, H.
Loveday, C.
Dolinsky, J.S.
LaDuca, H.
Ramus, S.J.
Menon, U.
Rosenthal, A.N.
Jacobs, I.
Gayther, S.A.
Dicks, E.
Nevanlinna, H.
Aittomäki, K.
Pelttari, L.M.
Ehrencrona, H.
Borg, Å.
Kvist, A.
Rivera, B.
Hansen, T.V.
Djursby, M.
Lee, A.
Dennis, J.
Bowtell, D.D.
Traficante, N.
Diez, O.
Balmaña, J.
Gruber, S.B.
Chenevix-Trench, G.
Investigators, K.
Jensen, A.
Kjær, S.K.
Høgdall, E.
Castéra, L.
Garber, J.
Janavicius, R.
Osorio, A.
Golmard, L.
Vega, A.
Couch, F.J.
Robson, M.
Gronwald, J.
Domchek, S.M.
Culver, J.O.
de la Hoya, M.
Easton, D.F.
Foulkes, W.D.
Tischkowitz, M.
Meindl, A.
Schmutzler, R.K.
Pharoah, P.D.
Antoniou, A.C.
(2020). Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D. Journal of the national cancer institute,
Vol.112
(12),
pp. 1242-1250.
show abstract
Background The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D.Methods We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided.Results Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32-36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44-46% for BC, for carriers with two first-degree relatives diagnosed with BC.Conclusions These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models..
Maguire, S.
Perraki, E.
Tomczyk, K.
Jones, M.E.
Fletcher, O.
Pugh, M.
Winter, T.
Thompson, K.
Cooke, R.
kConFab Consortium,
Trainer, A.
James, P.
Bojesen, S.
Flyger, H.
Nevanlinna, H.
Mattson, J.
Friedman, E.
Laitman, Y.
Palli, D.
Masala, G.
Zanna, I.
Ottini, L.
Silvestri, V.
Hollestelle, A.
Hooning, M.J.
Novaković, S.
Krajc, M.
Gago-Dominguez, M.
Castelao, J.E.
Olsson, H.
Hedenfalk, I.
Saloustros, E.
Georgoulias, V.
Easton, D.F.
Pharoah, P.
Dunning, A.M.
Bishop, D.T.
Neuhausen, S.L.
Steele, L.
Ashworth, A.
Closas, M.G.
Houlston, R.
Swerdlow, A.
Orr, N.
(2020). Common susceptibility loci for male breast cancer. Journal of the national cancer institute,
.
show abstract
BACKGROUND:The aetiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study (GWAS) of MBC identified two predisposition loci for the disease, both of which were also associated with risk of FBC. METHODS:We performed genome-wide single nucleotide polymorphism (SNP) genotyping of European ancestry MBC case subjects and controls, in three stages. Associations between directly genotyped and imputed SNPs with MBC were assessed using fixed-effects meta-analysis of 1,380 cases and 3,620 controls. Replication genotyping of 810 cases and 1,026 controls was used to validate variants with P-values < 1 x 10-06. Genetic correlation with FBC was evaluated using LD score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score (PRS) and MBC. All statistical tests were two-sided. RESULTS:The GWAS identified three novel MBC susceptibility loci that attained genome-wide significance (P < 5 x 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen-receptor (ER) positive FBC. Males in the top quintile of genetic risk had a four-fold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 x 10-30). CONCLUSIONS:These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic aetiology with FBC and identifying a four-fold high risk group of susceptible men..
Croft, J.
Ellis, S.
Sherborne, A.L.
Sharp, K.
Price, A.
Jenner, M.W.
Drayson, M.T.
Owen, R.G.
Chown, S.
Lindsay, J.
Karunanithi, K.
Hunter, H.
Gregory, W.M.
Davies, F.E.
Morgan, G.J.
Cook, G.
Atanesyan, L.
Savola, S.
Cairns, D.A.
Jackson, G.
Houlston, R.S.
Kaiser, M.F.
(2020). Copy number evolution and its relationship with patient outcome-an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial. Leukemia,
.
show abstract
Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis-relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse..
Loveday, C.
Sud, A.
Jones, M.E.
Broggio, J.
Scott, S.
Gronthound, F.
Torr, B.
Garrett, A.
Nicol, D.L.
Jhanji, S.
Boyce, S.A.
Williams, M.
Barry, C.
Riboli, E.
Kipps, E.
McFerran, E.
Muller, D.C.
Lyratzopoulos, G.
Lawler, M.
Abulafi, M.
Houlston, R.S.
Turnbull, C.
(2020). Prioritisation by FIT to mitigate the impact of delays in the 2-week wait colorectal cancer referral pathway during the COVID-19 pandemic: a UK modelling study. Gut,
.
show abstract
Objective To evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent from the COVID-19 pandemic.Design We modelled the reduction in CRC survival and life years lost resultant from per-patient delays of 2-6 months in the 2WW pathway. We stratified by age group, individual-level benefit in CRC survival versus age-specific nosocomial COVID-19-related fatality per referred patient undergoing colonoscopy. We modelled mitigation strategies using thresholds of FIT triage of 2, 10 and 150 µg Hb/g to prioritise 2WW referrals for colonoscopy. To construct the underlying models, we employed 10-year net CRC survival for England 2008-2017, 2WW pathway CRC case and referral volumes and per-day-delay HRs generated from observational studies of diagnosis-to-treatment interval.Results Delay of 2/4/6 months across all 11 266 patients with CRC diagnosed per typical year via the 2WW pathway were estimated to result in 653/1419/2250 attributable deaths and loss of 9214/20 315/32 799 life years. Risk-benefit from urgent investigatory referral is particularly sensitive to nosocomial COVID-19 rates for patients aged >60. Prioritisation out of delay for the 18% of symptomatic referrals with FIT >10 µg Hb/g would avoid 89% of these deaths attributable to presentational/diagnostic delay while reducing immediate requirement for colonoscopy by >80%.Conclusions Delays in the pathway to CRC diagnosis and treatment have potential to cause significant mortality and loss of life years. FIT triage of symptomatic patients in primary care could streamline access to colonoscopy, reduce delays for true-positive CRC cases and reduce nosocomial COVID-19 mortality in older true-negative 2WW referrals. However, this strategy offers benefit only in short-term rationalisation of limited endoscopy services: the appreciable false-negative rate of FIT in symptomatic patients means most colonoscopies will still be required..
Chattopadhyay, S.
Thomsen, H.
Yadav, P.
da Silva Filho, M.I.
Weinhold, N.
Nöthen, M.M.
Hoffman, P.
Bertsch, U.
Huhn, S.
Morgan, G.J.
Goldschmidt, H.
Houlston, R.
Hemminki, K.
Försti, A.
(2019). Genome-wide interaction and pathway-based identification of key regulators in multiple myeloma. Communications biology,
Vol.2,
pp. 89-?.
show abstract
Inherited genetic susceptibility to multiple myeloma has been investigated in a number of studies. Although 23 individual risk loci have been identified, much of the genetic heritability remains unknown. Here we carried out genome-wide interaction analyses on two European cohorts accounting for 3,999 cases and 7,266 controls and characterized genetic susceptibility to multiple myeloma with subsequent meta-analysis that discovered 16 unique interacting loci. These risk loci along with previously known variants explain 17% of the heritability in liability scale. The genes associated with the interacting loci were found to be enriched in transforming growth factor beta signaling and circadian rhythm regulation pathways suggesting immunoglobulin trait modulation, T H 17 cell differentiation and bone morphogenesis as mechanistic links between the predisposition markers and intrinsic multiple myeloma biology. Further tissue/cell-type enrichment analysis associated the discovered genes with hemic-immune system tissue types and immune-related cell types indicating overall involvement in immune response..
Cornish, A.J.
Hoang, P.H.
Dobbins, S.E.
Law, P.J.
Chubb, D.
Orlando, G.
Houlston, R.S.
(2019). Identification of recurrent noncoding mutations in B-cell lymphoma using capture Hi-C. Blood advances,
Vol.3
(1),
pp. 21-32.
show abstract
The identification of driver mutations is fundamental to understanding oncogenesis. Although genes frequently mutated in B-cell lymphoma have been identified, the search for driver mutations has largely focused on the coding genome. Here we report an analysis of the noncoding genome using whole-genome sequencing data from 117 patients with B-cell lymphoma. Using promoter capture Hi-C data in naive B cells, we define cis -regulatory elements, which represent an enriched subset of the noncoding genome in which to search for driver mutations. Regulatory regions were identified whose mutation significantly alters gene expression, including copy number variation at cis -regulatory elements targeting CD69 , IGLL5 , and MMP14 , and single nucleotide variants in a cis -regulatory element for TPRG1 We also show the commonality of pathways targeted by coding and noncoding mutations, exemplified by MMP14 , which regulates Notch signaling, a pathway important in lymphomagenesis and whose expression is associated with patient survival. This study provides an enhanced understanding of lymphomagenesis and describes the advantages of using chromosome conformation capture to decipher noncoding mutations relevant to cancer biology..
Studd, J.B.
Yang, M.
Li, Z.
Vijayakrishnan, J.
Lu, Y.
Yeoh, A.E.
Paulsson, K.
Houlston, R.S.
(2019). Genetic predisposition to B-cell acute lymphoblastic leukemia at 14q11 2 is mediated by a CEBPE promoter polymorphism. Leukemia,
Vol.33
(1),
pp. 1-14.
show abstract
Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. Genome-wide association studies have shown variation at 14q11.2 influences ALL risk. We sought to decipher causal variant(s) at 14q11.2 and the mechanism of tumorigenesis. We show rs2239630 G>A resides in the promoter of the CCAT enhancer-binding protein epsilon (CEBPE) gene. The rs2239630-A risk allele is associated with increased promotor activity and CEBPE expression. Depletion of CEBPE in ALL cells reduces cell growth, correspondingly CEBPE binds to the promoters of electron transport and energy generation genes. RNA-seq in CEBPE depleted cells demonstrates CEBPE regulates the expression of genes involved in B-cell development (IL7R), apoptosis (BCL2), and methotrexate resistance (RASS4L). CEBPE regulated genes significantly overlapped in CEBPE depleted cells, ALL blasts and IGH-CEBPE translocated ALL. This suggests CEBPE regulates a similar set of genes in each, consistent with a common biological mechanism of leukemogenesis for rs2239630 associated and CEBPE translocated ALL. Finally, we map IGH-CEBPE translocation breakpoints in two cases, implicating RAG recombinase activity in their formation..
Law, P.J.
Houlston, R.S.
(2019). Genetic predisposition to chronic lymphocytic leukemia. Hemasphere,
Vol.3,
pp. 37-3.
Ostrom, Q.T.
Coleman, W.
Huang, W.
Rubin, J.B.
Lathia, J.D.
Berens, M.E.
Speyer, G.
Liao, P.
Wrensch, M.R.
Eckel-Passow, J.E.
Armstrong, G.
Rice, T.
Wiencke, J.K.
McCoy, L.S.
Hansen, H.M.
Amos, C.I.
Bernstein, J.L.
Claus, E.B.
Houlston, R.S.
Il'yasova, D.
Jenkins, R.B.
Johansen, C.
Lachance, D.H.
Lai, R.K.
Merrell, R.T.
Olson, S.H.
Sadetzki, S.
Schildkraut, J.M.
Shete, S.
Andersson, U.
Rajaraman, P.
Chanock, S.J.
Linet, M.S.
Wang, Z.
Yeager, M.
GliomaScan consortium,
Melin, B.
Bondy, M.L.
Barnholtz-Sloan, J.S.
(2019). Sex-specific gene and pathway modeling of inherited glioma risk. Neuro oncol,
Vol.21
(1),
pp. 71-82.
show abstract
Background: To date, genome-wide association studies (GWAS) have identified 25 risk variants for glioma, explaining 30% of heritable risk. Most histologies occur with significantly higher incidence in males, and this difference is not explained by currently known risk factors. A previous GWAS identified sex-specific glioma risk variants, and this analysis aims to further elucidate risk variation by sex using gene- and pathway-based approaches. Methods: Results from the Glioma International Case-Control Study were used as a testing set, and results from 3 GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for nominally significant autosomal SNPs (P < 0.01 in a previous meta-analysis) and nominally significant X-chromosome SNPs (P < 0.01), 3 algorithms (Pascal, BimBam, and GATES) were used to generate gene scores, and Pascal was used to generate pathway scores. Results were considered statistically significant in the discovery set when P < 3.3 × 10-6 and in the validation set when P < 0.001 in 2 of 3 algorithms. Results: Twenty-five genes within 5 regions and 19 genes within 6 regions reached statistical significance in at least 2 of 3 algorithms in males and females, respectively. EGFR was significantly associated with all glioma and glioblastoma in males only and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the BioCarta telomeres pathway in both males and females. Conclusions: These results provide additional evidence that there may be differences by sex in genetic risk for glioma. Additional analyses may further elucidate the biological processes through which this risk is conferred..
Johansson, M.
Carreras-Torres, R.
Scelo, G.
Purdue, M.P.
Mariosa, D.
Muller, D.C.
Timpson, N.J.
Haycock, P.C.
Brown, K.M.
Wang, Z.
Ye, Y.
Hofmann, J.N.
Foll, M.
Gaborieau, V.
Machiela, M.J.
Colli, L.M.
Li, P.
Garnier, J.-.
Blanche, H.
Boland, A.
Burdette, L.
Prokhortchouk, E.
Skryabin, K.G.
Yeager, M.
Radojevic-Skodric, S.
Ognjanovic, S.
Foretova, L.
Holcatova, I.
Janout, V.
Mates, D.
Mukeriya, A.
Rascu, S.
Zaridze, D.
Bencko, V.
Cybulski, C.
Fabianova, E.
Jinga, V.
Lissowska, J.
Lubinski, J.
Navratilova, M.
Rudnai, P.
Benhamou, S.
Cancel-Tassin, G.
Cussenot, O.
Weiderpass, E.
Ljungberg, B.
Tumkur Sitaram, R.
Häggström, C.
Bruinsma, F.
Jordan, S.J.
Severi, G.
Winship, I.
Hveem, K.
Vatten, L.J.
Fletcher, T.
Larsson, S.C.
Wolk, A.
Banks, R.E.
Selby, P.J.
Easton, D.F.
Andreotti, G.
Beane Freeman, L.E.
Koutros, S.
Männistö, S.
Weinstein, S.
Clark, P.E.
Edwards, T.L.
Lipworth, L.
Gapstur, S.M.
Stevens, V.L.
Carol, H.
Freedman, M.L.
Pomerantz, M.M.
Cho, E.
Wilson, K.M.
Gaziano, J.M.
Sesso, H.D.
Freedman, N.D.
Parker, A.S.
Eckel-Passow, J.E.
Huang, W.-.
Kahnoski, R.J.
Lane, B.R.
Noyes, S.L.
Petillo, D.
Teh, B.T.
Peters, U.
White, E.
Anderson, G.L.
Johnson, L.
Luo, J.
Buring, J.
Lee, I.-.
Chow, W.-.
Moore, L.E.
Eisen, T.
Henrion, M.
Larkin, J.
Barman, P.
Leibovich, B.C.
Choueiri, T.K.
Lathrop, G.M.
Deleuze, J.-.
Gunter, M.
McKay, J.D.
Wu, X.
Houlston, R.S.
Chanock, S.J.
Relton, C.
Richards, J.B.
Martin, R.M.
Davey Smith, G.
Brennan, P.
(2019). The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study. Plos medicine,
Vol.16
(1),
pp. e1002724-?.
show abstract
Background Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.Methods and findings Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.Conclusions This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk..
Amirian, E.S.
Ostrom, Q.T.
Armstrong, G.N.
Lai, R.K.
Gu, X.
Jacobs, D.I.
Jalali, A.
Claus, E.B.
Barnholtz-Sloan, J.S.
Il'yasova, D.
Schildkraut, J.M.
Ali-Osman, F.
Sadetzki, S.
Jenkins, R.B.
Lachance, D.H.
Olson, S.H.
Bernstein, J.L.
Merrell, R.T.
Wrensch, M.R.
Johansen, C.
Houlston, R.S.
Scheurer, M.E.
Shete, S.
Amos, C.I.
Melin, B.
Bondy, M.L.
(2019). Aspirin, NSAIDs, and Glioma Risk: Original Data from the Glioma International Case-Control Study and a Meta-analysis. Cancer epidemiology, biomarkers & prevention : a publication of the american association for cancer research, cosponsored by the american society of preventive oncology,
Vol.28
(3),
pp. 555-562.
show abstract
Background There have been few studies of sufficient size to address the relationship between glioma risk and the use of aspirin or NSAIDs, and results have been conflicting. The purpose of this study was to examine the associations between glioma and aspirin/NSAID use, and to aggregate these findings with prior published studies using meta-analysis.Methods The Glioma International Case-Control Study (GICC) consists of 4,533 glioma cases and 4,171 controls recruited from 2010 to 2013. Interviews were conducted using a standardized questionnaire to obtain information on aspirin/NSAID use. We examined history of regular use for ≥6 months and duration-response. Restricted maximum likelihood meta-regression models were used to aggregate site-specific estimates, and to combine GICC estimates with previously published studies.Results A history of daily aspirin use for ≥6 months was associated with a 38% lower glioma risk, compared with not having a history of daily use [adjusted meta-OR = 0.62; 95% confidence interval (CI), 0.54-0.70]. There was a significant duration-response trend ( P = 1.67 × 10 -17 ), with lower ORs for increasing duration of aspirin use. Duration-response trends were not observed for NSAID use. In the meta-analysis aggregating GICC data with five previous studies, there was a marginally significant association between use of aspirin and glioma (mOR = 0.84; 95% CI, 0.70-1.02), but no association for NSAID use.Conclusions Our study suggests that aspirin may be associated with a reduced risk of glioma.Impact These results imply that aspirin use may be associated with decreased glioma risk. Further research examining the association between aspirin use and glioma risk is warranted..
Zheng, G.
Chattopadhyay, S.
Sud, A.
Sundquist, K.
Sundquist, J.
Försti, A.
Houlston, R.
Hemminki, A.
Hemminki, K.
(2019). Second primary cancers in patients with acute lymphoblastic, chronic lymphocytic and hairy cell leukaemia. British journal of haematology,
Vol.185
(2),
pp. 232-239.
show abstract
Improvement of survival in lymphocytic leukaemia has been accompanied by the occurrence of second primary cancer (SPCs). Based on Swedish Family Cancer Database, we applied bi-directional analyses in which relative risks (RRs) were calculated for any SPCs in patients with chronic lymphocytic leukaemia (CLL), acute lymphoblastic leukaemia (ALL) and hairy cell leukaemia (HCL) and the risks of these leukaemias as SPCs. After CLL, RRs were significant for 20 SPCs, and high for skin squamous cell cancer (24·58 for in situ and 7·63 for invasive), Merkel cell carcinoma (14·36), Hodgkin lymphoma (7·16) and Kaposi sarcoma (6·76). Conversely, 15 CLL cancer pairs were reciprocally increased. The increased risks were reciprocal for ALL and four cancers. RR for ALL was 15·35 after myeloid neoplasia. HCL showed reciprocally increased RRs with non-Hodgkin lymphoma and melanoma. The concordance between RRs for bi-directional associations between CLL and different cancers, and HCL and different cancers was highly significant. For CLL (also for HCL), the bi-directional risks with skin cancers and other immune-related cancers suggest the probable involvement of immune dysfunction. For ALL, treatment may contribute to risks of multiple SPCs. Increased risk of ALL after haematological neoplasms may indicate bone marrow dysfunction. These findings may help guide treatment decisions and prognostic assessment..
Atkins, I.
Kinnersley, B.
Ostrom, Q.T.
Labreche, K.
Il'yasova, D.
Armstrong, G.N.
Eckel-Passow, J.E.
Schoemaker, M.J.
Nöthen, M.M.
Barnholtz-Sloan, J.S.
Swerdlow, A.J.
Simon, M.
Rajaraman, P.
Chanock, S.J.
Shildkraut, J.
Bernstein, J.L.
Hoffmann, P.
Jöckel, K.-.
Lai, R.K.
Claus, E.B.
Olson, S.H.
Johansen, C.
Wrensch, M.R.
Melin, B.
Jenkins, R.B.
Sanson, M.
Bondy, M.L.
Houlston, R.S.
(2019). Transcriptome-Wide Association Study Identifies New Candidate Susceptibility Genes for Glioma. Cancer research,
Vol.79
(8),
pp. 2065-2071.
show abstract
Genome-wide association studies (GWAS) have so far identified 25 loci associated with glioma risk, with most showing specificity for either glioblastoma (GBM) or non-GBM tumors. The majority of these GWAS susceptibility variants reside in noncoding regions and the causal genes underlying the associations are largely unknown. Here we performed a transcriptome-wide association study to search for novel risk loci and candidate causal genes at known GWAS loci using Genotype-Tissue Expression Project (GTEx) data to predict cis -predicted gene expression in relation to GBM and non-GBM risk in conjunction with GWAS summary statistics on 12,488 glioma cases (6,183 GBM and 5,820 non-GBM) and 18,169 controls. Imposing a Bonferroni-corrected significance level of P < 5.69 × 10 -6 , we identified 31 genes, including GALNT6 at 12q13.33, as a candidate novel risk locus for GBM (mean Z = 4.43; P = 5.68 × 10 -6 ). GALNT6 resides at least 55 Mb away from any previously identified glioma risk variant, while all other 30 significantly associated genes were located within 1 Mb of known GWAS-identified loci and were not significant after conditioning on the known GWAS-identified variants. These data identify a novel locus ( GALNT6 at 12q13.33) and 30 genes at 12 known glioma risk loci associated with glioma risk, providing further insights into glioma tumorigenesis. SIGNIFICANCE: This study identifies new genes associated with glioma risk, increasing understanding of how these tumors develop..
Zhu, Y.
Wei, Y.
Zhang, R.
Dong, X.
Shen, S.
Zhao, Y.
Bai, J.
Albanes, D.
Caporaso, N.E.
Landi, M.T.
Zhu, B.
Chanock, S.J.
Gu, F.
Lam, S.
Tsao, M.-.
Shepherd, F.A.
Tardon, A.
Fernández-Somoano, A.
Fernandez-Tardon, G.
Chen, C.
Barnett, M.J.
Doherty, J.
Bojesen, S.E.
Johansson, M.
Brennan, P.
McKay, J.D.
Carreras-Torres, R.
Muley, T.
Risch, A.
Wichmann, H.-.
Bickeboeller, H.
Rosenberger, A.
Rennert, G.
Saliba, W.
Arnold, S.M.
Field, J.K.
Davies, M.P.
Marcus, M.W.
Wu, X.
Ye, Y.
Le Marchand, L.
Wilkens, L.R.
Melander, O.
Manjer, J.
Brunnström, H.
Hung, R.J.
Liu, G.
Brhane, Y.
Kachuri, L.
Andrew, A.S.
Duell, E.J.
Kiemeney, L.A.
van der Heijden, E.H.
Haugen, A.
Zienolddiny, S.
Skaug, V.
Grankvist, K.
Johansson, M.
Woll, P.J.
Cox, A.
Taylor, F.
Teare, D.M.
Lazarus, P.
Schabath, M.B.
Aldrich, M.C.
Houlston, R.S.
McLaughlin, J.
Stevens, V.L.
Shen, H.
Hu, Z.
Dai, J.
Amos, C.I.
Han, Y.
Zhu, D.
Goodman, G.E.
Chen, F.
Christiani, D.C.
(2019). Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer: A Mendelian Randomization Analysis. Cancer epidemiology, biomarkers & prevention : a publication of the american association for cancer research, cosponsored by the american society of preventive oncology,
Vol.28
(5),
pp. 935-942.
show abstract
Background Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear.Methods We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk.Results Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall non-small cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15-2.27; P = 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27-7.06; P = 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings.Conclusions Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention.Impact These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention..
Ofoegbu, T.C.
David, A.
Kelley, L.A.
Mezulis, S.
Islam, S.A.
Mersmann, S.F.
Strömich, L.
Vakser, I.A.
Houlston, R.S.
Sternberg, M.J.
(2019). PhyreRisk: A Dynamic Web Application to Bridge Genomics, Proteomics and 3D Structural Data to Guide Interpretation of Human Genetic Variants. Journal of molecular biology,
Vol.431
(13),
pp. 2460-2466.
show abstract
PhyreRisk is an open-access, publicly accessible web application for interactively bridging genomic, proteomic and structural data facilitating the mapping of human variants onto protein structures. A major advance over other tools for sequence-structure variant mapping is that PhyreRisk provides information on 20,214 human canonical proteins and an additional 22,271 alternative protein sequences (isoforms). Specifically, PhyreRisk provides structural coverage (partial or complete) for 70% (14,035 of 20,214 canonical proteins) of the human proteome, by storing 18,874 experimental structures and 84,818 pre-built models of canonical proteins and their isoforms generated using our in house Phyre2. PhyreRisk reports 55,732 experimentally, multi-validated protein interactions from IntAct and 24,260 experimental structures of protein complexes. Another major feature of PhyreRisk is that, rather than presenting a limited set of precomputed variant-structure mapping of known genetic variants, it allows the user to explore novel variants using, as input, genomic coordinates formats (Ensembl, VCF, reference SNP ID and HGVS notations) and Human Build GRCh37 and GRCh38. PhyreRisk also supports mapping variants using amino acid coordinates and searching for genes or proteins of interest. PhyreRisk is designed to empower researchers to translate genetic data into protein structural information, thereby providing a more comprehensive appreciation of the functional impact of variants. PhyreRisk is freely available at http://phyrerisk.bc.ic.ac.uk..
Hoang, P.H.
Cornish, A.J.
Dobbins, S.E.
Kaiser, M.
Houlston, R.S.
(2019). Mutational processes contributing to the development of multiple myeloma. Blood cancer journal,
Vol.9
(8),
pp. 60-?.
show abstract
To gain insight into multiple myeloma (MM) tumorigenesis, we analyzed the mutational signatures in 874 whole-exome and 850 whole-genome data from the CoMMpass Study. We identified that coding and non-coding regions are differentially dominated by distinct single-nucleotide variant (SNV) mutational signatures, as well as five de novo structural rearrangement signatures. Mutational signatures reflective of different principle mutational processes-aging, defective DNA repair, and apolipoprotein B editing complex (APOBEC)/activation-induced deaminase activity-characterize MM. These mutational signatures show evidence of subgroup specificity-APOBEC-attributed signatures associated with MAF translocation t(14;16) and t(14;20) MM; potentially DNA repair deficiency with t(11;14) and t(4;14); and aging with hyperdiploidy. Mutational signatures beyond that associated with APOBEC are independent of established prognostic markers and appear to have relevance to predicting high-risk MM..
Went, M.
Sud, A.
Li, N.
Johnson, D.C.
Mitchell, J.S.
Kaiser, M.
Houlston, R.S.
(2019). Regions of homozygosity as risk factors for multiple myeloma. Annals of human genetics,
Vol.83
(4),
pp. 231-238.
show abstract
Genomic regions of homozygosity (ROH), detectable in outbred populations, have been implicated as determinants of inherited risk. To examine whether ROH is associated with risk of multiple myeloma (MM), we performed whole-genome homozygosity analysis using single-nucleotide polymorphism genotype data from 2,282 MM cases and 5,197 controls, with replication in an additional 878 MM cases and 7,083 controls. Globally, the distribution of ROH between cases and controls was not significantly different. However, one ROH at chromosome 9q21, harboring the B-cell transcription factor gene KLF9, showed evidence of a consistent association and may therefore warrant further investigation as a candidate risk factor for MM. Overall, our analysis provides little support for a homozygosity signature being a significant factor in MM risk..
Loveday, C.
Sud, A.
Litchfield, K.
Levy, M.
Holroyd, A.
Broderick, P.
Kote-Jarai, Z.
Dunning, A.M.
Muir, K.
Peto, J.
Eeles, R.
Easton, D.F.
Dudakia, D.
Orr, N.
Pashayan, N.
UK Testicular Cancer Collaboration,
PRACTICAL Consortium,
Reid, A.
Huddart, R.A.
Houlston, R.S.
Turnbull, C.
(2019). Runs of homozygosity and testicular cancer risk. Andrology,
Vol.7
(4),
pp. 555-564.
show abstract
Background Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types.Objective To examine whether RoH are associated with TGCT risk.Methods We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform.Results Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p < 0.01. Intriguingly, RoH200 at 11p13-11p14.3 encompasses Wilms tumour 1 (WT1), a recognized cancer susceptibility gene with roles in sex determination and developmental transcriptional regulation, processes repeatedly implicated in TGCT aetiology.Discussion and conclusion Overall, our data do not support a major role in the risk of TGCT for recessively acting alleles acting through homozygosity, as measured by RoH in outbred populations of cases and controls..
Hung, R.J.
Spitz, M.R.
Houlston, R.S.
Schwartz, A.G.
Field, J.K.
Ying, J.
Li, Y.
Han, Y.
Ji, X.
Chen, W.
Wu, X.
Gorlov, I.P.
Na, J.
de Andrade, M.
Liu, G.
Brhane, Y.
Diao, N.
Wenzlaff, A.
Davies, M.P.
Liloglou, T.
Timofeeva, M.
Muley, T.
Rennert, H.
Saliba, W.
Ryan, B.M.
Bowman, E.
Barros-Dios, J.-.
Pérez-Ríos, M.
Morgenstern, H.
Zienolddiny, S.
Skaug, V.
Ugolini, D.
Bonassi, S.
van der Heijden, E.H.
Tardon, A.
Bojesen, S.E.
Landi, M.T.
Johansson, M.
Bickeböller, H.
Arnold, S.
Le Marchand, L.
Melander, O.
Andrew, A.
Grankvist, K.
Caporaso, N.
Teare, M.D.
Schabath, M.B.
Aldrich, M.C.
Kiemeney, L.A.
Wichmann, H.-.
Lazarus, P.
Mayordomo, J.
Neri, M.
Haugen, A.
Zhang, Z.-.
Ruano-Raviña, A.
Brenner, H.
Harris, C.C.
Orlow, I.
Rennert, G.
Risch, A.
Brennan, P.
Christiani, D.C.
Amos, C.I.
Yang, P.
Gorlova, O.Y.
(2019). Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15 33 TERT-CLPTM1Ll Region. Journal of thoracic oncology : official publication of the international association for the study of lung cancer,
Vol.14
(8),
pp. 1360-1369.
show abstract
Introduction Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer.Methods We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer.Results We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10 -16 ), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10 -16 ), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10 -14 ). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate.Conclusions We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease..
Speedy, H.E.
Beekman, R.
Chapaprieta, V.
Orlando, G.
Law, P.J.
Martín-García, D.
Gutiérrez-Abril, J.
Catovsky, D.
Beà, S.
Clot, G.
Puiggròs, M.
Torrents, D.
Puente, X.S.
Allan, J.M.
López-Otín, C.
Campo, E.
Houlston, R.S.
Martín-Subero, J.I.
(2019). Insight into genetic predisposition to chronic lymphocytic leukemia from integrative epigenomics. Nature communications,
Vol.10
(1),
pp. 3615-?.
show abstract
Genome-wide association studies have provided evidence for inherited genetic predisposition to chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms underlying CLL risk we analyze chromatin accessibility, active regulatory elements marked by H3K27ac, and DNA methylation at 42 risk loci in up to 486 primary CLLs. We identify that risk loci are significantly enriched for active chromatin in CLL with evidence of being CLL-specific or differentially regulated in normal B-cell development. We then use in situ promoter capture Hi-C, in conjunction with gene expression data to reveal likely target genes of the risk loci. Candidate target genes are enriched for pathways related to B-cell development such as MYC and BCL2 signalling. At 14 loci the analysis highlights 63 variants as the probable functional basis of CLL risk. By integrating genetic and epigenetic information our analysis reveals novel insights into the relationship between inherited predisposition and the regulatory chromatin landscape of CLL..
Sud, A.
Chattopadhyay, S.
Thomsen, H.
Sundquist, K.
Sundquist, J.
Houlston, R.S.
Hemminki, K.
(2019). Analysis of 153 115 patients with hematological malignancies refines the spectrum of familial risk. Blood,
Vol.134
(12),
pp. 960-969.
show abstract
Estimating familial cancer risks is clinically important in being able to discriminate between individuals in the population at differing risk for malignancy. To gain insight into the familial risk for the different hematological malignancies and their possible inter-relationship, we analyzed data on more than 16 million individuals from the Swedish Family-Cancer Database. After identifying 153 115 patients diagnosed with a primary hematological malignancy, we quantified familial relative risks (FRRs) by calculating standardized incident ratios (SIRs) in 391 131 of their first-degree relatives. The majority of hematological malignancies showed increased FRRs for the same tumor type, with the highest FRRs being observed for mixed cellularity Hodgkin lymphoma (SIR, 16.7), lymphoplasmacytic lymphoma (SIR, 15.8), and mantle cell lymphoma (SIR, 13.3). There was evidence for pleiotropic relationships; notably, chronic lymphocytic leukemia was associated with an elevated familial risk for other B-cell tumors and myeloproliferative neoplasms. Collectively, these data provide evidence for shared etiological factors for many hematological malignancies and provide information for identifying individuals at increased risk, as well as informing future gene discovery initiatives..
Cornish, A.J.
Tomlinson, I.P.
Houlston, R.S.
(2019). Mendelian randomisation: A powerful and inexpensive method for identifying and excluding non-genetic risk factors for colorectal cancer. Molecular aspects of medicine,
Vol.69,
pp. 41-47.
show abstract
Colorectal cancer (CRC) is the third most common cancer in economically developed countries and a major cause of cancer-related mortality. The importance of lifestyle and diet as major determinants of CRC risk is suggested by differences in CRC incidence between countries and in migration studies. Previous observational epidemiological studies have identified associations between modifiable environmental risk factors and CRC, but these studies can be susceptible to reverse causation and confounding, and their results can therefore conflict. Mendelian randomisation (MR) analysis represents an approach complementary to conventional observational studies examining associations between exposures and disease. The MR strategy employs allelic variants as instrumental variables (IVs), which act as proxies for non-genetic exposures. These allelic variants are randomly assigned during meiosis and can therefore inform on life-long exposure, whilst not being subject to reverse causation. In previous studies MR frameworks have associated several modifiable factors with CRC risk, including adiposity, hyperlipidaemia, fatty acid profile and alcohol consumption. In this review we detail the use of MR to investigate and discover CRC risk factors, and its future applications..
Law, P.J.
Timofeeva, M.
Fernandez-Rozadilla, C.
Broderick, P.
Studd, J.
Fernandez-Tajes, J.
Farrington, S.
Svinti, V.
Palles, C.
Orlando, G.
Sud, A.
Holroyd, A.
Penegar, S.
Theodoratou, E.
Vaughan-Shaw, P.
Campbell, H.
Zgaga, L.
Hayward, C.
Campbell, A.
Harris, S.
Deary, I.J.
Starr, J.
Gatcombe, L.
Pinna, M.
Briggs, S.
Martin, L.
Jaeger, E.
Sharma-Oates, A.
East, J.
Leedham, S.
Arnold, R.
Johnstone, E.
Wang, H.
Kerr, D.
Kerr, R.
Maughan, T.
Kaplan, R.
Al-Tassan, N.
Palin, K.
Hänninen, U.A.
Cajuso, T.
Tanskanen, T.
Kondelin, J.
Kaasinen, E.
Sarin, A.-.
Eriksson, J.G.
Rissanen, H.
Knekt, P.
Pukkala, E.
Jousilahti, P.
Salomaa, V.
Ripatti, S.
Palotie, A.
Renkonen-Sinisalo, L.
Lepistö, A.
Böhm, J.
Mecklin, J.-.
Buchanan, D.D.
Win, A.-.
Hopper, J.
Jenkins, M.E.
Lindor, N.M.
Newcomb, P.A.
Gallinger, S.
Duggan, D.
Casey, G.
Hoffmann, P.
Nöthen, M.M.
Jöckel, K.-.
Easton, D.F.
Pharoah, P.D.
Peto, J.
Canzian, F.
Swerdlow, A.
Eeles, R.A.
Kote-Jarai, Z.
Muir, K.
Pashayan, N.
PRACTICAL consortium,
Harkin, A.
Allan, K.
McQueen, J.
Paul, J.
Iveson, T.
Saunders, M.
Butterbach, K.
Chang-Claude, J.
Hoffmeister, M.
Brenner, H.
Kirac, I.
Matošević, P.
Hofer, P.
Brezina, S.
Gsur, A.
Cheadle, J.P.
Aaltonen, L.A.
Tomlinson, I.
Houlston, R.S.
Dunlop, M.G.
(2019). Association analyses identify 31 new risk loci for colorectal cancer susceptibility. Nature communications,
Vol.10
(1),
pp. 2154-?.
show abstract
Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention..
Labreche, K.
Daniau, M.
Sud, A.
Law, P.J.
Royer-Perron, L.
Holroyd, A.
Broderick, P.
Went, M.
Benazra, M.
Ahle, G.
Soubeyran, P.
Taillandier, L.
Chinot, O.L.
Casasnovas, O.
Bay, J.-.
Jardin, F.
Oberic, L.
Fabbro, M.
Damaj, G.
Brion, A.
Mokhtari, K.
Philippe, C.
Sanson, M.
Houillier, C.
Soussain, C.
Hoang-Xuan, K.
Houlston, R.S.
Alentorn, A.
LOC Network,
(2019). A genome-wide association study identifies susceptibility loci for primary central nervous system lymphoma at 6p25 3 and 3p22 1: a LOC network study. Neuro-oncology,
.
show abstract
Background Primary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin lymphoma. PCNSL is a distinct subtype of non-Hodgkin lymphoma, with over 95% of tumors belonging to the diffuse large B-cell lymphoma (DLBCL) group. We have conducted a genome-wide association study (GWAS) on immunocompetent patients to address the possibility that common genetic variants influence the risk of developing PCNSL.Methods We performed a meta-analysis of two new genome-wide association studies of PCNSL totaling 475 cases and 1,134 controls of European ancestry. To increase genomic resolution, we imputed >10 million single-nucleotide polymorphisms (SNPs) using the 1000 Genomes Project combined with UK10K as reference. In addition we performed a transcription factor binding disruption analysis and investigated the patterns of local chromatin patterns by capture Hi-C data.Results We identified independent risk loci at 3p22.1 (rs41289586, ANO10, P = 2.17 x 10-8) and 6p25.3 near EXOC2 (rs116446171, P = 1.95 x 10-13). In contrast the lack of an association between rs41289586 and DLBCL, suggests distinct germline predisposition to PCNSL and DLBCL. We found looping chromatin interactions between non-coding regions at 6p25.3 (rs11646171) with the IRF4 promoter and at 8q24.21 (rs13254990) with the MYC promoter, both genes with strong relevance to B-cell tumorigenesis.Conclusion To our knowledge this is the first study providing insight into the genetic predisposition to PCNSL. Our findings represent an important step in defining the contribution of common genetic variation to the risk of developing PCNSL..
Went, M.
Kinnersley, B.
Sud, A.
Johnson, D.C.
Weinhold, N.
Försti, A.
van Duin, M.
Orlando, G.
Mitchell, J.S.
Kuiper, R.
Walker, B.A.
Gregory, W.M.
Hoffmann, P.
Jackson, G.H.
Nöthen, M.M.
da Silva Filho, M.I.
Thomsen, H.
Broyl, A.
Davies, F.E.
Thorsteinsdottir, U.
Hansson, M.
Kaiser, M.
Sonneveld, P.
Goldschmidt, H.
Stefansson, K.
Hemminki, K.
Nilsson, B.
Morgan, G.J.
Houlston, R.S.
(2019). Transcriptome-wide association study of multiple myeloma identifies candidate susceptibility genes. Human genomics,
Vol.13
(1),
pp. 37-?.
show abstract
Background While genome-wide association studies (GWAS) of multiple myeloma (MM) have identified variants at 23 regions influencing risk, the genes underlying these associations are largely unknown. To identify candidate causal genes at these regions and search for novel risk regions, we performed a multi-tissue transcriptome-wide association study (TWAS).Results GWAS data on 7319 MM cases and 234,385 controls was integrated with Genotype-Tissue Expression Project (GTEx) data assayed in 48 tissues (sample sizes, N = 80-491), including lymphocyte cell lines and whole blood, to predict gene expression. We identified 108 genes at 13 independent regions associated with MM risk, all of which were in 1 Mb of known MM GWAS risk variants. Of these, 94 genes, located in eight regions, had not previously been considered as a candidate gene for that locus.Conclusions Our findings highlight the value of leveraging expression data from multiple tissues to identify candidate genes responsible for GWAS associations which provide insight into MM tumorigenesis. Among the genes identified, a number have plausible roles in MM biology, notably APOBEC3C, APOBEC3H, APOBEC3D, APOBEC3F, APOBEC3G, or have been previously implicated in other malignancies. The genes identified in this TWAS can be explored for follow-up and validation to further understand their role in MM biology..
Takahashi, H.
Cornish, A.J.
Sud, A.
Law, P.J.
Disney-Hogg, L.
Calvocoressi, L.
Lu, L.
Hansen, H.M.
Smirnov, I.
Walsh, K.M.
Schramm, J.
Hoffmann, P.
Nöthen, M.M.
Jöckel, K.-.
Schildkraut, J.M.
Simon, M.
Bondy, M.
Wrensch, M.
Wiemels, J.L.
Claus, E.B.
Turnbull, C.
Houlston, R.S.
(2019). Mendelian randomization provides support for obesity as a risk factor for meningioma. Scientific reports,
Vol.9
(1),
pp. 309-?.
show abstract
Little is known about the causes of meningioma. Obesity and obesity-related traits have been reported in several epidemiological observational studies to be risk factors for meningioma. We performed an analysis of genetic variants associated with obesity-related traits to assess the relationship with meningioma risk using Mendelian randomization (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. We considered 11 obesity-related traits, identified genetic instruments for these factors, and assessed their association with meningioma risk using data from a genome-wide association study comprising 1,606 meningioma patients and 9,823 controls. To evaluate the causal relationship between the obesity-related traits and meningioma risk, we consider the estimated odds ratio (OR) of meningioma for each genetic instrument. We identified positive associations between body mass index (odds ratio [OR SD ] = 1.27, 95% confidence interval [CI] = 1.03-1.56, P = 0.028) and body fat percentage (OR SD = 1.28, 95% CI = 1.01-1.63, P = 0.042) with meningioma risk, albeit non-significant after correction for multiple testing. Associations for basal metabolic rate, diastolic blood pressure, fasting glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, systolic blood pressure, total cholesterol, triglycerides and waist circumference with risk of meningioma were non-significant. Our analysis provides additional support for obesity being associated with an increased risk of meningioma..
Vijayakrishnan, J.
Qian, M.
Studd, J.B.
Yang, W.
Kinnersley, B.
Law, P.J.
Broderick, P.
Raetz, E.A.
Allan, J.
Pui, C.-.
Vora, A.
Evans, W.E.
Moorman, A.
Yeoh, A.
Yang, W.
Li, C.
Bartram, C.R.
Mullighan, C.G.
Zimmerman, M.
Hunger, S.P.
Schrappe, M.
Relling, M.V.
Stanulla, M.
Loh, M.L.
Houlston, R.S.
Yang, J.J.
(2019). Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk. Nature communications,
Vol.10
(1),
pp. 5348-?.
show abstract
There is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10 -8 ), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10 -8 ) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10 -8 ), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10 -8 ). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL..
Jiang, X.
Finucane, H.K.
Schumacher, F.R.
Schmit, S.L.
Tyrer, J.P.
Han, Y.
Michailidou, K.
Lesseur, C.
Kuchenbaecker, K.B.
Dennis, J.
Conti, D.V.
Casey, G.
Gaudet, M.M.
Huyghe, J.R.
Albanes, D.
Aldrich, M.C.
Andrew, A.S.
Andrulis, I.L.
Anton-Culver, H.
Antoniou, A.C.
Antonenkova, N.N.
Arnold, S.M.
Aronson, K.J.
Arun, B.K.
Bandera, E.V.
Barkardottir, R.B.
Barnes, D.R.
Batra, J.
Beckmann, M.W.
Benitez, J.
Benlloch, S.
Berchuck, A.
Berndt, S.I.
Bickeböller, H.
Bien, S.A.
Blomqvist, C.
Boccia, S.
Bogdanova, N.V.
Bojesen, S.E.
Bolla, M.K.
Brauch, H.
Brenner, H.
Brenton, J.D.
Brook, M.N.
Brunet, J.
Brunnström, H.
Buchanan, D.D.
Burwinkel, B.
Butzow, R.
Cadoni, G.
Caldés, T.
Caligo, M.A.
Campbell, I.
Campbell, P.T.
Cancel-Tassin, G.
Cannon-Albright, L.
Campa, D.
Caporaso, N.
Carvalho, A.L.
Chan, A.T.
Chang-Claude, J.
Chanock, S.J.
Chen, C.
Christiani, D.C.
Claes, K.B.
Claessens, F.
Clements, J.
Collée, J.M.
Correa, M.C.
Couch, F.J.
Cox, A.
Cunningham, J.M.
Cybulski, C.
Czene, K.
Daly, M.B.
deFazio, A.
Devilee, P.
Diez, O.
Gago-Dominguez, M.
Donovan, J.L.
Dörk, T.
Duell, E.J.
Dunning, A.M.
Dwek, M.
Eccles, D.M.
Edlund, C.K.
Edwards, D.R.
Ellberg, C.
Evans, D.G.
Fasching, P.A.
Ferris, R.L.
Liloglou, T.
Figueiredo, J.C.
Fletcher, O.
Fortner, R.T.
Fostira, F.
Franceschi, S.
Friedman, E.
Gallinger, S.J.
Ganz, P.A.
Garber, J.
García-Sáenz, J.A.
Gayther, S.A.
Giles, G.G.
Godwin, A.K.
Goldberg, M.S.
Goldgar, D.E.
Goode, E.L.
Goodman, M.T.
Goodman, G.
Grankvist, K.
Greene, M.H.
Gronberg, H.
Gronwald, J.
Guénel, P.
Håkansson, N.
Hall, P.
Hamann, U.
Hamdy, F.C.
Hamilton, R.J.
Hampe, J.
Haugen, A.
Heitz, F.
Herrero, R.
Hillemanns, P.
Hoffmeister, M.
Høgdall, E.
Hong, Y.-.
Hopper, J.L.
Houlston, R.
Hulick, P.J.
Hunter, D.J.
Huntsman, D.G.
Idos, G.
Imyanitov, E.N.
Ingles, S.A.
Isaacs, C.
Jakubowska, A.
James, P.
Jenkins, M.A.
Johansson, M.
Johansson, M.
John, E.M.
Joshi, A.D.
Kaneva, R.
Karlan, B.Y.
Kelemen, L.E.
Kühl, T.
Khaw, K.-.
Khusnutdinova, E.
Kibel, A.S.
Kiemeney, L.A.
Kim, J.
Kjaer, S.K.
Knight, J.A.
Kogevinas, M.
Kote-Jarai, Z.
Koutros, S.
Kristensen, V.N.
Kupryjanczyk, J.
Lacko, M.
Lam, S.
Lambrechts, D.
Landi, M.T.
Lazarus, P.
Le, N.D.
Lee, E.
Lejbkowicz, F.
Lenz, H.-.
Leslie, G.
Lessel, D.
Lester, J.
Levine, D.A.
Li, L.
Li, C.I.
Lindblom, A.
Lindor, N.M.
Liu, G.
Loupakis, F.
Lubiński, J.
Maehle, L.
Maier, C.
Mannermaa, A.
Marchand, L.L.
Margolin, S.
May, T.
McGuffog, L.
Meindl, A.
Middha, P.
Miller, A.
Milne, R.L.
MacInnis, R.J.
Modugno, F.
Montagna, M.
Moreno, V.
Moysich, K.B.
Mucci, L.
Muir, K.
Mulligan, A.M.
Nathanson, K.L.
Neal, D.E.
Ness, A.R.
Neuhausen, S.L.
Nevanlinna, H.
Newcomb, P.A.
Newcomb, L.F.
Nielsen, F.C.
Nikitina-Zake, L.
Nordestgaard, B.G.
Nussbaum, R.L.
Offit, K.
Olah, E.
Olama, A.A.
Olopade, O.I.
Olshan, A.F.
Olsson, H.
Osorio, A.
Pandha, H.
Park, J.Y.
Pashayan, N.
Parsons, M.T.
Pejovic, T.
Penney, K.L.
Peters, W.H.
Phelan, C.M.
Phipps, A.I.
Plaseska-Karanfilska, D.
Pring, M.
Prokofyeva, D.
Radice, P.
Stefansson, K.
Ramus, S.J.
Raskin, L.
Rennert, G.
Rennert, H.S.
van Rensburg, E.J.
Riggan, M.J.
Risch, H.A.
Risch, A.
Roobol, M.J.
Rosenstein, B.S.
Rossing, M.A.
De Ruyck, K.
Saloustros, E.
Sandler, D.P.
Sawyer, E.J.
Schabath, M.B.
Schleutker, J.
Schmidt, M.K.
Setiawan, V.W.
Shen, H.
Siegel, E.M.
Sieh, W.
Singer, C.F.
Slattery, M.L.
Sorensen, K.D.
Southey, M.C.
Spurdle, A.B.
Stanford, J.L.
Stevens, V.L.
Stintzing, S.
Stone, J.
Sundfeldt, K.
Sutphen, R.
Swerdlow, A.J.
Tajara, E.H.
Tangen, C.M.
Tardon, A.
Taylor, J.A.
Teare, M.D.
Teixeira, M.R.
Terry, M.B.
Terry, K.L.
Thibodeau, S.N.
Thomassen, M.
Bjørge, L.
Tischkowitz, M.
Toland, A.E.
Torres, D.
Townsend, P.A.
Travis, R.C.
Tung, N.
Tworoger, S.S.
Ulrich, C.M.
Usmani, N.
Vachon, C.M.
Van Nieuwenhuysen, E.
Vega, A.
Aguado-Barrera, M.E.
Wang, Q.
Webb, P.M.
Weinberg, C.R.
Weinstein, S.
Weissler, M.C.
Weitzel, J.N.
West, C.M.
White, E.
Whittemore, A.S.
Wichmann, H.-.
Wiklund, F.
Winqvist, R.
Wolk, A.
Woll, P.
Woods, M.
Wu, A.H.
Wu, X.
Yannoukakos, D.
Zheng, W.
Zienolddiny, S.
Ziogas, A.
Zorn, K.K.
Lane, J.M.
Saxena, R.
Thomas, D.
Hung, R.J.
Diergaarde, B.
McKay, J.
Peters, U.
Hsu, L.
García-Closas, M.
Eeles, R.A.
Chenevix-Trench, G.
Brennan, P.J.
Haiman, C.A.
Simard, J.
Easton, D.F.
Gruber, S.B.
Pharoah, P.D.
Price, A.L.
Pasaniuc, B.
Amos, C.I.
Kraft, P.
Lindström, S.
(2019). Shared heritability and functional enrichment across six solid cancers. Nature communications,
Vol.10
(1),
pp. 431-?.
show abstract
Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r g = 0.57, p = 4.6 × 10 -8 ), breast and ovarian cancer (r g = 0.24, p = 7 × 10 -5 ), breast and lung cancer (r g = 0.18, p =1.5 × 10 -6 ) and breast and colorectal cancer (r g = 0.15, p = 1.1 × 10 -4 ). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis..
Zheng, G.
Chattopadhyay, S.
Sud, A.
Sundquist, K.
Sundquist, J.
Försti, A.
Houlston, R.S.
Hemminki, A.
Hemminki, K.
(2019). Types of second primary cancers influence survival in chronic lymphocytic and hairy cell leukemia patients. Blood cancer journal,
Vol.9
(4),
pp. 40-?.
Shah, V.
Sherborne, A.L.
Walker, B.A.
Johnson, D.C.
Boyle, E.M.
Ellis, S.
Begum, D.B.
Proszek, P.Z.
Jones, J.R.
Pawlyn, C.
Savola, S.
Jenner, M.W.
Drayson, M.T.
Owen, R.G.
Houlston, R.S.
Cairns, D.A.
Gregory, W.M.
Cook, G.
Davies, F.E.
Jackson, G.H.
Morgan, G.J.
Kaiser, M.F.
(2018). Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients. Leukemia,
Vol.32
(1),
pp. 102-110.
show abstract
Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10 -7 ), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10 -14 ) and 1.68 (P=2.18 × 10 -14 ), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10 -27 ) for all patients and 3.19 (P=1.23 × 10 -18 ) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10 -15 ), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment..
Lawler, M.
Alsina, D.
Adams, R.A.
Anderson, A.S.
Brown, G.
Fearnhead, N.S.
Fenwick, S.W.
Halloran, S.P.
Hochhauser, D.
Hull, M.A.
Koelzer, V.H.
McNair, A.G.
Monahan, K.J.
Näthke, I.
Norton, C.
Novelli, M.R.
Steele, R.J.
Thomas, A.L.
Wilde, L.M.
Wilson, R.H.
Tomlinson, I.
Bowel Cancer UK Critical Research Gaps in Colorectal Cancer Initiative,
(2018). Critical research gaps and recommendations to inform research prioritisation for more effective prevention and improved outcomes in colorectal cancer. Gut,
Vol.67
(1),
pp. 179-193.
show abstract
Objective Colorectal cancer (CRC) leads to significant morbidity/mortality worldwide. Defining critical research gaps (RG), their prioritisation and resolution, could improve patient outcomes.Design RG analysis was conducted by a multidisciplinary panel of patients, clinicians and researchers (n=71). Eight working groups (WG) were constituted: discovery science; risk; prevention; early diagnosis and screening; pathology; curative treatment; stage IV disease; and living with and beyond CRC. A series of discussions led to development of draft papers by each WG, which were evaluated by a 20-strong patient panel. A final list of RGs and research recommendations (RR) was endorsed by all participants.Results Fifteen critical RGs are summarised below: RG1: Lack of realistic models that recapitulate tumour/tumour micro/macroenvironment; RG2: Insufficient evidence on precise contributions of genetic/environmental/lifestyle factors to CRC risk; RG3: Pressing need for prevention trials; RG4: Lack of integration of different prevention approaches; RG5: Lack of optimal strategies for CRC screening; RG6: Lack of effective triage systems for invasive investigations; RG7: Imprecise pathological assessment of CRC; RG8: Lack of qualified personnel in genomics, data sciences and digital pathology; RG9: Inadequate assessment/communication of risk, benefit and uncertainty of treatment choices; RG10: Need for novel technologies/interventions to improve curative outcomes; RG11: Lack of approaches that recognise molecular interplay between metastasising tumours and their microenvironment; RG12: Lack of reliable biomarkers to guide stage IV treatment; RG13: Need to increase understanding of health related quality of life (HRQOL) and promote residual symptom resolution; RG14: Lack of coordination of CRC research/funding; RG15: Lack of effective communication between relevant stakeholders.Conclusion Prioritising research activity and funding could have a significant impact on reducing CRC disease burden over the next 5 years..
Loveday, C.
Litchfield, K.
Levy, M.
Holroyd, A.
Broderick, P.
Kote-Jarai, Z.
Dunning, A.M.
Muir, K.
Peto, J.
Eeles, R.
Easton, D.F.
Dudakia, D.
Orr, N.
Pashayan, N.
Reid, A.
Huddart, R.A.
Houlston, R.S.
Turnbull, C.
(2018). Validation of loci at 2q14 2 and 15q21 3 as risk factors for testicular cancer. Oncotarget,
Vol.9
(16),
pp. 12630-12638.
show abstract
Testicular germ cell tumor (TGCT), the most common cancer in men aged 18 to 45 years, has a strong heritable basis. Genome-wide association studies (GWAS) have proposed single nucleotide polymorphisms (SNPs) at a number of loci influencing TGCT risk. To further evaluate the association of recently proposed risk SNPs with TGCT at 2q14.2, 3q26.2, 7q36.3, 10q26.13 and 15q21.3, we analyzed genotype data on 3,206 cases and 7,422 controls. Our analysis provides independent replication of the associations for risk SNPs at 2q14.2 (rs2713206 at P = 3.03 × 10-2; P-meta = 3.92 × 10-8; nearest gene, TFCP2L1) and rs12912292 at 15q21.3 (P = 7.96 × 10-11; P-meta = 1.55 × 10-19; nearest gene PRTG). Case-only analyses did not reveal specific associations with TGCT histology. TFCP2L1 joins the growing list of genes located within TGCT risk loci with biologically plausible roles in developmental transcriptional regulation, further highlighting the importance of this phenomenon in TGCT oncogenesis..
Tanskanen, T.
van den Berg, L.
Välimäki, N.
Aavikko, M.
Ness-Jensen, E.
Hveem, K.
Wettergren, Y.
Bexe Lindskog, E.
Tõnisson, N.
Metspalu, A.
Silander, K.
Orlando, G.
Law, P.J.
Tuupanen, S.
Gylfe, A.E.
Hänninen, U.A.
Cajuso, T.
Kondelin, J.
Sarin, A.-.
Pukkala, E.
Jousilahti, P.
Salomaa, V.
Ripatti, S.
Palotie, A.
Järvinen, H.
Renkonen-Sinisalo, L.
Lepistö, A.
Böhm, J.
Mecklin, J.-.
Al-Tassan, N.A.
Palles, C.
Martin, L.
Barclay, E.
Tenesa, A.
Farrington, S.M.
Timofeeva, M.N.
Meyer, B.F.
Wakil, S.M.
Campbell, H.
Smith, C.G.
Idziaszczyk, S.
Maughan, T.S.
Kaplan, R.
Kerr, R.
Kerr, D.
Buchanan, D.D.
Win, A.K.
Hopper, J.
Jenkins, M.A.
Newcomb, P.A.
Gallinger, S.
Conti, D.
Schumacher, F.R.
Casey, G.
Cheadle, J.P.
Dunlop, M.G.
Tomlinson, I.P.
Houlston, R.S.
Palin, K.
Aaltonen, L.A.
(2018). Genome-wide association study and meta-analysis in Northern European populations replicate multiple colorectal cancer risk loci. International journal of cancer,
Vol.142
(3),
pp. 540-546.
show abstract
Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10 -4 ; OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p = 1.50 × 10 -9 ; OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations..
Kinnersley, B.
Houlston, R.S.
Bondy, M.L.
(2018). Genome-Wide Association Studies in Glioma. Cancer epidemiology, biomarkers & prevention : a publication of the american association for cancer research, cosponsored by the american society of preventive oncology,
Vol.27
(4),
pp. 418-428.
show abstract
Since the first reports in 2009, genome-wide association studies (GWAS) have been successful in identifying germline variants associated with glioma susceptibility. In this review, we describe a chronological history of glioma GWAS, culminating in the most recent study comprising 12,496 cases and 18,190 controls. We additionally summarize associations at the 27 glioma-risk SNPs that have been reported so far. Future efforts are likely to be principally focused on assessing association of germline-risk SNPs with particular molecular subgroups of glioma, as well as investigating the functional basis of the risk loci in tumor formation. These ongoing studies will be important to maximize the impact of research into glioma susceptibility, both in terms of insight into tumor etiology as well as opportunities for clinical translation. Cancer Epidemiol Biomarkers Prev; 27(4); 418-28. ©2018 AACRSee all articles in this CEBP Focus section, "Genome-Wide Association Studies in Cancer.".
Disney-Hogg, L.
Sud, A.
Law, P.J.
Cornish, A.J.
Kinnersley, B.
Ostrom, Q.T.
Labreche, K.
Eckel-Passow, J.E.
Armstrong, G.N.
Claus, E.B.
Il'yasova, D.
Schildkraut, J.
Barnholtz-Sloan, J.S.
Olson, S.H.
Bernstein, J.L.
Lai, R.K.
Swerdlow, A.J.
Simon, M.
Hoffmann, P.
Nöthen, M.M.
Jöckel, K.-.
Chanock, S.
Rajaraman, P.
Johansen, C.
Jenkins, R.B.
Melin, B.S.
Wrensch, M.R.
Sanson, M.
Bondy, M.L.
Houlston, R.S.
(2018). Influence of obesity-related risk factors in the aetiology of glioma. British journal of cancer,
Vol.118
(7),
pp. 1020-1027.
show abstract
Background Obesity and related factors have been implicated as possible aetiological factors for the development of glioma in epidemiological observation studies. We used genetic markers in a Mendelian randomisation framework to examine whether obesity-related traits influence glioma risk. This methodology reduces bias from confounding and is not affected by reverse causation. Methods Genetic instruments were identified for 10 key obesity-related risk factors, and their association with glioma risk was evaluated using data from a genome-wide association study of 12,488 glioma patients and 18,169 controls. The estimated odds ratio of glioma associated with each of the genetically defined obesity-related traits was used to infer evidence for a causal relationship. Results No convincing association with glioma risk was seen for genetic instruments for body mass index, waist-to-hip ratio, lipids, type-2 diabetes, hyperglycaemia or insulin resistance. Similarly, we found no evidence to support a relationship between obesity-related traits with subtypes of glioma-glioblastoma (GBM) or non-GBM tumours. Conclusions This study provides no evidence to implicate obesity-related factors as causes of glioma..
Takahashi, H.
Cornish, A.J.
Sud, A.
Law, P.J.
Kinnersley, B.
Ostrom, Q.T.
Labreche, K.
Eckel-Passow, J.E.
Armstrong, G.N.
Claus, E.B.
Il'yasova, D.
Schildkraut, J.
Barnholtz-Sloan, J.S.
Olson, S.H.
Bernstein, J.L.
Lai, R.K.
Schoemaker, M.J.
Simon, M.
Hoffmann, P.
Nöthen, M.M.
Jöckel, K.-.
Chanock, S.
Rajaraman, P.
Johansen, C.
Jenkins, R.B.
Melin, B.S.
Wrensch, M.R.
Sanson, M.
Bondy, M.L.
Turnbull, C.
Houlston, R.S.
(2018). Mendelian randomisation study of the relationship between vitamin D and risk of glioma. Scientific reports,
Vol.8
(1),
pp. 2339-?.
show abstract
To examine for a causal relationship between vitamin D and glioma risk we performed an analysis of genetic variants associated with serum 25-hydroxyvitamin D (25(OH)D) levels using Mendelian randomisation (MR), an approach unaffected by biases from confounding. Two-sample MR was undertaken using genome-wide association study data. Single nucleotide polymorphisms (SNPs) associated with 25(OH)D levels were used as instrumental variables (IVs). We calculated MR estimates for the odds ratio (OR) for 25(OH)D levels with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighted (IVW) and maximum likelihood estimation (MLE) methods. A non-significant association between 25(OH)D levels and glioma risk was shown using both the IVW (OR = 1.21, 95% confidence interval [CI] = 0.90-1.62, P = 0.201) and MLE (OR = 1.20, 95% CI = 0.98-1.48, P = 0.083) methods. In an exploratory analysis of tumour subtype, an inverse relationship between 25(OH)D levels and glioblastoma (GBM) risk was identified using the MLE method (OR = 0.62, 95% CI = 0.43-0.89, P = 0.010), but not the IVW method (OR = 0.62, 95% CI = 0.37-1.04, P = 0.070). No statistically significant association was shown between 25(OH)D levels and non-GBM glioma. Our results do not provide evidence for a causal relationship between 25(OH)D levels and all forms of glioma risk. More evidence is required to explore the relationship between 25(OH)D levels and risk of GBM..
Labreche, K.
Kinnersley, B.
Berzero, G.
Di Stefano, A.L.
Rahimian, A.
Detrait, I.
Marie, Y.
Grenier-Boley, B.
Hoang-Xuan, K.
Delattre, J.-.
Idbaih, A.
Houlston, R.S.
Sanson, M.
(2018). Diffuse gliomas classified by 1p/19q co-deletion, TERT promoter and IDH mutation status are associated with specific genetic risk loci. Acta neuropathologica,
Vol.135
(5),
pp. 743-755.
show abstract
Recent genome-wide association studies of glioma have led to the discovery of single nucleotide polymorphisms (SNPs) at 25 loci influencing risk. Gliomas are heterogeneous, hence to investigate the relationship between risk SNPs and glioma subtype we analysed 1659 tumours profiled for IDH mutation, TERT promoter mutation and 1p/19q co-deletion. These data allowed definition of five molecular subgroups of glioma: triple-positive (IDH mutated, 1p/19q co-deletion, TERT promoter mutated); TERT-IDH (IDH mutated, TERT promoter mutated, 1p/19q-wild-type); IDH-only (IDH mutated, 1p/19q wild-type, TERT promoter wild-type); triple-negative (IDH wild-type, 1p/19q wild-type, TERT promoter wild-type) and TERT-only (TERT promoter mutated, IDH wild-type, 1p/19q wild-type). Most glioma risk loci showed subtype specificity: (1) the 8q24.21 SNP for triple-positive glioma; (2) 5p15.33, 9p21.3, 17p13.1 and 20q13.33 SNPs for TERT-only glioma; (3) 1q44, 2q33.3, 3p14.1, 11q21, 11q23.3, 14q12, and 15q24.2 SNPs for IDH mutated glioma. To link risk SNPs to target candidate genes we analysed Hi-C and gene expression data, highlighting the potential role of IDH1 at 2q33.3, MYC at 8q24.21 and STMN3 at 20q13.33. Our observations provide further insight into the nature of susceptibility to glioma..
Litchfield, K.
Loveday, C.
Levy, M.
Dudakia, D.
Rapley, E.
Nsengimana, J.
Bishop, D.T.
Reid, A.
Huddart, R.
Broderick, P.
Houlston, R.S.
Turnbull, C.
(2018). Large-scale Sequencing of Testicular Germ Cell Tumour (TGCT) Cases Excludes Major TGCT Predisposition Gene. European urology,
Vol.73
(6),
pp. 828-831.
show abstract
Testicular germ cell tumour (TGCT), the most common cancer in young men, has a significant heritable basis that has long raised questions as to the existence of underlying major high-penetrance susceptibility gene(s). To determine the contribution of rare gene mutations to the inherited risk of TGCT, we analysed germline whole-exome data for 919 TGCT cases and 1609 cancer-free controls. We compared frequencies between TGCT cases and controls of rare (<1%) and low-frequency (1-5%) coding variants (1) individually and (2) collapsed at the gene level via burden testing (T1, disruptive; T2, all deleterious; and T3, all nonsynonymous) using Fisher's exact test with Bonferroni correction of significance thresholds. No individual variant or individual gene showed a significant association with TGCT after correction for multiple testing. In the largest whole-exome sequencing study of testicular cancer reported to date, our findings do not support the existence of a major high-penetrance TGCT susceptibility gene (of odds ratio >10 and allele frequency [combined]>0.01%). Owing to its power, this study cannot exclude the existence of susceptibility genes responsible for occasional TGCT families or of rare mutations that confer very modest relative risks. In concert with findings from genome-wide association studies, our data support the notion that inherited susceptibility is largely polygenic with substantial contribution from common variation. PATIENT SUMMARY:In the largest study of its kind, we sequenced ∼20 000 genes in 919 men with testicular germ cell tumour (TGCT) and 1609 TGCT-free individuals and found no evidence of a single major gene underlying predisposition to TGCT (in the manner of BRCA1 for breast cancer). Instead, familial risk of TGCT is likely to be due to varying dosages of hundreds of minor genetic factors..
Berntsson, S.G.
Merrell, R.T.
Amirian, E.S.
Armstrong, G.N.
Lachance, D.
Smits, A.
Zhou, R.
Jacobs, D.I.
Wrensch, M.R.
Olson, S.H.
Il'yasova, D.
Claus, E.B.
Barnholtz-Sloan, J.S.
Schildkraut, J.
Sadetzki, S.
Johansen, C.
Houlston, R.S.
Jenkins, R.B.
Bernstein, J.L.
Lai, R.
Shete, S.
Amos, C.I.
Bondy, M.L.
Melin, B.S.
(2018). Glioma-related seizures in relation to histopathological subtypes: a report from the glioma international case-control study. Journal of neurology,
Vol.265
(6),
pp. 1432-1442.
show abstract
BACKGROUND:The purpose of this study was to evaluate the distribution of glioma-related seizures and seizure control at the time of tumor diagnosis with respect to tumor histologic subtypes, tumor treatment and patient characteristics, and to compare seizure history preceding tumor diagnosis (or study enrollment) between glioma patients and healthy controls. METHODS:The Glioma International Case Control study (GICC) risk factor questionnaire collected information on demographics, past medical/medication history, and occupational history. Cases from eight centers were also asked detailed questions on seizures in relation to glioma diagnosis; cases (n = 4533) and controls (n = 4171) were also asked about seizures less than 2 years from diagnosis and previous seizure history more than 2 years prior to tumor diagnosis, including childhood seizures. RESULTS:Low-grade gliomas (LGGs), particularly oligodendrogliomas/oligoastrocytomas, had the highest proportion of glioma-related seizures. Patients with low-grade astrocytoma demonstrated the most medically refractory seizures. A total of 83% of patients were using only one antiepileptic drug (AED), which was levetiracetam in 71% of cases. Gross total resection was strongly associated with reduced seizure frequency (p < 0.009). No significant difference was found between glioma cases and controls in terms of seizure occurring more than 2 years before diagnosis or during childhood. CONCLUSIONS:Our study showed that glioma-related seizures were most common in low-grade gliomas. Gross total resection was associated with lower seizure frequency. Additionally, having a history of childhood seizures is not a risk factor ***for developing glioma-related seizures or glioma..
Li, Y.
Xiao, X.
Han, Y.
Gorlova, O.
Qian, D.
Leighl, N.
Johansen, J.S.
Barnett, M.
Chen, C.
Goodman, G.
Cox, A.
Taylor, F.
Woll, P.
Wichmann, H.-.
Manz, J.
Muley, T.
Risch, A.
Rosenberger, A.
Arnold, S.M.
Haura, E.B.
Bolca, C.
Holcatova, I.
Janout, V.
Kontic, M.
Lissowska, J.
Mukeria, A.
Ognjanovic, S.
Orlowski, T.M.
Scelo, G.
Swiatkowska, B.
Zaridze, D.
Bakke, P.
Skaug, V.
Zienolddiny, S.
Duell, E.J.
Butler, L.M.
Houlston, R.
Soler Artigas, M.
Grankvist, K.
Johansson, M.
Shepherd, F.A.
Marcus, M.W.
Brunnström, H.
Manjer, J.
Melander, O.
Muller, D.C.
Overvad, K.
Trichopoulou, A.
Tumino, R.
Liu, G.
Bojesen, S.E.
Wu, X.
Marchand, L.L.
Albanes, D.
Bickeböller, H.
Aldrich, M.C.
Bush, W.S.
Tardon, A.
Rennert, G.
Teare, M.D.
Field, J.K.
Kiemeney, L.A.
Lazarus, P.
Haugen, A.
Lam, S.
Schabath, M.B.
Andrew, A.S.
Bertazzi, P.A.
Pesatori, A.C.
Christiani, D.C.
Caporaso, N.
Johansson, M.
McKay, J.D.
Brennan, P.
Hung, R.J.
Amos, C.I.
(2018). Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population. Carcinogenesis,
Vol.39
(3),
pp. 336-346.
Chattopadhyay, S.
Zheng, G.
Sud, A.
Yu, H.
Sundquist, K.
Sundquist, J.
Försti, A.
Hemminki, A.
Houlston, R.
Hemminki, K.
(2018). Risk of second primary cancer following myeloid neoplasia and risk of myeloid neoplasia as second primary cancer: a nationwide, observational follow up study in Sweden. The lancet. haematology,
Vol.5
(8),
pp. e368-e377.
show abstract
Background Although advances in the treatment of myeloid neoplasms have led to improved patient survival, this improvement has been accompanied by an increased risk of second primary cancer (ie, the risk of another cancer after myeloid neoplasia). We aimed to assess bi-directional associations between myeloid cancers and other cancers-ie, development of second primary cancer in patients who have previously had myeloid cancer, and risks of myeloid neoplasia in patients who have previously had another cancer-to provide insight into possible mechanisms beyond side-effects of treatment and shared risk factors.Methods Using the Swedish Family-Cancer Database, we identified 35 928 individuals with primary myeloid cancer, including myeloproliferative neoplasms, acute myeloid leukaemia, chronic myeloid leukaemia, and myelodysplastic syndrome diagnosed between 1958 and 2015. The Swedish Family-Cancer Database includes every individual registered as a resident in Sweden starting in 1932, with full parental history. The primary endpoint was the assessment of relative risks (RRs) for second primary cancer, which we performed using means of incidence rate ratios, regressed over a generalised Poisson model.Findings Between 1958 and 2015, overall relative risk of second primary cancers was significantly increased after acute myeloid leukaemia (RR 1·29, 95% CI 1·17-1·41), chronic myeloid leukaemia (1·52, 1·35-1·69), myelodysplastic syndrome (1·42, 1·26-1·59), and all myeloproliferative neoplasms (1·37, 1·30-1·43) relative to the incidence of these cancers as first primary cancer. With myeloid neoplasia as a second primary cancer, risks were significantly increased for acute myeloid leukaemia (1·57, 1·48-1·65), chronic myeloid leukaemia (1·26, 1·13-1·40), and myelodysplastic syndrome (1·54, 1·42-1·67) relative to the incidence of these myeloid neoplasms as first primary cancers. Relative risk of upper aerodigestive tract cancer, squamous cell skin cancer, and non-Hodgkin lymphoma as second primary cancers were increased after all four types of myeloid neoplasia relative to their incidence as first primary cancers. High risks of myelodysplastic syndrome and acute myeloid leukaemia as second primary cancers were found after haematological cancers (RRs between 5·08 and 10·04).Interpretation The relative risks of second primary cancer are important for the long-term management of patients with myeloid cancers. The bi-directional associations of myeloid cancers with many other cancers suggest a number of candidate mechanisms that might contribute to the development and aetiology of a second primary cancer. These mechanisms might include immune dysfunction or the effects of treatment, and these should be assessed in future investigations.Funding Deutsche Krebshilfe, Jane and Aatos Erkko Foundation, Sigrid Juselius Foundation, Finnish Cancer Organizations, Swedish Research Council, ALF from Region Skåne, and Bloodwise..
Sud, A.
Chattopadhyay, S.
Thomsen, H.
Sundquist, K.
Sundquist, J.
Houlston, R.S.
Hemminki, K.
(2018). Familial risks of acute myeloid leukemia, myelodysplastic syndromes, and myeloproliferative neoplasms. Blood,
Vol.132
(9),
pp. 973-976.
Vijayakrishnan, J.
Studd, J.
Broderick, P.
Kinnersley, B.
Holroyd, A.
Law, P.J.
Kumar, R.
Allan, J.M.
Harrison, C.J.
Moorman, A.V.
Vora, A.
Roman, E.
Rachakonda, S.
Kinsey, S.E.
Sheridan, E.
Thompson, P.D.
Irving, J.A.
Koehler, R.
Hoffmann, P.
Nöthen, M.M.
Heilmann-Heimbach, S.
Jöckel, K.-.
Easton, D.F.
Pharaoh, P.D.
Dunning, A.M.
Peto, J.
Canzian, F.
Swerdlow, A.
Eeles, R.A.
Kote-Jarai, Z.
Muir, K.
Pashayan, N.
PRACTICAL Consortium,
Greaves, M.
Zimmerman, M.
Bartram, C.R.
Schrappe, M.
Stanulla, M.
Hemminki, K.
Houlston, R.S.
(2018). Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia. Nature communications,
Vol.9
(1),
pp. 1340-?.
show abstract
Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10-9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10-8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology..
Ostrom, Q.T.
Kinnersley, B.
Wrensch, M.R.
Eckel-Passow, J.E.
Armstrong, G.
Rice, T.
Chen, Y.
Wiencke, J.K.
McCoy, L.S.
Hansen, H.M.
Amos, C.I.
Bernstein, J.L.
Claus, E.B.
Il'yasova, D.
Johansen, C.
Lachance, D.H.
Lai, R.K.
Merrell, R.T.
Olson, S.H.
Sadetzki, S.
Schildkraut, J.M.
Shete, S.
Rubin, J.B.
Lathia, J.D.
Berens, M.E.
Andersson, U.
Rajaraman, P.
Chanock, S.J.
Linet, M.S.
Wang, Z.
Yeager, M.
GliomaScan consortium,
Houlston, R.S.
Jenkins, R.B.
Melin, B.
Bondy, M.L.
Barnholtz-Sloan, J.S.
(2018). Sex-specific glioma genome-wide association study identifies new risk locus at 3p21 31 in females, and finds sex-differences in risk at 8q24 21. Scientific reports,
Vol.8
(1),
pp. 7352-?.
show abstract
Incidence of glioma is approximately 50% higher in males. Previous analyses have examined exposures related to sex hormones in women as potential protective factors for these tumors, with inconsistent results. Previous glioma genome-wide association studies (GWAS) have not stratified by sex. Potential sex-specific genetic effects were assessed in autosomal SNPs and sex chromosome variants for all glioma, GBM and non-GBM patients using data from four previous glioma GWAS. Datasets were analyzed using sex-stratified logistic regression models and combined using meta-analysis. There were 4,831 male cases, 5,216 male controls, 3,206 female cases and 5,470 female controls. A significant association was detected at rs11979158 (7p11.2) in males only. Association at rs55705857 (8q24.21) was stronger in females than in males. A large region on 3p21.31 was identified with significant association in females only. The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex..
Loveday, C.
Law, P.
Litchfield, K.
Levy, M.
Holroyd, A.
Broderick, P.
Kote-Jarai, Z.
Dunning, A.M.
Muir, K.
Peto, J.
Eeles, R.
Easton, D.F.
Dudakia, D.
Orr, N.
Pashayan, N.
UK Testicular Cancer Collaboration, T.H.
Reid, A.
Huddart, R.A.
Houlston, R.S.
Turnbull, C.
(2018). Large-scale Analysis Demonstrates Familial Testicular Cancer to have Polygenic Aetiology. European urology,
Vol.74
(3),
pp. 248-252.
show abstract
Testicular germ cell tumour (TGCT) is the most common cancer in young men. Multiplex TGCT families have been well reported and analyses of population cancer registries have demonstrated a four- to eightfold risk to male relatives of TGCT patients. Early linkage analysis and recent large-scale germline exome analysis in TGCT cases demonstrate absence of major high-penetrance TGCT susceptibility gene(s). Serial genome-wide association study analyses in sporadic TGCT have in total reported 49 independent risk loci. To date, it has not been demonstrated whether familial TGCT arises due to enrichment of the same common variants underpinning susceptibility to sporadic TGCT or is due to shared environmental/lifestyle factors or disparate rare genetic TGCT susceptibility factors. Here we present polygenic risk score analysis of 37 TGCT susceptibility single-nucleotide polymorphisms in 236 familial and 3931 sporadic TGCT cases, and 12 368 controls, which demonstrates clear enrichment for TGCT susceptibility alleles in familial compared to sporadic cases (p=0.0001), with the majority of familial cases (84-100%) being attributable to polygenic enrichment. These analyses reveal TGCT as the first rare malignancy of early adulthood in which familial clustering is driven by the aggregate effects of polygenic variation in the absence of a major high-penetrance susceptibility gene.Patient summary To date, it has been unclear whether familial clusters of testicular germ cell tumour (TGCT) arise due to genetics or shared environmental or lifestyle factors. We present large-scale genetic analyses comparing 236 familial TGCT cases, 3931 isolated TGCT cases, and 12 368 controls. We show that familial TGCT is caused, at least in part, by presence of a higher dose of the same common genetic variants that cause susceptibility to TGCT in general..
Turnbull, C.
Sud, A.
Houlston, R.S.
(2018). Cancer genetics, precision prevention and a call to action. Nature genetics,
Vol.50
(9),
pp. 1212-1218.
show abstract
More than 15 years have passed since the identification, through linkage, of 'first-wave' susceptibility genes for common cancers (BRCA1, BRCA2, MLH1 and MSH2). These genes have strong frequency-penetrance profiles, such that the associated clinical utility probably remains relevant regardless of the context of ascertainment. 'Second-wave' genes, not tractable by linkage, were subsequently identified by mutation screening of candidate genes (PALB2, ATM, CHEK2, BRIP1, RAD51C and RAD51D). Their innately weaker frequency-penetrance profiles have rendered delineation of cancer associations, risks and variant pathogenicity challenging, thereby compromising their clinical application. Early germline exome-sequencing endeavors for common cancers did not yield the long-anticipated slew of 'next-wave' genes but instead implied a highly polygenic genomic architecture requiring much larger experiments to make any substantive inroads into gene discovery. As such, the 'genetic economics' of frequency penetrance clearly indicates that focused identification of carriers of first-wave-gene mutations is most impactful for cancer control. With screening, prevention and early detection at the forefront of the cancer management agenda, we propose that the time is nigh for the initiation of national population-testing programs to identify carriers of first-wave gene mutation carriers. To fully deliver a precision prevention program, long-term, large-scale mutation studies that capture longitudinal clinical data and serial biosamples are required..
Claus, E.B.
Cornish, A.J.
Broderick, P.
Schildkraut, J.M.
Dobbins, S.E.
Holroyd, A.
Calvocoressi, L.
Lu, L.
Hansen, H.M.
Smirnov, I.
Walsh, K.M.
Schramm, J.
Hoffmann, P.
Nöthen, M.M.
Jöckel, K.-.
Swerdlow, A.
Larsen, S.B.
Johansen, C.
Simon, M.
Bondy, M.
Wrensch, M.
Houlston, R.S.
Wiemels, J.L.
(2018). Genome-wide association analysis identifies a meningioma risk locus at 11p15 5. Neuro-oncology,
Vol.20
(11),
pp. 1485-1493.
show abstract
Background Meningiomas are adult brain tumors originating in the meningeal coverings of the brain and spinal cord, with significant heritable basis. Genome-wide association studies (GWAS) have previously identified only a single risk locus for meningioma, at 10p12.31.Methods To identify a susceptibility locus for meningioma, we conducted a meta-analysis of 2 GWAS, imputed using a merged reference panel from the 1000 Genomes Project and UK10K data, with validation in 2 independent sample series totaling 2138 cases and 12081 controls.Results We identified a new susceptibility locus for meningioma at 11p15.5 (rs2686876, odds ratio = 1.44, P = 9.86 × 10-9). A number of genes localize to the region of linkage disequilibrium encompassing rs2686876, including RIC8A, which plays a central role in the development of neural crest-derived structures, such as the meninges.Conclusions This finding advances our understanding of the genetic basis of meningioma development and provides additional support for a polygenic model of meningioma..
Orlando, G.
Law, P.J.
Cornish, A.J.
Dobbins, S.E.
Chubb, D.
Broderick, P.
Litchfield, K.
Hariri, F.
Pastinen, T.
Osborne, C.S.
Taipale, J.
Houlston, R.S.
(2018). Promoter capture Hi-C-based identification of recurrent noncoding mutations in colorectal cancer. Nature genetics,
Vol.50
(10),
pp. 1375-1380.
show abstract
Efforts are being directed to systematically analyze the non-coding regions of the genome for cancer-driving mutations 1-6 . cis-regulatory elements (CREs) represent a highly enriched subset of the non-coding regions of the genome in which to search for such mutations. Here we use high-throughput chromosome conformation capture techniques (Hi-C) for 19,023 promoter fragments to catalog the regulatory landscape of colorectal cancer in cell lines, mapping CREs and integrating these with whole-genome sequence and expression data from The Cancer Genome Atlas 7,8 . We identify a recurrently mutated CRE interacting with the ETV1 promoter affecting gene expression. ETV1 expression influences cell viability and is associated with patient survival. We further refine our understanding of the regulatory effects of copy-number variations, showing that RASL11A is targeted by a previously identified enhancer amplification 1 . This study reveals new insights into the complex genetic alterations driving tumor development, providing a paradigm for employing chromosome conformation capture to decipher non-coding CREs relevant to cancer biology..
Chattopadhyay, S.
Sud, A.
Zheng, G.
Yu, H.
Sundquist, K.
Sundquist, J.
Försti, A.
Houlston, R.
Hemminki, A.
Hemminki, K.
(2018). Second primary cancers in non-Hodgkin lymphoma: Bidirectional analyses suggesting role for immune dysfunction. International journal of cancer,
Vol.143
(10),
pp. 2449-2457.
show abstract
Second primary cancers (SPCs) account for an increasing proportion of all cancer diagnoses. It is unlikely that prior therapy is solely responsible for SPC risk. To investigate risk of SPC after diagnosis of non-Hodgkin lymphoma (NHL) and 10 of its subtypes we conducted a novel bidirectional analysis, SPCs after NHL and NHL as SPC. Using the Swedish Family-Cancer Database, we identified 19,833 individuals with primary NHL diagnosed between 1993 and 2015. We calculated relative risks (RRs) of SPCs in NHL survivors and, for bi-directional analysis, risk of NHL as SPC. The overall RRs were significantly bidirectionally increased for NHL and 7 cancers. After diagnosis of NHL risks were increased for upper aerodigestive tract (RR = 1.96), colorectal (1.35), kidney (3.10), bladder (1.54) and squamous cell skin cancer (SCC) (4.12), melanoma (1.98) and Hodgkin lymphoma (9.38). The concordance between RRs for each bidirectional association between NHL and 31 different cancers was highly significant (r = 0.86, p < 0.0001). Melanoma was bidirectionally associated with all 10 subtypes of NHL. The observed bidirectional associations between NHL and cancer suggest that therapy-related carcinogenic mechanisms cannot solely explain the findings. Considering that skin SCC and melanoma are usually treated by surgery and that these cancers and NHL are most responsive of any cancer to immune suppression, the consistent bidirectional results provide population-level evidence that immune suppressed state is a key underlying mechanism in the context of SPCs. Furthermore, the quantified risks for NHL subtypes have direct clinical application in the management of NHL patients..
Ostrom, Q.T.
Kinnersley, B.
Armstrong, G.
Rice, T.
Chen, Y.
Wiencke, J.K.
McCoy, L.S.
Hansen, H.M.
Amos, C.I.
Bernstein, J.L.
Claus, E.B.
Eckel-Passow, J.E.
Il'yasova, D.
Johansen, C.
Lachance, D.H.
Lai, R.K.
Merrell, R.T.
Olson, S.H.
Sadetzki, S.
Schildkraut, J.M.
Shete, S.
Rubin, J.B.
Andersson, U.
Rajaraman, P.
Chanock, S.J.
Linet, M.S.
Wang, Z.
Yeager, M.
GliomaScan consortium,
Houlston, R.S.
Jenkins, R.B.
Wrensch, M.R.
Melin, B.
Bondy, M.L.
Barnholtz-Sloan, J.S.
(2018). Age-specific genome-wide association study in glioblastoma identifies increased proportion of 'lower grade glioma'-like features associated with younger age. International journal of cancer,
Vol.143
(10),
pp. 2359-2366.
show abstract
Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age-at-diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age-at-diagnosis has been explored, genome-wide association studies (GWAS) have not previously been stratified by age. Potential age-specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18-53, 54-64, 65+) datasets were analyzed using age-stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta-analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p 54-63 = 1.50x10 -9 , OR 54-63 = 1.28, 95%CI 54-63 = 1.18-1.39; p 64+ = 2.14x10 -11 , OR 64+ = 1.32, 95%CI 64+ = 1.21-1.43] and rs11979158 [p 54-63 = 6.13x10 -8 , OR 54-63 = 1.35, 95%CI 54-63 = 1.21-1.50; p 64+ = 2.18x10 -10 , OR 64+ = 1.42, 95%CI 64+ = 1.27-1.58]) but only in persons >54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18-53 (p 18-53 = 9.30 × 10 -11 , OR 18-53 = 1.76, 95%CI 18-53 = 1.49-2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of 'LGG'-like tumor characteristics in GBM samples in those 18-53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54-63] and 0.8% [64+] (p = 0.0005). Age-specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18-53 suggests that more younger individuals may present initially with 'secondary glioblastoma.'.
Sud, A.
Thomsen, H.
Orlando, G.
Försti, A.
Law, P.J.
Broderick, P.
Cooke, R.
Hariri, F.
Pastinen, T.
Easton, D.F.
Pharoah, P.D.
Dunning, A.M.
Peto, J.
Canzian, F.
Eeles, R.
Kote-Jarai, Z.
Muir, K.
Pashayan, N.
Campa, D.
PRACTICAL Consortium,
Hoffmann, P.
Nöthen, M.M.
Jöckel, K.-.
von Strandmann, E.P.
Swerdlow, A.J.
Engert, A.
Orr, N.
Hemminki, K.
Houlston, R.S.
(2018). Genome-wide association study implicates immune dysfunction in the development of Hodgkin lymphoma. Blood,
Vol.132
(19),
pp. 2040-2052.
show abstract
To further our understanding of inherited susceptibility to Hodgkin lymphoma (HL), we performed a meta-analysis of 7 genome-wide association studies totaling 5325 HL cases and 22 423 control patients. We identify 5 new HL risk loci at 6p21.31 (rs649775; P = 2.11 × 10-10), 6q23.3 (rs1002658; P = 2.97 × 10-8), 11q23.1 (rs7111520; P = 1.44 × 10-11), 16p11.2 (rs6565176; P = 4.00 × 10-8), and 20q13.12 (rs2425752; P = 2.01 × 10-8). Integration of gene expression, histone modification, and in situ promoter capture Hi-C data at the 5 new and 13 known risk loci implicates dysfunction of the germinal center reaction, disrupted T-cell differentiation and function, and constitutive NF-κB activation as mechanisms of predisposition. These data provide further insights into the genetic susceptibility and biology of HL..
Hoang, P.H.
Dobbins, S.E.
Cornish, A.J.
Chubb, D.
Law, P.J.
Kaiser, M.
Houlston, R.S.
(2018). Whole-genome sequencing of multiple myeloma reveals oncogenic pathways are targeted somatically through multiple mechanisms. Leukemia,
Vol.32
(11),
pp. 2459-2470.
Kinnersley, B.
Sud, A.
Coker, E.A.
Tym, J.E.
Di Micco, P.
Al-Lazikani, B.
Houlston, R.S.
(2018). Leveraging Human Genetics to Guide Cancer Drug Development. Jco clinical cancer informatics,
Vol.2,
pp. 1-11.
show abstract
Purpose The high attrition rate of cancer drug development programs is a barrier to realizing the promise of precision oncology. We have examined whether the genetic insights from genome-wide association studies of cancer can guide drug development and repurposing in oncology.Materials and methods Across 37 cancers, we identified 955 genetic risk variants from the National Human Genome Research Institute-European Bioinformatics Institute genome-wide association study catalog. We linked these variants to target genes using strategies that were based on linkage disequilibrium, DNA three-dimensional structure, and integration of predicted gene function and expression. With the use of the Informa Pharmaprojects database, we identified genes that are targets of unique drugs and assessed the level of enrichment that would be afforded by incorporation of genetic information in preclinical and phase II studies. For targets not under development, we implemented machine learning approaches to assess druggability.Results For all preclinical targets incorporating genetic information, a 2.00-fold enrichment of a drug being successfully approved could be achieved (95% CI, 1.14- to 3.48-fold; P = .02). For phase II targets, a 2.75-fold enrichment could be achieved (95% CI, 1.42- to 5.35-fold; P < .001). Application of genetic information suggests potential repurposing of 15 approved nononcology drugs.Conclusion The findings illustrate the value of using insights from the genetics of inherited cancer susceptibility discovery projects as part of a data-driven strategy to inform drug discovery. Support for cancer germline genetic information for prospective targets is available online from the Institute of Cancer Research..
Shah, V.
Johnson, D.C.
Sherborne, A.L.
Ellis, S.
Aldridge, F.M.
Howard-Reeves, J.
Begum, F.
Price, A.
Kendall, J.
Chiecchio, L.
Savola, S.
Jenner, M.W.
Drayson, M.T.
Owen, R.G.
Gregory, W.M.
Morgan, G.J.
Davies, F.E.
Houlston, R.S.
Cook, G.
Cairns, D.A.
Jackson, G.
Kaiser, M.F.
National Cancer Research Institute Haematology Clinical Studies Group,
(2018). Subclonal TP53 copy number is associated with prognosis in multiple myeloma. Blood,
Vol.132
(23),
pp. 2465-2469.
show abstract
Multiple myeloma (MM) is a genetically heterogeneous cancer of bone marrow plasma cells with variable outcome. To assess the prognostic relevance of clonal heterogeneity of TP53 copy number, we profiled tumors from 1777 newly diagnosed Myeloma XI trial patients with multiplex ligation-dependent probe amplification (MLPA). Subclonal TP53 deletions were independently associated with shorter overall survival, with a hazard ratio of 1.8 (95% confidence interval, 1.2-2.8; P = .01). Clonal, but not subclonal, TP53 deletions were associated with clinical markers of advanced disease, specifically lower platelet counts ( P < .001) and increased lactate dehydrogenase ( P < .001), as well as a higher frequency of features indicative of genomic instability, del(13q) ( P = .002) or del(1p) ( P = .006). Biallelic TP53 loss-of-function by mutation and deletion was rare (2.4%) and associated with advanced disease. We present a framework for identifying subclonal TP53 deletions by MLPA, to improve patient stratification in MM and tailor therapy, enabling management strategies..
Went, M.
Sud, A.
Försti, A.
Halvarsson, B.-.
Weinhold, N.
Kimber, S.
van Duin, M.
Thorleifsson, G.
Holroyd, A.
Johnson, D.C.
Li, N.
Orlando, G.
Law, P.J.
Ali, M.
Chen, B.
Mitchell, J.S.
Gudbjartsson, D.F.
Kuiper, R.
Stephens, O.W.
Bertsch, U.
Broderick, P.
Campo, C.
Bandapalli, O.R.
Einsele, H.
Gregory, W.A.
Gullberg, U.
Hillengass, J.
Hoffmann, P.
Jackson, G.H.
Jöckel, K.-.
Johnsson, E.
Kristinsson, S.Y.
Mellqvist, U.-.
Nahi, H.
Easton, D.
Pharoah, P.
Dunning, A.
Peto, J.
Canzian, F.
Swerdlow, A.
Eeles, R.A.
Kote-Jarai, Z.
Muir, K.
Pashayan, N.
Nickel, J.
Nöthen, M.M.
Rafnar, T.
Ross, F.M.
da Silva Filho, M.I.
Thomsen, H.
Turesson, I.
Vangsted, A.
Andersen, N.F.
Waage, A.
Walker, B.A.
Wihlborg, A.-.
Broyl, A.
Davies, F.E.
Thorsteinsdottir, U.
Langer, C.
Hansson, M.
Goldschmidt, H.
Kaiser, M.
Sonneveld, P.
Stefansson, K.
Morgan, G.J.
Hemminki, K.
Nilsson, B.
Houlston, R.S.
PRACTICAL consortium,
(2018). Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma. Nature communications,
Vol.9
(1),
pp. 3707-?.
show abstract
Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM..
Ji, X.
Bossé, Y.
Landi, M.T.
Gui, J.
Xiao, X.
Qian, D.
Joubert, P.
Lamontagne, M.
Li, Y.
Gorlov, I.
de Biasi, M.
Han, Y.
Gorlova, O.
Hung, R.J.
Wu, X.
McKay, J.
Zong, X.
Carreras-Torres, R.
Christiani, D.C.
Caporaso, N.
Johansson, M.
Liu, G.
Bojesen, S.E.
Le Marchand, L.
Albanes, D.
Bickeböller, H.
Aldrich, M.C.
Bush, W.S.
Tardon, A.
Rennert, G.
Chen, C.
Teare, M.D.
Field, J.K.
Kiemeney, L.A.
Lazarus, P.
Haugen, A.
Lam, S.
Schabath, M.B.
Andrew, A.S.
Shen, H.
Hong, Y.-.
Yuan, J.-.
Bertazzi, P.A.
Pesatori, A.C.
Ye, Y.
Diao, N.
Su, L.
Zhang, R.
Brhane, Y.
Leighl, N.
Johansen, J.S.
Mellemgaard, A.
Saliba, W.
Haiman, C.
Wilkens, L.
Fernandez-Somoano, A.
Fernandez-Tardon, G.
van der Heijden, E.H.
Kim, J.H.
Dai, J.
Hu, Z.
Davies, M.P.
Marcus, M.W.
Brunnström, H.
Manjer, J.
Melander, O.
Muller, D.C.
Overvad, K.
Trichopoulou, A.
Tumino, R.
Doherty, J.
Goodman, G.E.
Cox, A.
Taylor, F.
Woll, P.
Brüske, I.
Manz, J.
Muley, T.
Risch, A.
Rosenberger, A.
Grankvist, K.
Johansson, M.
Shepherd, F.
Tsao, M.-.
Arnold, S.M.
Haura, E.B.
Bolca, C.
Holcatova, I.
Janout, V.
Kontic, M.
Lissowska, J.
Mukeria, A.
Ognjanovic, S.
Orlowski, T.M.
Scelo, G.
Swiatkowska, B.
Zaridze, D.
Bakke, P.
Skaug, V.
Zienolddiny, S.
Duell, E.J.
Butler, L.M.
Koh, W.-.
Gao, Y.-.
Houlston, R.
McLaughlin, J.
Stevens, V.
Nickle, D.C.
Obeidat, M.
Timens, W.
Zhu, B.
Song, L.
Artigas, M.S.
Tobin, M.D.
Wain, L.V.
Gu, F.
Byun, J.
Kamal, A.
Zhu, D.
Tyndale, R.F.
Wei, W.-.
Chanock, S.
Brennan, P.
Amos, C.I.
(2018). Identification of susceptibility pathways for the role of chromosome 15q25 1 in modifying lung cancer risk. Nature communications,
Vol.9
(1),
pp. 3221-?.
show abstract
Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer..
He, Y.
Timofeeva, M.
Farrington, S.M.
Vaughan-Shaw, P.
Svinti, V.
Walker, M.
Zgaga, L.
Meng, X.
Li, X.
Spiliopoulou, A.
Jiang, X.
Hyppönen, E.
Kraft, P.
Kiel, D.P.
SUNLIGHT consortium,
Hayward, C.
Campbell, A.
Porteous, D.
Vucic, K.
Kirac, I.
Filipovic, M.
Harris, S.E.
Deary, I.J.
Houlston, R.
Tomlinson, I.P.
Campbell, H.
Theodoratou, E.
Dunlop, M.G.
(2018). Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study. Bmc medicine,
Vol.16
(1),
pp. 142-?.
show abstract
BACKGROUND:Whilst observational studies establish that lower plasma 25-hydroxyvitamin D (25-OHD) levels are associated with higher risk of colorectal cancer (CRC), establishing causality has proven challenging. Since vitamin D is modifiable, these observations have substantial clinical and public health implications. Indeed, many health agencies already recommend supplemental vitamin D. Here, we explore causality in a large Mendelian randomisation (MR) study using an improved genetic instrument for circulating 25-OHD. METHODS:We developed a weighted genetic score for circulating 25-OHD using six genetic variants that we recently reported to be associated with circulating 25-OHD in a large genome-wide association study (GWAS) meta-analysis. Using this score as instrumental variable in MR analyses, we sought to determine whether circulating 25-OHD is causally linked with CRC risk. We conducted MR analysis using individual-level data from 10,725 CRC cases and 30,794 controls (Scotland, UK Biobank and Croatia). We then applied estimates from meta-analysis of 11 GWAS of CRC risk (18,967 cases; 48,168 controls) in a summary statistics MR approach. RESULTS:The new genetic score for 25-OHD was strongly associated with measured plasma 25-OHD levels in 2821 healthy Scottish controls (P = 1.47 × 10- 11), improving upon previous genetic instruments (F-statistic 46.0 vs. 13.0). However, individual-level MR revealed no association between 25-OHD score and CRC risk (OR 1.03/unit log-transformed circulating 25-OHD, 95% CI 0.51-2.07, P = 0.93). Similarly, we found no evidence for a causal relationship between 25-OHD and CRC risk using summary statistics MR analysis (OR 0.91, 95% CI 0.69-1.19, P = 0.48). CONCLUSIONS:Despite the scale of this study and employing an improved score capturing more of the genetic contribution to circulating 25-OHD, we found no evidence for a causal relationship between circulating 25-OHD and CRC risk. Although the magnitude of effect for vitamin D suggested by observational studies can confidently be excluded, smaller effects sizes and non-linear relationships remain plausible. Circulating vitamin D may be a CRC biomarker, but a causal effect on CRC risk remains unproven..
Disney-Hogg, L.
Cornish, A.J.
Sud, A.
Law, P.J.
Kinnersley, B.
Jacobs, D.I.
Ostrom, Q.T.
Labreche, K.
Eckel-Passow, J.E.
Armstrong, G.N.
Claus, E.B.
Il'yasova, D.
Schildkraut, J.
Barnholtz-Sloan, J.S.
Olson, S.H.
Bernstein, J.L.
Lai, R.K.
Schoemaker, M.J.
Simon, M.
Hoffmann, P.
Nöthen, M.M.
Jöckel, K.-.
Chanock, S.
Rajaraman, P.
Johansen, C.
Jenkins, R.B.
Melin, B.S.
Wrensch, M.R.
Sanson, M.
Bondy, M.L.
Houlston, R.S.
(2018). Impact of atopy on risk of glioma: a Mendelian randomisation study. Bmc medicine,
Vol.16
(1),
pp. 42-?.
show abstract
Background An inverse relationship between allergies with glioma risk has been reported in several but not all epidemiological observational studies. We performed an analysis of genetic variants associated with atopy to assess the relationship with glioma risk using Mendelian randomisation (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.Methods Two-sample MR was undertaken using genome-wide association study data. We used single nucleotide polymorphisms (SNPs) associated with atopic dermatitis, asthma and hay fever, IgE levels, and self-reported allergy as instrumental variables. We calculated MR estimates for the odds ratio (OR) for each risk factor with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighting (IVW), maximum likelihood estimation (MLE), weighted median estimate (WME) and mode-based estimate (MBE) methods. Violation of MR assumptions due to directional pleiotropy were sought using MR-Egger regression and HEIDI-outlier analysis.Results Under IVW, MLE, WME and MBE methods, associations between glioma risk with asthma and hay fever, self-reported allergy and IgE levels were non-significant. An inverse relationship between atopic dermatitis and glioma risk was found by IVW (OR 0.96, 95% confidence interval (CI) 0.93-1.00, P = 0.041) and MLE (OR 0.96, 95% CI 0.94-0.99, P = 0.003), but not by WME (OR 0.96, 95% CI 0.91-1.01, P = 0.114) or MBE (OR 0.97, 95% CI 0.92-1.02, P = 0.194).Conclusions Our investigation does not provide strong evidence for relationship between atopy and the risk of developing glioma, but findings do not preclude a small effect in relation to atopic dermatitis. Our analysis also serves to illustrate the value of using several MR methods to derive robust conclusions..
Went, M.
Sud, A.
Speedy, H.
Sunter, N.J.
Försti, A.
Law, P.J.
Johnson, D.C.
Mirabella, F.
Holroyd, A.
Li, N.
Orlando, G.
Weinhold, N.
van Duin, M.
Chen, B.
Mitchell, J.S.
Mansouri, L.
Juliusson, G.
Smedby, K.E.
Jayne, S.
Majid, A.
Dearden, C.
Allsup, D.J.
Bailey, J.R.
Pratt, G.
Pepper, C.
Fegan, C.
Rosenquist, R.
Kuiper, R.
Stephens, O.W.
Bertsch, U.
Broderick, P.
Einsele, H.
Gregory, W.M.
Hillengass, J.
Hoffmann, P.
Jackson, G.H.
Jöckel, K.-.
Nickel, J.
Nöthen, M.M.
da Silva Filho, M.I.
Thomsen, H.
Walker, B.A.
Broyl, A.
Davies, F.E.
Hansson, M.
Goldschmidt, H.
Dyer, M.J.
Kaiser, M.
Sonneveld, P.
Morgan, G.J.
Hemminki, K.
Nilsson, B.
Catovsky, D.
Allan, J.M.
Houlston, R.S.
(2018). Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology. Blood cancer journal,
Vol.9
(1),
pp. 1-?.
show abstract
The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (R g = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies..
Gu, F.
Zhang, H.
Hyland, P.L.
Berndt, S.
Gapstur, S.M.
Wheeler, W.
ELLIPSE consortium, T.
Amos, C.I.
Bezieau, S.
Bickeböller, H.
Brenner, H.
Brennan, P.
Chang-Claude, J.
Conti, D.V.
Doherty, J.A.
Gruber, S.B.
Harrison, T.A.
Hayes, R.B.
Hoffmeister, M.
Houlston, R.S.
Hung, R.J.
Jenkins, M.A.
Kraft, P.
Lawrenson, K.
McKay, J.
Markt, S.
Mucci, L.
Phelan, C.M.
Qu, C.
Risch, A.
Rossing, M.A.
Wichmann, H.-.
Shi, J.
Schernhammer, E.
Yu, K.
Landi, M.T.
Caporaso, N.E.
(2017). Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia. International journal of cancer,
Vol.141
(9),
pp. 1794-1802.
Broderick, P.
Dobbins, S.E.
Chubb, D.
Kinnersley, B.
Dunlop, M.G.
Tomlinson, I.
Houlston, R.S.
(2017). Validation of Recently Proposed Colorectal Cancer Susceptibility Gene Variants in an Analysis of Families and Patients-a Systematic Review. Gastroenterology,
Vol.152
(1),
pp. 75-77.e4.
show abstract
High-throughput sequencing analysis has accelerated searches for genes associated with risk for colorectal cancer (CRC); germline mutations in NTHL1, RPS20, FANCM, FAN1, TP53, BUB1, BUB3, LRP6, and PTPN12 have been recently proposed to increase CRC risk. We attempted to validate the association between variants in these genes and development of CRC in a systematic review of 11 publications, using sequence data from 863 familial CRC cases and 1604 individuals without CRC (controls). All cases were diagnosed at an age of 55 years or younger and did not carry mutations in an established CRC predisposition gene. We found sufficient evidence for NTHL1 to be considered a CRC predisposition gene-members of 3 unrelated Dutch families were homozygous for inactivating p.Gln90Ter mutations; a Canadian woman with polyposis, CRC, and multiple tumors was reported to be heterozygous for the inactivating NTHL1 p.Gln90Ter/c.709+1G>A mutations; and a man with polyposis was reported to carry p.Gln90Ter/p.Gln287Ter; whereas no inactivating homozygous or compound heterozygous mutations were detected in controls. Variants that disrupted RPS20 were detected in a Finnish family with early-onset CRC (p.Val50SerfsTer23), a 39-year old individual with metachronous CRC (p.Leu61GlufsTer11 mutation), and a 41-year-old individual with CRC (missense p.Val54Leu), but not in controls. We therefore found published evidence to support the association between variants in NTHL1 and RPS20 with CRC, but not of other recently reported CRC susceptibility variants. We urge the research community to adopt rigorous statistical and biological approaches coupled with independent replication before making claims of pathogenicity..
Macauda, A.
Calvetti, D.
Maccari, G.
Hemminki, K.
Försti, A.
Goldschmidt, H.
Weinhold, N.
Houlston, R.
Andersen, V.
Vogel, U.
Buda, G.
Varkonyi, J.
Sureda, A.
Martinez Lopez, J.
Watek, M.
Butrym, A.
Sarasquete, M.E.
Dudziński, M.
Jurczyszyn, A.
Druzd-Sitek, A.
Kruszewski, M.
Subocz, E.
Petrini, M.
Iskierka-Jażdżewska, E.
Raźny, M.
Szombath, G.
Marques, H.
Zawirska, D.
Chraniuk, D.
Halka, J.
Hove Jacobsen, S.E.
Mazur, G.
García Sanz, R.
Dumontet, C.
Moreno, V.
Stępień, A.
Beider, K.
Pelosini, M.
Manuel Reis, R.
Krawczyk-Kulis, M.
Rymko, M.
Avet-Loiseau, H.
Lesueur, F.
Grząśko, N.
Ostrovsky, O.
Jamroziak, K.
Vangsted, A.J.
Jerez, A.
Tomczak, W.
Zaucha, J.M.
Kadar, K.
Sainz, J.
Nagler, A.
Landi, S.
Gemignani, F.
Canzian, F.
(2017). Identification of miRSNPs associated with the risk of multiple myeloma. International journal of cancer,
Vol.140
(3),
pp. 526-534.
show abstract
Multiple myeloma (MM) is a malignancy of plasma cells usually infiltrating the bone marrow, associated with the production of a monoclonal immunoglobulin (M protein) which can be detected in the blood and/or urine. Multiple lines of evidence suggest that genetic factors are involved in MM pathogenesis, and several studies have identified single nucleotide polymorphisms (SNPs) associated with the susceptibility to the disease. SNPs within miRNA-binding sites in target genes (miRSNPs) may alter the strength of miRNA-mRNA interactions, thus deregulating protein expression. MiRSNPs are known to be associated with risk of various types of cancer, but they have never been investigated in MM. We performed an in silico genome-wide search for miRSNPs predicted to alter binding of miRNAs to their target sequences. We selected 12 miRSNPs and tested their association with MM risk. Our study population consisted of 1,832 controls and 2,894 MM cases recruited from seven European countries and Israel in the context of the IMMEnSE (International Multiple Myeloma rESEarch) consortium. In this population two SNPs showed an association with p < 0.05: rs286595 (located in gene MRLP22) and rs14191881 (located in gene TCF19). Results from IMMEnSE were meta-analyzed with data from a previously published genome-wide association study (GWAS). The SNPs rs13409 (located in the 3'UTR of the POU5F1 gene), rs1419881 (TCF19), rs1049633, rs1049623 (both in DDR1) showed significant associations with MM risk. In conclusion, we sought to identify genetic polymorphisms associated with MM risk starting from genome-wide prediction of miRSNPs. For some mirSNPs, we have shown promising associations with MM risk..
Vijayakrishnan, J.
Kumar, R.
Henrion, M.Y.
Moorman, A.V.
Rachakonda, P.S.
Hosen, I.
da Silva Filho, M.I.
Holroyd, A.
Dobbins, S.E.
Koehler, R.
Thomsen, H.
Irving, J.A.
Allan, J.M.
Lightfoot, T.
Roman, E.
Kinsey, S.E.
Sheridan, E.
Thompson, P.D.
Hoffmann, P.
Nöthen, M.M.
Heilmann-Heimbach, S.
Jöckel, K.H.
Greaves, M.
Harrison, C.J.
Bartram, C.R.
Schrappe, M.
Stanulla, M.
Hemminki, K.
Houlston, R.S.
(2017). A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26 13 and 12q23 1. Leukemia,
Vol.31
(3),
pp. 573-579.
show abstract
Genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of childhood acute lymphoblastic leukemia (ALL). To identify new susceptibility loci for the largest subtype of ALL, B-cell precursor ALL (BCP-ALL), we conducted a meta-analysis of two GWASs with imputation using 1000 Genomes and UK10K Project data as reference (totaling 1658 cases and 7224 controls). After genotyping an additional 2525 cases and 3575 controls, we identify new susceptibility loci for BCP-ALL mapping to 10q26.13 (rs35837782, LHPP, P=1.38 × 10 -11 ) and 12q23.1 (rs4762284, ELK3, P=8.41 × 10 -9 ). We also provide confirmatory evidence for the existence of independent risk loci at 9p21.3, but show that the association marked by rs77728904 can be accounted for by linkage disequilibrium with the rare high-impact CDKN2A p.Ala148Thr variant rs3731249. Our data provide further insights into genetic susceptibility to ALL and its biology..
Studd, J.B.
Vijayakrishnan, J.
Yang, M.
Migliorini, G.
Paulsson, K.
Houlston, R.S.
(2017). Genetic and regulatory mechanism of susceptibility to high-hyperdiploid acute lymphoblastic leukaemia at 10p21 2. Nature communications,
Vol.8,
pp. 14616-?.
show abstract
Despite high-hyperdiploid acute lymphoblastic leukaemia (HD-ALL) being the most common subgroup of paediatric ALL, its aetiology remains unknown. Genome-wide association studies have demonstrated association at 10q21.2. Here, we sought to determine how this region influences HD-ALL risk. We impute genotypes across the locus, finding the single nucleotide polymorphism rs7090445 highly associated with HD-ALL (P=1.54 × 10 -38 ), and residing in a predicted enhancer element. We show this region physically interacts with the transcription start site of ARID5B, that alleles of rs7090445 have differential enhancer activity and influence RUNX3 binding. RUNX3 knock-down reduces ARID5B expression and rs7090445 enhancer activity. Individuals carrying the rs7090445-C risk allele also have reduced ARID5B expression. Finally, the rs7090445-C risk allele is preferentially retained in HD-ALL blasts consistent with inherited genetic variation contributing to arrest of normal lymphocyte development, facilitating leukaemic clonal expansion. These data provide evidence for a biological mechanism underlying hereditary risk of HD-ALL at 10q21.2..
Frampton, M.
Houlston, R.S.
(2017). Modeling the prevention of colorectal cancer from the combined impact of host and behavioral risk factors. Genetics in medicine : official journal of the american college of medical genetics,
Vol.19
(3),
pp. 314-321.
show abstract
Purpose This study investigated the utility of modeling modifiable lifestyle risk factors in addition to genetic variation in colorectal cancer (CRC) screening/prevention.Methods We derived a polygenic risk score for CRC susceptibility variants in combination with the established nongenetic risk factors of inflammatory bowel disease (IBD), adiposity, alcohol, red meat, fruit, vegetables, smoking, physical activity, and aspirin. We used the 37 known risk variants and 50 and 100% of all risk variants as calculated from a heritability estimate. We derived absolute risk from UK population age structure, incidence, and mortality rate data.Results Taking into account all risk factors (known variants), 42.2% of 55- to 59-year-old men with CRC have a risk at least as high as that of an average 60-year-old, the minimum eligible age for the UK NHS National Bowel Cancer Screening Program. If the male population is stratified by known variants and IBD status, then risk-difference estimates imply that for 10,000 50-year-old men in the 99th percentile, 760 cases could be prevented over a 25-year period through the modifiable risk factors, but in the lowest percentile, only 90 could be prevented.Conclusion CRC screening and prevention centered on modifiable risk factors could be optimized if targeted at individuals at higher polygenic risk.Genet Med 19 3, 314-321..
Sud, A.
Hemminki, K.
Houlston, R.S.
(2017). Candidate gene association studies and risk of Hodgkin lymphoma: a systematic review and meta-analysis. Hematological oncology,
Vol.35
(1),
pp. 34-50.
show abstract
To evaluate the contribution of association studies of candidate polymorphisms to inherited predisposition to Hodgkin lymphoma (HL), we conducted a systematic review and meta-analysis of published case-control studies. Of the variants examined more than once in candidate gene association studies, we identified 21 studies that reported on 12 polymorphic variants in 10 genes. Data were also extracted from a published genome wide association study to allow analysis of an additional 47 variants in a further 30 genes. Promising associations were seen in nine of the variants (p < 0.05). Given that the estimated false positive report probabilities (FPRPs) for all associations are high (i.e. FPRP > 0.2), these findings should be interpreted with caution. While studies of candidate polymorphisms may be an attractive means of identifying risk factors for HL, future studies should employ sample sizes adequately powered to identify variants having only modest effects on HL risk. Furthermore, because of aetiological heterogeneity within HL, stratification of genotyping according to age, tumour Epstein-Barr virus status and histology is essential. Copyright © 2015 John Wiley & Sons, Ltd..
Zhou, F.
Wang, Y.
Liu, H.
Ready, N.
Han, Y.
Hung, R.J.
Brhane, Y.
McLaughlin, J.
Brennan, P.
Bickeböller, H.
Rosenberger, A.
Houlston, R.S.
Caporaso, N.
Landi, M.T.
Brüske, I.
Risch, A.
Ye, Y.
Wu, X.
Christiani, D.C.
Goodman, G.
Chen, C.
Transdisciplinary Research in Cancer of the Lung (TRICL) Research Team,
Amos, C.I.
Wei, Q.
(2017). Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk-A re-analysis of eight GWASs. Molecular carcinogenesis,
Vol.56
(4),
pp. 1227-1238.
show abstract
Purpose mRNA degradation is an important regulatory step for controlling gene expression and cell functions. Genetic abnormalities involved in mRNA degradation genes were found to be associated with cancer risks. Therefore, we systematically investigated the roles of genetic variants in the general mRNA degradation pathway in lung cancer risk.Experimental design Meta-analyses were conducted using summary data from six lung cancer genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung and additional two GWASs from Harvard University and deCODE in the International Lung Cancer Consortium. Expression quantitative trait loci analysis (eQTL) was used for in silico functional validation of the identified significant susceptibility loci.Results This pathway-based analysis included 6816 single nucleotide polymorphisms (SNP) in 68 genes in 14 463 lung cancer cases and 44 188 controls. In the single-locus analysis, we found that 20 SNPs were associated with lung cancer risk with a false discovery rate threshold of <0.05. Among the 11 newly identified SNPs in CNOT6, which were in high linkage disequilibrium, the rs2453176 with a RegulomDB score "1f" was chosen as the tagSNP for further analysis. We found that the rs2453176 T allele was significantly associated with lung cancer risk (odds ratio = 1.11, 95% confidence interval = 1.04-1.18) in the eight GWASs. In the eQTL analysis, we found that levels of CNOT6 mRNA expression were significantly correlated with the rs2453176 T allele, which provided additional biological basis for the observed positive association.Conclusion The CNOT6 rs2453176 SNP may be a new functional susceptible locus for lung cancer risk. © 2016 Wiley Periodicals, Inc..
Melin, B.S.
Barnholtz-Sloan, J.S.
Wrensch, M.R.
Johansen, C.
Il'yasova, D.
Kinnersley, B.
Ostrom, Q.T.
Labreche, K.
Chen, Y.
Armstrong, G.
Liu, Y.
Eckel-Passow, J.E.
Decker, P.A.
Labussière, M.
Idbaih, A.
Hoang-Xuan, K.
Di Stefano, A.-.
Mokhtari, K.
Delattre, J.-.
Broderick, P.
Galan, P.
Gousias, K.
Schramm, J.
Schoemaker, M.J.
Fleming, S.J.
Herms, S.
Heilmann, S.
Nöthen, M.M.
Wichmann, H.-.
Schreiber, S.
Swerdlow, A.
Lathrop, M.
Simon, M.
Sanson, M.
Andersson, U.
Rajaraman, P.
Chanock, S.
Linet, M.
Wang, Z.
Yeager, M.
GliomaScan Consortium,
Wiencke, J.K.
Hansen, H.
McCoy, L.
Rice, T.
Kosel, M.L.
Sicotte, H.
Amos, C.I.
Bernstein, J.L.
Davis, F.
Lachance, D.
Lau, C.
Merrell, R.T.
Shildkraut, J.
Ali-Osman, F.
Sadetzki, S.
Scheurer, M.
Shete, S.
Lai, R.K.
Claus, E.B.
Olson, S.H.
Jenkins, R.B.
Houlston, R.S.
Bondy, M.L.
(2017). Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors. Nature genetics,
Vol.49
(5),
pp. 789-794.
show abstract
Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10 -9 , odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10 -10 , OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10 -8 , OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10 -11 , OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10 -10 , OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10 -9 , OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10 -10 , OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10 -10 , OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10 -9 , OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10 -8 , OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10 -10 , OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10 -11 , OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10 -9 , OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology..
Scales, M.
Chubb, D.
Dobbins, S.E.
Johnson, D.C.
Li, N.
Sternberg, M.J.
Weinhold, N.
Stein, C.
Jackson, G.
Davies, F.E.
Walker, B.A.
Wardell, C.P.
Houlston, R.S.
Morgan, G.J.
(2017). Search for rare protein altering variants influencing susceptibility to multiple myeloma. Oncotarget,
Vol.8
(22),
pp. 36203-36210.
show abstract
The genetic basis underlying the inherited risk of developing multiple myeloma (MM) is largely unknown. To examine the impact of rare protein altering variants on the risk of developing MM we analyzed high-coverage exome sequencing data on 513 MM cases and 1,569 healthy controls, performing both single variant and gene burden tests. We did not identify any recurrent coding low-frequency alleles (1-5%) with moderate effect that were statistically associated with MM. In a gene burden analysis we did however identify a promising relationship between variation in the marrow kinetochore microtubule stromal gene KIF18A, which plays a role in control mitotic chromosome positioning dynamics, and risk of MM (P =3.6x10-6). Further analysis showed KIF18A displays a distinct pattern of expression across molecular subgroups of MM as well as being associated with patient survival. Our results inform future study design and provide a resource for contextualizing the impact of candidate MM susceptibility genes..
Sud, A.
Thomsen, H.
Sundquist, K.
Houlston, R.S.
Hemminki, K.
(2017). Risk of Second Cancer in Hodgkin Lymphoma Survivors and Influence of Family History. Journal of clinical oncology : official journal of the american society of clinical oncology,
Vol.35
(14),
pp. 1584-1590.
show abstract
Purpose Although advances in Hodgkin lymphoma (HL) treatment have led to improved disease-free survival, this has been accompanied by an increased risk of second cancers. We sought to quantify the second cancer risks and to investigate the impact of family history. Patients and Methods Using the Swedish Family-Cancer Project Database, we identified 9,522 individuals with primary HL diagnosed between 1965 and 2012. We calculated standardized incidence ratios and cumulative incidence of second cancer in HL survivors and compared the standardized incidence ratios of lung, breast, colorectal, and all second cancers in HL survivors with and without a site-specific family history of cancer. Interactions between family history of cancer and HL treatment were evaluated under additive and multiplicative models. Results Overall, the risk of a second cancer in HL survivors was increased 2.39-fold (95% CI, 2.29 to 2.53). The 30-year cumulative incidence of breast cancer in women diagnosed with HL at younger than 35 years of age was 13.8%. We observed no significant difference in cancer risk over successive time periods. The risk of all second cancers was 1.3-fold higher for HL survivors with a first-degree relative with cancer ( P < .001), with 3.3-fold, 2.1-fold, and 1.8-fold differences shown for lung, colorectal, and breast cancers, respectively. Moreover, a greater than additive interaction between family history of lung cancer and HL treatment was shown ( P = .03). Conclusion HL survivorship is associated with a substantive risk of a second cancer. Notably, the risk is higher in individuals with a family history of cancer. This information should be used to inform risk-adapted therapy and to assist in screening to reduce long-term morbidity and mortality in patients with HL..
Tamm, R.
Mägi, R.
Tremmel, R.
Winter, S.
Mihailov, E.
Smid, A.
Möricke, A.
Klein, K.
Schrappe, M.
Stanulla, M.
Houlston, R.
Weinshilboum, R.
Mlinarič Raščan, I.
Metspalu, A.
Milani, L.
Schwab, M.
Schaeffeler, E.
(2017). Polymorphic variation in TPMT is the principal determinant of TPMT phenotype: A meta-analysis of three genome-wide association studies. Clinical pharmacology and therapeutics,
Vol.101
(5),
pp. 684-695.
show abstract
Thiopurine-related hematotoxicity in pediatric acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases has been linked to genetically defined variability in thiopurine S-methyltransferase (TPMT) activity. While gene testing of TPMT is being clinically implemented, it is unclear if additional genetic variation influences TPMT activity with consequences for thiopurine-related toxicity. To examine this possibility, we performed a genome-wide association study (GWAS) of red blood cell TPMT activity in 844 Estonian individuals and 245 pediatric ALL cases. Additionally, we correlated genome-wide genotypes to human hepatic TPMT activity in 123 samples. Only genetic variants mapping to chromosome 6, including the TPMT gene region, were significantly associated with TPMT activity (P < 5.0 × 10-8 ) in each of the three GWAS and a joint meta-analysis of 1,212 cases (top hit P = 1.2 × 10-72 ). This finding is consistent with TPMT genotype being the primary determinant of TPMT activity, reinforcing the rationale for genetic testing of TPMT alleles in routine clinical practice to individualize mercaptopurine dosage..
Liu, H.
Liu, Z.
Wang, Y.
Stinchcombe, T.E.
Owzar, K.
Han, Y.
Hung, R.J.
Brhane, Y.
McLaughlin, J.
Brennan, P.
Bickeböller, H.
Rosenberger, A.
Houlston, R.S.
Caporaso, N.
Landi, M.T.
Brüske, I.
Risch, A.
Wu, X.
Ye, Y.
Christiani, D.C.
Amos, C.I.
Wei, Q.
Transdisciplinary Research in Cancer of the Lung (TRICL) Research Team,
(2017). Functional variants in DCAF4 associated with lung cancer risk in European populations. Carcinogenesis,
Vol.38
(5),
pp. 541-551.
show abstract
Cullin-RING ubiquitin ligases (CRLs) responsible for substrate specificity of ubiquitination play a key role in cell-cycle control and DNA damage response. In this study, we assessed associations between 16 599 SNPs in 115 CRL genes and lung cancer risk by using summary data of six published genome-wide association studies (GWASs) of 12 160 cases and 16 838 cases of European ancestry. As a result, we identified three independent SNPs in DCAF4 (rs117781739, rs12587742 and rs2240980) associated with lung cancer risk (odds ratio = 0.91, 1.09 and 1.09, respectively; 95% confidence interval = 0.88-0.95, 1.05-1.14 and 1.05-1.13, respectively; and P = 3.99 × 10-6, 4.97 × 10-5 and 1.44 × 10-5, respectively) after multiple comparison correction by a false discovery rate <0.05. Since SNP rs12587742 is located within the promoter region and one CpG island of DCAF4, we further performed in silico functional analyses and found that the rs12587742 variant A allele was associated with an increased mRNA expression (P = 2.20 × 10-16, 1.79 × 10-13 and 0.001 in blood cells, normal lung tissues and tumor tissues of lung squamous carcinoma, respectively) and a decreased methylation status (P = 2.48 × 10-9 and 0.032 in adipose and lung tumor tissues, respectively). Moreover, evidence from differential expression analyses further supported an oncogenic effect of DCAF4 on lung cancer, with higher mRNA levels in both lung squamous carcinoma and adenocarcinoma (P = 4.48 × 10-11 and 1.22 × 10-9, respectively) than in adjacent normal tissues. Taken together, our results suggest that rs12587742 is associated with an increased lung cancer risk, possibly by up-regulating mRNA expression and decreasing methylation status of DCAF4..
Shah, V.
Boyd, K.D.
Houlston, R.S.
Kaiser, M.F.
(2017). Constitutional mutation in CDKN2A is associated with long term survivorship in multiple myeloma: a case report. Bmc cancer,
Vol.17
(1),
pp. 718-?.
show abstract
Multiple Myeloma is a cancer of plasma cells associated with significantly reduced survival. Long term survivorship from myeloma is very rare and despite advances in its treatment the disease is generally considered incurable. We report a patient diagnosed with myeloma carrying a germline mutation of a tumour suppressor gene who has effectively been cured.A 36-year-old woman was diagnosed with IgG lambda myeloma in 1985. She was treated with melphalan chemotherapy followed by high-dose melphalan and autologous stem cell rescue and since remained in complete remission despite not having received any additional therapy. After eliciting a prior history of multiple primary melanomas and breast cancer, she was tested for and shown to be a carrier for a germline mutation in CDKN2A.This is the second case report of germline mutation of CDKN2A being associated with myeloma. CDKN2A is a stabiliser of p53. Long term survivorship after high dose DNA damaging chemotherapy with melphalan in this patient is compatible with an increased chemo-sensitivity due to impairment of the DNA repair pathway..
Yin, J.
Liu, H.
Liu, Z.
Owzar, K.
Han, Y.
Su, L.
Wei, Y.
Hung, R.J.
Brhane, Y.
McLaughlin, J.
Brennan, P.
Bickeboeller, H.
Rosenberger, A.
Houlston, R.S.
Caporaso, N.
Landi, M.T.
Heinrich, J.
Risch, A.
Christiani, D.C.
Amos, C.I.
Wei, Q.
(2017). Pathway-analysis of published genome-wide association studies of lung cancer: A potential role for the CYP4F3 locus. Molecular carcinogenesis,
Vol.56
(6),
pp. 1663-1672.
show abstract
The fatty acids (FAs) metabolism is suggested to play a pivotal role in the development of lung cancer, and we explored that by conducting a pathway-based analysis. We performed a meta-analysis of published datasets of six genome wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium, which included 12 160 cases with lung cancer and 16 838 cancer-free controls. A total of 30 722 single-nucleotide polymorphisms (SNPs) from 317 genes relevant to FA metabolic pathways were identified. An additional dataset from the Harvard Lung Cancer Study with 984 cases and 970 healthy controls was also added to the final meta-analysis. In the initial meta-analysis, 26 of 28 SNPs that passed false discovery rate multiple tests were mapped to the CYP4F3 gene. Among the 26 top ranked hits was a proxy SNP, CYP4F3 rs4646904 (P = 8.65 × 10 -6 , FDR = 0.018), which is suggested to change splicing pattern/efficiency and to be associated with gene expression levels. However, after adding data of rs4646904 from the Harvard GWAS, the significance in the combined analysis was reduced to P = 3.52 × 10 -3 [odds ratio (OR) = 1.07, 95% confidence interval (95%CI) = 1.03-1.12]. Interestingly, the small Harvard dataset also pointed to the same direction of the association in subgroups of smokers (OR = 1.07) and contributed to a combined OR of 1.13 (95% CI = 1.06-1.20, P = 6.70 × 10 -5 ). The results suggest that a potentially functional SNP in CYP4F3 (rs4646904) may contribute to the etiology of lung cancer, especially in smokers. Additional mechanistic studies are warranted to unravel the potential biological significance of the finding..
Rodriguez-Broadbent, H.
Law, P.J.
Sud, A.
Palin, K.
Tuupanen, S.
Gylfe, A.
Hänninen, U.A.
Cajuso, T.
Tanskanen, T.
Kondelin, J.
Kaasinen, E.
Sarin, A.-.
Ripatti, S.
Eriksson, J.G.
Rissanen, H.
Knekt, P.
Pukkala, E.
Jousilahti, P.
Salomaa, V.
Palotie, A.
Renkonen-Sinisalo, L.
Lepistö, A.
Böhm, J.
Mecklin, J.-.
Al-Tassan, N.A.
Palles, C.
Martin, L.
Barclay, E.
Farrington, S.M.
Timofeeva, M.N.
Meyer, B.F.
Wakil, S.M.
Campbell, H.
Smith, C.G.
Idziaszczyk, S.
Maughan, T.S.
Kaplan, R.
Kerr, R.
Kerr, D.
Passarelli, M.N.
Figueiredo, J.C.
Buchanan, D.D.
Win, A.K.
Hopper, J.L.
Jenkins, M.A.
Lindor, N.M.
Newcomb, P.A.
Gallinger, S.
Conti, D.
Schumacher, F.
Casey, G.
Aaltonen, L.A.
Cheadle, J.P.
Tomlinson, I.P.
Dunlop, M.G.
Houlston, R.S.
(2017). Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer. International journal of cancer,
Vol.140
(12),
pp. 2701-2708.
show abstract
While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20-1.79, p = 1.68 × 10 -4 ). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92-1.18, p = 0.49), 0.94 (95% CI: 0.84-1.05, p = 0.27), and 0.98 (95% CI: 0.85-1.12, p = 0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49-0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia..
Law, P.J.
Berndt, S.I.
Speedy, H.E.
Camp, N.J.
Sava, G.P.
Skibola, C.F.
Holroyd, A.
Joseph, V.
Sunter, N.J.
Nieters, A.
Bea, S.
Monnereau, A.
Martin-Garcia, D.
Goldin, L.R.
Clot, G.
Teras, L.R.
Quintela, I.
Birmann, B.M.
Jayne, S.
Cozen, W.
Majid, A.
Smedby, K.E.
Lan, Q.
Dearden, C.
Brooks-Wilson, A.R.
Hall, A.G.
Purdue, M.P.
Mainou-Fowler, T.
Vajdic, C.M.
Jackson, G.H.
Cocco, P.
Marr, H.
Zhang, Y.
Zheng, T.
Giles, G.G.
Lawrence, C.
Call, T.G.
Liebow, M.
Melbye, M.
Glimelius, B.
Mansouri, L.
Glenn, M.
Curtin, K.
Diver, W.R.
Link, B.K.
Conde, L.
Bracci, P.M.
Holly, E.A.
Jackson, R.D.
Tinker, L.F.
Benavente, Y.
Boffetta, P.
Brennan, P.
Maynadie, M.
McKay, J.
Albanes, D.
Weinstein, S.
Wang, Z.
Caporaso, N.E.
Morton, L.M.
Severson, R.K.
Riboli, E.
Vineis, P.
Vermeulen, R.C.
Southey, M.C.
Milne, R.L.
Clavel, J.
Topka, S.
Spinelli, J.J.
Kraft, P.
Ennas, M.G.
Summerfield, G.
Ferri, G.M.
Harris, R.J.
Miligi, L.
Pettitt, A.R.
North, K.E.
Allsup, D.J.
Fraumeni, J.F.
Bailey, J.R.
Offit, K.
Pratt, G.
Hjalgrim, H.
Pepper, C.
Chanock, S.J.
Fegan, C.
Rosenquist, R.
de Sanjose, S.
Carracedo, A.
Dyer, M.J.
Catovsky, D.
Campo, E.
Cerhan, J.R.
Allan, J.M.
Rothman, N.
Houlston, R.
Slager, S.
(2017). Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia. Nature communications,
Vol.8,
pp. 14175-?.
show abstract
Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10 -13 ), 1q42.13 (rs41271473, P=1.06 × 10 -10 ), 4q24 (rs71597109, P=1.37 × 10 -10 ), 4q35.1 (rs57214277, P=3.69 × 10 -8 ), 6p21.31 (rs3800461, P=1.97 × 10 -8 ), 11q23.2 (rs61904987, P=2.64 × 10 -11 ), 18q21.1 (rs1036935, P=3.27 × 10 -8 ), 19p13.3 (rs7254272, P=4.67 × 10 -8 ) and 22q13.33 (rs140522, P=2.70 × 10 -9 ). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response..
Litchfield, K.
Levy, M.
Orlando, G.
Loveday, C.
Law, P.J.
Migliorini, G.
Holroyd, A.
Broderick, P.
Karlsson, R.
Haugen, T.B.
Kristiansen, W.
Nsengimana, J.
Fenwick, K.
Assiotis, I.
Kote-Jarai, Z.
Dunning, A.M.
Muir, K.
Peto, J.
Eeles, R.
Easton, D.F.
Dudakia, D.
Orr, N.
Pashayan, N.
UK Testicular Cancer Collaboration,
PRACTICAL Consortium,
Bishop, D.T.
Reid, A.
Huddart, R.A.
Shipley, J.
Grotmol, T.
Wiklund, F.
Houlston, R.S.
Turnbull, C.
(2017). Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor. Nature genetics,
Vol.49
(7),
pp. 1133-1140.
show abstract
Genome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new GWAS, a meta-analysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Defective microtubule assembly and dysregulation of KIT-MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT..
Rasche, L.
Angtuaco, E.
McDonald, J.E.
Buros, A.
Stein, C.
Pawlyn, C.
Thanendrarajan, S.
Schinke, C.
Samant, R.
Yaccoby, S.
Walker, B.A.
Epstein, J.
Zangari, M.
van Rhee, F.
Meissner, T.
Goldschmidt, H.
Hemminki, K.
Houlston, R.
Barlogie, B.
Davies, F.E.
Morgan, G.J.
Weinhold, N.
(2017). Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma. Blood,
Vol.130
(1),
pp. 30-34.
show abstract
18 F-Fluorodeoxyglucose (FDG)-positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging with background signal suppression (DWIBS) are 2 powerful functional imaging modalities in the evaluation of malignant plasma cell (PC) disease multiple myeloma (MM). Preliminary observations have suggested that MM patients with extensive disease according to DWIBS may be reported as being disease-free on FDG-PET ("PET false-negative"). The aim of this study was to describe the proportion of PET false-negativity in a representative set of 227 newly diagnosed MM patients with simultaneous assessment of FDG-PET and DWIBS, and to identify tumor-intrinsic features associated with this pattern. We found the incidence of PET false-negativity to be 11%. Neither tumor load-associated parameters, such as degree of bone marrow PC infiltration, nor the PC proliferation rate were associated with this subset. However, the gene coding for hexokinase-2, which catalyzes the first step of glycolysis, was significantly lower expressed in PET false-negative cases (5.3-fold change, P < .001) which provides a mechanistic explanation for this feature. In conclusion, we demonstrate a relevant number of patients with FDG-PET false-negative MM and a strong association between hexokinase-2 expression and this negativity: a finding which may also be relevant for clinical imaging of other hematological cancers..
da Silva Filho, M.I.
Försti, A.
Weinhold, N.
Meziane, I.
Campo, C.
Huhn, S.
Nickel, J.
Hoffmann, P.
Nöthen, M.M.
Jöckel, K.-.
Landi, S.
Mitchell, J.S.
Johnson, D.
Morgan, G.J.
Houlston, R.
Goldschmidt, H.
Jauch, A.
Milani, P.
Merlini, G.
Rowcieno, D.
Hawkins, P.
Hegenbart, U.
Palladini, G.
Wechalekar, A.
Schönland, S.O.
Hemminki, K.
(2017). Genome-wide association study of immunoglobulin light chain amyloidosis in three patient cohorts: comparison with myeloma. Leukemia,
Vol.31
(8),
pp. 1735-1742.
show abstract
Immunoglobulin light chain (AL) amyloidosis is characterized by tissue deposition of amyloid fibers derived from immunoglobulin light chain. AL amyloidosis and multiple myeloma (MM) originate from monoclonal gammopathy of undetermined significance. We wanted to characterize germline susceptibility to AL amyloidosis using a genome-wide association study (GWAS) on 1229 AL amyloidosis patients from Germany, UK and Italy, and 7526 healthy local controls. For comparison with MM, recent GWAS data on 3790 cases were used. For AL amyloidosis, single nucleotide polymorphisms (SNPs) at 10 loci showed evidence of an association at P<10 -5 with homogeneity of results from the 3 sample sets; some of these were previously documented to influence MM risk, including the SNP at the IRF4 binding site. In AL amyloidosis, rs9344 at the splice site of cyclin D1, promoting translocation (11;14), reached the highest significance, P=7.80 × 10 -11 ; the SNP was only marginally significant in MM. SNP rs79419269 close to gene SMARCD3 involved in chromatin remodeling was also significant (P=5.2 × 10 -8 ). These data provide evidence for common genetic susceptibility to AL amyloidosis and MM. Cyclin D1 is a more prominent driver in AL amyloidosis than in MM, but the links to aggregation of light chains need to be demonstrated..
Levy, M.
Hall, D.
Sud, A.
Law, P.
Litchfield, K.
Dudakia, D.
Haugen, T.B.
Karlsson, R.
Reid, A.
Huddart, R.A.
Grotmol, T.
Wiklund, F.
Houlston, R.S.
Turnbull, C.
(2017). Mendelian randomisation analysis provides no evidence for a relationship between adult height and testicular cancer risk. Andrology,
Vol.5
(5),
pp. 914-922.
show abstract
Observational studies have suggested anthropometric traits, particularly increased height are associated with an elevated risk of testicular cancer (testicular germ cell tumour). However, there is an inconsistency between study findings, suggesting the possibility of the influence of confounding factors. To examine the association between anthropometric traits and testicular germ cell tumour using an unbiased approach, we performed a Mendelian randomisation study. We used genotype data from genome wide association studies of testicular germ cell tumour totalling 5518 cases and 19,055 controls. Externally weighted polygenic risk scores were created and used to evaluate associations with testicular germ cell tumour risk per one standard deviation (s.d) increase in genetically-defined adult height, adult BMI, adult waist hip ratio adjusted for BMI (WHRadjBMI), adult hip circumference adjusted for BMI (HIPadjBMI), adult waist circumference adjusted for BMI (WCadjBMI), birth weight (BW) and childhood obesity. Mendelian randomisation analysis did not demonstrate an association between any anthropometric trait and testicular germ cell tumour risk. In particular, despite good power, there was no global evidence for association between height and testicular germ cell tumour. However, three SNPs for adult height individually showed association with testicular germ cell tumour (rs4624820: OR = 1.47, 95% CI: 1.41-1.55, p = 2.7 × 10 -57 ; rs12228415: OR = 1.17, 95% CI: 1.11-1.22, p = 3.1 × 10 -10 ; rs7568069: OR = 1.13, 95% CI: 1.07-1.18, p = 1.1 × 10 -6 ). This Mendelian randomisation analysis, based on the largest testicular germ cell tumour genome wide association dataset to date, does not support a causal etiological association between anthropometric traits and testicular germ cell tumour aetiology. Our findings are more compatible with confounding by shared environmental factors, possibly related to prenatal growth with exposure to these risk factors occurring in utero..
Li, N.
Johnson, D.C.
Weinhold, N.
Kimber, S.
Dobbins, S.E.
Mitchell, J.S.
Kinnersley, B.
Sud, A.
Law, P.J.
Orlando, G.
Scales, M.
Wardell, C.P.
Försti, A.
Hoang, P.H.
Went, M.
Holroyd, A.
Hariri, F.
Pastinen, T.
Meissner, T.
Goldschmidt, H.
Hemminki, K.
Morgan, G.J.
Kaiser, M.
Houlston, R.S.
(2017). Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism. Cell reports,
Vol.20
(11),
pp. 2556-2564.
show abstract
Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15..
Scelo, G.
Purdue, M.P.
Brown, K.M.
Johansson, M.
Wang, Z.
Eckel-Passow, J.E.
Ye, Y.
Hofmann, J.N.
Choi, J.
Foll, M.
Gaborieau, V.
Machiela, M.J.
Colli, L.M.
Li, P.
Sampson, J.N.
Abedi-Ardekani, B.
Besse, C.
Blanche, H.
Boland, A.
Burdette, L.
Chabrier, A.
Durand, G.
Le Calvez-Kelm, F.
Prokhortchouk, E.
Robinot, N.
Skryabin, K.G.
Wozniak, M.B.
Yeager, M.
Basta-Jovanovic, G.
Dzamic, Z.
Foretova, L.
Holcatova, I.
Janout, V.
Mates, D.
Mukeriya, A.
Rascu, S.
Zaridze, D.
Bencko, V.
Cybulski, C.
Fabianova, E.
Jinga, V.
Lissowska, J.
Lubinski, J.
Navratilova, M.
Rudnai, P.
Szeszenia-Dabrowska, N.
Benhamou, S.
Cancel-Tassin, G.
Cussenot, O.
Baglietto, L.
Boeing, H.
Khaw, K.-.
Weiderpass, E.
Ljungberg, B.
Sitaram, R.T.
Bruinsma, F.
Jordan, S.J.
Severi, G.
Winship, I.
Hveem, K.
Vatten, L.J.
Fletcher, T.
Koppova, K.
Larsson, S.C.
Wolk, A.
Banks, R.E.
Selby, P.J.
Easton, D.F.
Pharoah, P.
Andreotti, G.
Freeman, L.E.
Koutros, S.
Albanes, D.
Männistö, S.
Weinstein, S.
Clark, P.E.
Edwards, T.L.
Lipworth, L.
Gapstur, S.M.
Stevens, V.L.
Carol, H.
Freedman, M.L.
Pomerantz, M.M.
Cho, E.
Kraft, P.
Preston, M.A.
Wilson, K.M.
Michael Gaziano, J.
Sesso, H.D.
Black, A.
Freedman, N.D.
Huang, W.-.
Anema, J.G.
Kahnoski, R.J.
Lane, B.R.
Noyes, S.L.
Petillo, D.
Teh, B.T.
Peters, U.
White, E.
Anderson, G.L.
Johnson, L.
Luo, J.
Buring, J.
Lee, I.-.
Chow, W.-.
Moore, L.E.
Wood, C.
Eisen, T.
Henrion, M.
Larkin, J.
Barman, P.
Leibovich, B.C.
Choueiri, T.K.
Mark Lathrop, G.
Rothman, N.
Deleuze, J.-.
McKay, J.D.
Parker, A.S.
Wu, X.
Houlston, R.S.
Brennan, P.
Chanock, S.J.
(2017). Genome-wide association study identifies multiple risk loci for renal cell carcinoma. Nature communications,
Vol.8,
pp. 15724-?.
show abstract
Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10 -10 ), 3p22.1 (rs67311347, P=2.5 × 10 -8 ), 3q26.2 (rs10936602, P=8.8 × 10 -9 ), 8p21.3 (rs2241261, P=5.8 × 10 -9 ), 10q24.33-q25.1 (rs11813268, P=3.9 × 10 -8 ), 11q22.3 (rs74911261, P=2.1 × 10 -10 ) and 14q24.2 (rs4903064, P=2.2 × 10 -24 ). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility..
Sud, A.
Hemminki, K.
Houlston, R.S.
(2017). Second cancer risk following Hodgkin lymphoma. Oncotarget,
Vol.8
(45),
pp. 78261-78262.
Johnson, D.C.
Lenive, O.
Mitchell, J.
Jackson, G.
Owen, R.
Drayson, M.
Cook, G.
Jones, J.R.
Pawlyn, C.
Davies, F.E.
Walker, B.A.
Wardell, C.
Gregory, W.M.
Cairns, D.
Morgan, G.J.
Houlston, R.S.
Houlston, R.S.
Kaiser, M.F.
(2017). Neutral tumor evolution in myeloma is associated with poor prognosis. Blood,
Vol.130
(14),
pp. 1639-1643.
show abstract
Recent studies suggest that the evolutionary history of a cancer is important in forecasting clinical outlook. To gain insight into the clonal dynamics of multiple myeloma (MM) and its possible influence on patient outcomes, we analyzed whole exome sequencing tumor data for 333 patients from Myeloma XI, a UK phase 3 trial and 434 patients from the CoMMpass study, all of which had received immunomodulatory drug (IMiD) therapy. By analyzing mutant allele frequency distributions in tumors, we found that 17% to 20% of MM is under neutral evolutionary dynamics. These tumors are associated with poorer patient survival in nonintensively treated patients, which is consistent with the reduced therapeutic efficacy of microenvironment-modulating IMiDs. Our findings provide evidence that knowledge of the evolutionary history of MM has relevance for predicting patient outcomes and personalizing therapy..
May-Wilson, S.
Sud, A.
Law, P.J.
Palin, K.
Tuupanen, S.
Gylfe, A.
Hänninen, U.A.
Cajuso, T.
Tanskanen, T.
Kondelin, J.
Kaasinen, E.
Sarin, A.-.
Eriksson, J.G.
Rissanen, H.
Knekt, P.
Pukkala, E.
Jousilahti, P.
Salomaa, V.
Ripatti, S.
Palotie, A.
Renkonen-Sinisalo, L.
Lepistö, A.
Böhm, J.
Mecklin, J.-.
Al-Tassan, N.A.
Palles, C.
Farrington, S.M.
Timofeeva, M.N.
Meyer, B.F.
Wakil, S.M.
Campbell, H.
Smith, C.G.
Idziaszczyk, S.
Maughan, T.S.
Fisher, D.
Kerr, R.
Kerr, D.
Passarelli, M.N.
Figueiredo, J.C.
Buchanan, D.D.
Win, A.K.
Hopper, J.L.
Jenkins, M.A.
Lindor, N.M.
Newcomb, P.A.
Gallinger, S.
Conti, D.
Schumacher, F.
Casey, G.
Aaltonen, L.A.
Cheadle, J.P.
Tomlinson, I.P.
Dunlop, M.G.
Houlston, R.S.
(2017). Pro-inflammatory fatty acid profile and colorectal cancer risk: A Mendelian randomisation analysis. European journal of cancer (oxford, england : 1990),
Vol.84,
pp. 228-238.
show abstract
Background While dietary fat has been established as a risk factor for colorectal cancer (CRC), associations between fatty acids (FAs) and CRC have been inconsistent. Using Mendelian randomisation (MR), we sought to evaluate associations between polyunsaturated (PUFA), monounsaturated (MUFA) and saturated FAs (SFAs) and CRC risk.Methods We analysed genotype data on 9254 CRC cases and 18,386 controls of European ancestry. Externally weighted polygenic risk scores were generated and used to evaluate associations with CRC per one standard deviation increase in genetically defined plasma FA levels.Results Risk reduction was observed for oleic and palmitoleic MUFAs (OROA = 0.77, 95% CI: 0.65-0.92, P = 3.9 × 10-3; ORPOA = 0.36, 95% CI: 0.15-0.84, P = 0.018). PUFAs linoleic and arachidonic acid had negative and positive associations with CRC respectively (ORLA = 0.95, 95% CI: 0.93-0.98, P = 3.7 × 10-4; ORAA = 1.05, 95% CI: 1.02-1.07, P = 1.7 × 10-4). The SFA stearic acid was associated with increased CRC risk (ORSA = 1.17, 95% CI: 1.01-1.35, P = 0.041).Conclusion Results from our analysis are broadly consistent with a pro-inflammatory FA profile having a detrimental effect in terms of CRC risk..
Machiela, M.J.
Hofmann, J.N.
Carreras-Torres, R.
Brown, K.M.
Johansson, M.
Wang, Z.
Foll, M.
Li, P.
Rothman, N.
Savage, S.A.
Gaborieau, V.
McKay, J.D.
Ye, Y.
Henrion, M.
Bruinsma, F.
Jordan, S.
Severi, G.
Hveem, K.
Vatten, L.J.
Fletcher, T.
Koppova, K.
Larsson, S.C.
Wolk, A.
Banks, R.E.
Selby, P.J.
Easton, D.F.
Pharoah, P.
Andreotti, G.
Freeman, L.E.
Koutros, S.
Albanes, D.
Mannisto, S.
Weinstein, S.
Clark, P.E.
Edwards, T.E.
Lipworth, L.
Gapstur, S.M.
Stevens, V.L.
Carol, H.
Freedman, M.L.
Pomerantz, M.M.
Cho, E.
Kraft, P.
Preston, M.A.
Wilson, K.M.
Gaziano, J.M.
Sesso, H.S.
Black, A.
Freedman, N.D.
Huang, W.-.
Anema, J.G.
Kahnoski, R.J.
Lane, B.R.
Noyes, S.L.
Petillo, D.
Colli, L.M.
Sampson, J.N.
Besse, C.
Blanche, H.
Boland, A.
Burdette, L.
Prokhortchouk, E.
Skryabin, K.G.
Yeager, M.
Mijuskovic, M.
Ognjanovic, M.
Foretova, L.
Holcatova, I.
Janout, V.
Mates, D.
Mukeriya, A.
Rascu, S.
Zaridze, D.
Bencko, V.
Cybulski, C.
Fabianova, E.
Jinga, V.
Lissowska, J.
Lubinski, J.
Navratilova, M.
Rudnai, P.
Szeszenia-Dabrowska, N.
Benhamou, S.
Cancel-Tassin, G.
Cussenot, O.
Bueno-de-Mesquita, H.B.
Canzian, F.
Duell, E.J.
Ljungberg, B.
Sitaram, R.T.
Peters, U.
White, E.
Anderson, G.L.
Johnson, L.
Luo, J.
Buring, J.
Lee, I.-.
Chow, W.-.
Moore, L.E.
Wood, C.
Eisen, T.
Larkin, J.
Choueiri, T.K.
Lathrop, G.M.
Teh, B.T.
Deleuze, J.-.
Wu, X.
Houlston, R.S.
Brennan, P.
Chanock, S.J.
Scelo, G.
Purdue, M.P.
(2017). Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma. European urology,
Vol.72
(5),
pp. 747-754.
show abstract
Background Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.Objective We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.Design, setting, and participants Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.Outcome measurements and statistical analysis Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.Results and limitations Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R 2 >0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13).Conclusions Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.Patient summary Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma..
Sud, A.
Kinnersley, B.
Houlston, R.S.
(2017). Genome-wide association studies of cancer: current insights and future perspectives. Nature reviews. cancer,
Vol.17
(11),
pp. 692-704.
show abstract
Genome-wide association studies (GWAS) provide an agnostic approach for investigating the genetic basis of complex diseases. In oncology, GWAS of nearly all common malignancies have been performed, and over 450 genetic variants associated with increased risks have been identified. As well as revealing novel pathways important in carcinogenesis, these studies have shown that common genetic variation contributes substantially to the heritable risk of many common cancers. The clinical application of GWAS is starting to provide opportunities for drug discovery and repositioning as well as for cancer prevention. However, deciphering the functional and biological basis of associations is challenging and is in part a barrier to fully unlocking the potential of GWAS..
Feng, Y.
Wang, Y.
Liu, H.
Liu, Z.
Mills, C.
Han, Y.
Hung, R.J.
Brhane, Y.
McLaughlin, J.
Brennan, P.
Bickeboeller, H.
Rosenberger, A.
Houlston, R.S.
Caporaso, N.E.
Teresa Landi, M.
Brueske, I.
Risch, A.
Ye, Y.
Wu, X.
Christiani, D.C.
Amos, C.I.
Wei, Q.
(2017). Genetic variants of PTPN2 are associated with lung cancer risk: a re-analysis of eight GWASs in the TRICL-ILCCO consortium. Scientific reports,
Vol.7
(1),
pp. 825-?.
show abstract
The T-cell protein tyrosine phosphatase (TCPTP) pathway consists of signaling events mediated by TCPTP. Mutations and genetic variants of some genes in the TCPTP pathway are associated with lung cancer risk and survival. In the present study, we first investigated associations of 5,162 single nucleotide polymorphisms (SNPs) in 43 genes of this TCPTP pathway with lung cancer risk by using summary data of six published genome-wide association studies (GWAS) of 12,160 cases and 16,838 controls. We identified 11 independent SNPs in eight genes after correction for multiple comparisons by a false discovery rate <0.20. Then, we performed in silico functional analyses for these 11 SNPs by eQTL analysis, two of which, PTPN2 SNPs rs2847297 and rs2847282, were chosen as tagSNPs. We further included two additional GWAS datasets of Harvard University (984 cases and 970 controls) and deCODE (1,319 cases and 26,380 controls), and the overall effects of these two SNPs among all eight GWAS studies remained significant (OR = 0.95, 95% CI = 0.92-0.98, and P = 0.004 for rs2847297; OR = 0.95, 95% CI = 0.92-0.99, and P = 0.009 for rs2847282). In conclusion, the PTPN2 rs2847297 and rs2847282 may be potential susceptible loci for lung cancer risk..
Sud, A.
Thomsen, H.
Law, P.J.
Försti, A.
Filho, M.I.
Holroyd, A.
Broderick, P.
Orlando, G.
Lenive, O.
Wright, L.
Cooke, R.
Easton, D.
Pharoah, P.
Dunning, A.
Peto, J.
Canzian, F.
Eeles, R.
Kote-Jarai, Z.
Muir, K.
Pashayan, N.
PRACTICAL consortium,
Hoffmann, P.
Nöthen, M.M.
Jöckel, K.-.
Strandmann, E.P.
Lightfoot, T.
Kane, E.
Roman, E.
Lake, A.
Montgomery, D.
Jarrett, R.F.
Swerdlow, A.J.
Engert, A.
Orr, N.
Hemminki, K.
Houlston, R.S.
(2017). Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility. Nature communications,
Vol.8
(1),
pp. 1892-?.
show abstract
Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgkin lymphoma at 6q22.33 (rs9482849, P = 1.52 × 10 -8 ) and for nodular sclerosis Hodgkin lymphoma at 3q28 (rs4459895, P = 9.43 × 10 -17 ), 6q23.3 (rs6928977, P = 4.62 × 10 -11 ), 10p14 (rs3781093, P = 9.49 × 10 -13 ), 13q34 (rs112998813, P = 4.58 × 10 -8 ) and 16p13.13 (rs34972832, P = 2.12 × 10 -8 ). Additionally, independent loci within the HLA region are observed for nodular sclerosis Hodgkin lymphoma (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity Hodgkin lymphoma (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response..
Liu, N.Q.
Ter Huurne, M.
Nguyen, L.N.
Peng, T.
Wang, S.-.
Studd, J.B.
Joshi, O.
Ongen, H.
Bramsen, J.B.
Yan, J.
Andersen, C.L.
Taipale, J.
Dermitzakis, E.T.
Houlston, R.S.
Hubner, N.C.
Stunnenberg, H.G.
(2017). The non-coding variant rs1800734 enhances DCLK3 expression through long-range interaction and promotes colorectal cancer progression. Nature communications,
Vol.8,
pp. 14418-?.
show abstract
Genome-wide association studies have identified a great number of non-coding risk variants for colorectal cancer (CRC). To date, the majority of these variants have not been functionally studied. Identification of allele-specific transcription factor (TF) binding is of great importance to understand regulatory consequences of such variants. A recently developed proteome-wide analysis of disease-associated SNPs (PWAS) enables identification of TF-DNA interactions in an unbiased manner. Here we perform a large-scale PWAS study to comprehensively characterize TF-binding landscape that is associated with CRC, which identifies 731 allele-specific TF binding at 116 CRC risk loci. This screen identifies the A-allele of rs1800734 within the promoter region of MLH1 as perturbing the binding of TFAP4 and consequently increasing DCLK3 expression through a long-range interaction, which promotes cancer malignancy through enhancing expression of the genes related to epithelial-to-mesenchymal transition..
Went, M.
Sud, A.
Law, P.J.
Johnson, D.C.
Weinhold, N.
Försti, A.
van Duin, M.
Mitchell, J.S.
Chen, B.
Kuiper, R.
Stephens, O.W.
Bertsch, U.
Campo, C.
Einsele, H.
Gregory, W.M.
Henrion, M.
Hillengass, J.
Hoffmann, P.
Jackson, G.H.
Lenive, O.
Nickel, J.
Nöthen, M.M.
da Silva Filho, M.I.
Thomsen, H.
Walker, B.A.
Broyl, A.
Davies, F.E.
Langer, C.
Hansson, M.
Kaiser, M.
Sonneveld, P.
Goldschmidt, H.
Hemminki, K.
Nilsson, B.
Morgan, G.J.
Houlston, R.S.
(2017). Assessing the effect of obesity-related traits on multiple myeloma using a Mendelian randomisation approach. Blood cancer journal,
Vol.7
(6),
pp. e573-?.
Law, P.J.
Sud, A.
Mitchell, J.S.
Henrion, M.
Orlando, G.
Lenive, O.
Broderick, P.
Speedy, H.E.
Johnson, D.C.
Kaiser, M.
Weinhold, N.
Cooke, R.
Sunter, N.J.
Jackson, G.H.
Summerfield, G.
Harris, R.J.
Pettitt, A.R.
Allsup, D.J.
Carmichael, J.
Bailey, J.R.
Pratt, G.
Rahman, T.
Pepper, C.
Fegan, C.
von Strandmann, E.P.
Engert, A.
Försti, A.
Chen, B.
Filho, M.I.
Thomsen, H.
Hoffmann, P.
Noethen, M.M.
Eisele, L.
Jöckel, K.-.
Allan, J.M.
Swerdlow, A.J.
Goldschmidt, H.
Catovsky, D.
Morgan, G.J.
Hemminki, K.
Houlston, R.S.
(2017). Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci. Scientific reports,
Vol.7,
pp. 41071-?.
show abstract
B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10 -9 ) with opposing effects between CLL (P = 1.97 × 10 -8 ) and HL (P = 3.31 × 10 -3 ). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10 -12 ) was associated with increased CLL and HL risk (P = 4.68 × 10 -12 ), and reduced MM risk (P = 1.12 × 10 -2 ), and Gly70 in HLA-DQB1 (P = 3.15 × 10 -10 ) showed opposing effects between CLL (P = 3.52 × 10 -3 ) and HL (P = 3.41 × 10 -9 ). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs..
Chubb, D.
Broderick, P.
Dobbins, S.E.
Houlston, R.S.
(2016). CanVar: A resource for sharing germline variation in cancer patients. F1000research,
Vol.5,
pp. 2813-?.
show abstract
The advent of high-throughput sequencing has accelerated our ability to discover genes predisposing to disease and is transforming clinical genomic sequencing. In both contexts knowledge of the spectrum and frequency of genetic variation in the general population and in disease cohorts is vital to the interpretation of sequencing data. While population level data is becoming increasingly available from publicly accessible sources, as exemplified by The Exome Aggregation Consortium (ExAC), the availability of large-scale disease-specific frequency information is limited. These data are of particular importance to contextualise findings from clinical mutation screens and small gene discovery projects. This is especially true for cancer, which is typified by a number of hereditary predisposition syndromes. Although mutation frequencies in tumours are available from resources such as Cosmic and The Cancer Genome Atlas, a similar facility for germline variation is lacking. Here we present the Cancer Variation Resource (CanVar) an online database which has been developed using the ExAC framework to provide open access to germline variant frequency data from the sequenced exomes of cancer patients. In its first release, CanVar catalogues the exomes of 1,006 familial early-onset colorectal cancer (CRC) patients sequenced at The Institute of Cancer Research. It is anticipated that CanVar will host data for additional cancers, providing a resource for others studying cancer predisposition and an example of how the research community can utilise the ExAC framework to share sequencing data..
Bolton, K.L.
Tyrer, J.
Song, H.
Ramus, S.J.
Notaridou, M.
Jones, C.
Sher, T.
Gentry-Maharaj, A.
Wozniak, E.
Tsai, Y.-.
Weidhaas, J.
Paik, D.
Van Den Berg, D.J.
Stram, D.O.
Pearce, C.L.
Wu, A.H.
Brewster, W.
Anton-Culver, H.
Ziogas, A.
Narod, S.A.
Levine, D.A.
Kaye, S.B.
Brown, R.
Paul, J.
Flanagan, J.
Sieh, W.
McGuire, V.
Whittemore, A.S.
Campbell, I.
Gore, M.E.
Lissowska, J.
Yang, H.P.
Medrek, K.
Gronwald, J.
Lubinski, J.
Jakubowska, A.
Le, N.D.
Cook, L.S.
Kelemen, L.E.
Brooks-Wilson, A.
Massuger, L.F.
Kiemeney, L.A.
Aben, K.K.
van Altena, A.M.
Houlston, R.
Tomlinson, I.
Palmieri, R.T.
Moorman, P.G.
Schildkraut, J.
Iversen, E.S.
Phelan, C.
Vierkant, R.A.
Cunningham, J.M.
Goode, E.L.
Fridley, B.L.
Kruger-Kjaer, S.
Blaeker, J.
Hogdall, E.
Hogdall, C.
Gross, J.
Karlan, B.Y.
Ness, R.B.
Edwards, R.P.
Odunsi, K.
Moyisch, K.B.
Baker, J.A.
Modugno, F.
Heikkinenen, T.
Butzow, R.
Nevanlinna, H.
Leminen, A.
Bogdanova, N.
Antonenkova, N.
Doerk, T.
Hillemanns, P.
Dürst, M.
Runnebaum, I.
Thompson, P.J.
Carney, M.E.
Goodman, M.T.
Lurie, G.
Wang-Gohrke, S.
Hein, R.
Chang-Claude, J.
Rossing, M.A.
Cushing-Haugen, K.L.
Doherty, J.
Chen, C.
Rafnar, T.
Besenbacher, S.
Sulem, P.
Stefansson, K.
Birrer, M.J.
Terry, K.L.
Hernandez, D.
Cramer, D.W.
Vergote, I.
Amant, F.
Lambrechts, D.
Despierre, E.
Fasching, P.A.
Beckmann, M.W.
Thiel, F.C.
Ekici, A.B.
Chen, X.
Johnatty, S.E.
Webb, P.M.
Beesley, J.
Chanock, S.
Garcia-Closas, M.
Sellers, T.
Easton, D.F.
Berchuck, A.
Chenevix-Trench, G.
Pharoah, P.D.
Gayther, S.A.
(2016). Erratum: Corrigendum: Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nature genetics,
Vol.48
(1),
pp. 101-101.
Amirian, E.S.
Zhou, R.
Wrensch, M.R.
Olson, S.H.
Scheurer, M.E.
Il'yasova, D.
Lachance, D.
Armstrong, G.N.
McCoy, L.S.
Lau, C.C.
Claus, E.B.
Barnholtz-Sloan, J.S.
Schildkraut, J.
Ali-Osman, F.
Sadetzki, S.
Johansen, C.
Houlston, R.S.
Jenkins, R.B.
Bernstein, J.L.
Merrell, R.T.
Davis, F.G.
Lai, R.
Shete, S.
Amos, C.I.
Melin, B.S.
Bondy, M.L.
(2016). Approaching a Scientific Consensus on the Association between Allergies and Glioma Risk: A Report from the Glioma International Case-Control Study. Cancer epidemiology, biomarkers & prevention,
Vol.25
(2),
pp. 282-290.
show abstract
Abstract
Background: Several previous studies have found inverse associations between glioma susceptibility and a history of allergies or other atopic conditions. Some evidence indicates that respiratory allergies are likely to be particularly relevant with regard to glioma risk. Using data from the Glioma International Case-Control Study (GICC), we examined the effects of respiratory allergies and other atopic conditions on glioma risk.
Methods: The GICC contains detailed information on history of atopic conditions for 4,533 cases and 4,171 controls, recruited from 14 study sites across five countries. Using two-stage random-effects restricted maximum likelihood modeling to calculate meta-analysis ORs, we examined the associations between glioma and allergy status, respiratory allergy status, asthma, and eczema.
Results: Having a history of respiratory allergies was associated with an approximately 30% lower glioma risk, compared with not having respiratory allergies (mOR, 0.72; 95% confidence interval, 0.58–0.90). This association was similar when restricting to high-grade glioma cases. Asthma and eczema were also significantly protective against glioma.
Conclusion: A substantial amount of data on the inverse association between atopic conditions and glioma has accumulated, and findings from the GICC study further strengthen the existing evidence that the relationship between atopy and glioma is unlikely to be coincidental.
Impact: As the literature approaches a consensus on the impact of allergies in glioma risk, future research can begin to shift focus to what the underlying biologic mechanism behind this association may be, which could, in turn, yield new opportunities for immunotherapy or cancer prevention. Cancer Epidemiol Biomarkers Prev; 25(2); 282–90. ©2016 AACR..
Amirian, E.S.
Armstrong, G.N.
Zhou, R.
Lau, C.C.
Claus, E.B.
Barnholtz-Sloan, J.S.
Il'yasova, D.
Schildkraut, J.
Ali-Osman, F.
Sadetzki, S.
Johansen, C.
Houlston, R.S.
Jenkins, R.B.
Lachance, D.
Olson, S.H.
Bernstein, J.L.
Merrell, R.T.
Wrensch, M.R.
Davis, F.G.
Lai, R.
Shete, S.
Amos, C.I.
Scheurer, M.E.
Aldape, K.
Alafuzoff, I.
Brännström, T.
Broholm, H.
Collins, P.
Giannini, C.
Rosenblum, M.
Tihan, T.
Melin, B.S.
Bondy, M.L.
(2016). The Glioma International Case-Control Study: A Report From the Genetic Epidemiology of Glioma International Consortium. American journal of epidemiology,
Vol.183
(2),
pp. 85-91.
show abstract
Decades of research have established only a few etiological factors for glioma, which is a rare and highly fatal brain cancer. Common methodological challenges among glioma studies include small sample sizes, heterogeneity of tumor subtypes, and retrospective exposure assessment. Here, we briefly describe the Glioma International Case-Control (GICC) Study (recruitment, 2010-2013), a study being conducted by the Genetic Epidemiology of Glioma International Consortium that integrates data from multiple data collection sites, uses a common protocol and questionnaire, and includes biospecimen collection. To our knowledge, the GICC Study is the largest glioma study to date that includes collection of blood samples, which will allow for genetic analysis and interrogation of gene-environment interactions..
Frampton, M.J.
Law, P.
Litchfield, K.
Morris, E.J.
Kerr, D.
Turnbull, C.
Tomlinson, I.P.
Houlston, R.S.
(2016). Implications of polygenic risk for personalised colorectal cancer screening. Annals of oncology,
Vol.27
(3),
pp. 429-434.
Kang, X.
Liu, H.
Onaitis, M.W.
Liu, Z.
Owzar, K.
Han, Y.
Su, L.
Wei, Y.
Hung, R.J.
Brhane, Y.
McLaughlin, J.
Brennan, P.
Bickeböller, H.
Rosenberger, A.
Houlston, R.S.
Caporaso, N.
Landi, M.T.
Heinrich, J.
Risch, A.
Wu, X.
Ye, Y.
Christiani, D.C.
Amos, C.I.
Wei, Q.
(2016). Polymorphisms of the centrosomal gene (FGFR1OP) and lung cancer risk: a meta-analysis of 14 463 cases and 44 188 controls. Carcinogenesis,
Vol.37
(3),
pp. 280-289.
Kinnersley, B.
Chubb, D.
Dobbins, S.E.
Frampton, M.
Buch, S.
Timofeeva, M.N.
Castellví-Bel, S.
Farrington, S.M.
Forsti, A.
Hampe, J.
Hemminki, K.
Hofstra, R.M.
Northwood, E.
Palles, C.
Pinheiro, M.
Ruiz-Ponte, C.
Schafmayer, C.
Teixeira, M.R.
Westers, H.
van Wezel, T.
Timothy Bishop, D.
Tomlinson, I.
Dunlop, M.G.
Houlston, R.S.
(2016). Correspondence: SEMA4A variation and risk of colorectal cancer. Nature communications,
Vol.7
(1).
Kinnersley, B.
Kamatani, Y.
Labussière, M.
Wang, Y.
Galan, P.
Mokhtari, K.
Delattre, J.-.
Gousias, K.
Schramm, J.
Schoemaker, M.J.
Swerdlow, A.
Fleming, S.J.
Herms, S.
Heilmann, S.
Nöthen, M.M.
Simon, M.
Sanson, M.
Lathrop, M.
Houlston, R.S.
(2016). Search for new loci and low-frequency variants influencing glioma risk by exome-array analysis. European journal of human genetics,
Vol.24
(5),
pp. 717-724.
Orlando, G.
Law, P.J.
Palin, K.
Tuupanen, S.
Gylfe, A.
Hänninen, U.A.
Cajuso, T.
Tanskanen, T.
Kondelin, J.
Kaasinen, E.
Sarin, A.-.
Kaprio, J.
Eriksson, J.G.
Rissanen, H.
Knekt, P.
Pukkala, E.
Jousilahti, P.
Salomaa, V.
Ripatti, S.
Palotie, A.
Järvinen, H.
Renkonen-Sinisalo, L.
Lepistö, A.
Böhm, J.
Mecklin, J.-.
Al-Tassan, N.A.
Palles, C.
Martin, L.
Barclay, E.
Tenesa, A.
Farrington, S.
Timofeeva, M.N.
Meyer, B.F.
Wakil, S.M.
Campbell, H.
Smith, C.G.
Idziaszczyk, S.
Maughan, T.S.
Kaplan, R.
Kerr, R.
Kerr, D.
Buchanan, D.D.
Win, A.K.
Hopper, J.
Jenkins, M.
Lindor, N.M.
Newcomb, P.A.
Gallinger, S.
Conti, D.
Schumacher, F.
Casey, G.
Taipale, J.
Cheadle, J.P.
Dunlop, M.G.
Tomlinson, I.P.
Aaltonen, L.A.
Houlston, R.S.
(2016). Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease. Human molecular genetics,
Vol.25
(11),
pp. 2349-2359.
show abstract
To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P = 3.15 × 10 -8 , odds ratio = 1.10, 95% confidence interval = 1.06-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r 2 = 0.90, D' = 0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR]) < 0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD..
Cheng, T.H.
Thompson, D.J.
O'Mara, T.A.
Painter, J.N.
Glubb, D.M.
Flach, S.
Lewis, A.
French, J.D.
Freeman-Mills, L.
Church, D.
Gorman, M.
Martin, L.
National Study of Endometrial Cancer Genetics Group (NSECG),
Hodgson, S.
Webb, P.M.
Australian National Endometrial Cancer Study Group (ANECS),
Attia, J.
Holliday, E.G.
McEvoy, M.
Scott, R.J.
Henders, A.K.
Martin, N.G.
Montgomery, G.W.
Nyholt, D.R.
Ahmed, S.
Healey, C.S.
Shah, M.
Dennis, J.
Fasching, P.A.
Beckmann, M.W.
Hein, A.
Ekici, A.B.
Hall, P.
Czene, K.
Darabi, H.
Li, J.
Dörk, T.
Dürst, M.
Hillemanns, P.
Runnebaum, I.
Amant, F.
Schrauwen, S.
Zhao, H.
Lambrechts, D.
Depreeuw, J.
Dowdy, S.C.
Goode, E.L.
Fridley, B.L.
Winham, S.J.
Njølstad, T.S.
Salvesen, H.B.
Trovik, J.
Werner, H.M.
Ashton, K.
Otton, G.
Proietto, T.
Liu, T.
Mints, M.
Tham, E.
RENDOCAS,
Consortium, C.
Jun Li, M.
Yip, S.H.
Wang, J.
Bolla, M.K.
Michailidou, K.
Wang, Q.
Tyrer, J.P.
Dunlop, M.
Houlston, R.
Palles, C.
Hopper, J.L.
AOCS Group,
Peto, J.
Swerdlow, A.J.
Burwinkel, B.
Brenner, H.
Meindl, A.
Brauch, H.
Lindblom, A.
Chang-Claude, J.
Couch, F.J.
Giles, G.G.
Kristensen, V.N.
Cox, A.
Cunningham, J.M.
Pharoah, P.D.
Dunning, A.M.
Edwards, S.L.
Easton, D.F.
Tomlinson, I.
Spurdle, A.B.
(2016). Five endometrial cancer risk loci identified through genome-wide association analysis. Nature genetics,
Vol.48
(6),
pp. 667-674.
show abstract
We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer..
Yuan, H.
Liu, H.
Liu, Z.
Owzar, K.
Han, Y.
Su, L.
Wei, Y.
Hung, R.J.
McLaughlin, J.
Brhane, Y.
Brennan, P.
Bickeboeller, H.
Rosenberger, A.
Houlston, R.S.
Caporaso, N.
Landi, M.T.
Heinrich, J.
Risch, A.
Christiani, D.C.
Gümüş, Z.H.
Klein, R.J.
Amos, C.I.
Wei, Q.
(2016). A Novel Genetic Variant in Long Non-coding RNA Gene NEXN-AS1 is Associated with Risk of Lung Cancer. Scientific reports,
Vol.6,
pp. 34234-?.
show abstract
Lung cancer etiology is multifactorial, and growing evidence has indicated that long non-coding RNAs (lncRNAs) are important players in lung carcinogenesis. We performed a large-scale meta-analysis of 690,564 SNPs in 15,531 autosomal lncRNAs by using datasets from six previously published genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium in populations of European ancestry. Previously unreported significant SNPs (P value < 1 × 10-7) were further validated in two additional independent lung cancer GWAS datasets from Harvard University and deCODE. In the final meta-analysis of all eight GWAS datasets with 17,153 cases and 239,337 controls, a novel risk SNP rs114020893 in the lncRNA NEXN-AS1 region at 1p31.1 remained statistically significant (odds ratio = 1.17; 95% confidence interval = 1.11-1.24; P = 8.31 × 10-9). In further in silico analysis, rs114020893 was predicted to change the secondary structure of the lncRNA. Our finding indicates that SNP rs114020893 of NEXN-AS1 at 1p31.1 may contribute to lung cancer susceptibility..
Mitchell, J.S.
Li, N.
Weinhold, N.
Försti, A.
Ali, M.
van Duin, M.
Thorleifsson, G.
Johnson, D.C.
Chen, B.
Halvarsson, B.-.
Gudbjartsson, D.F.
Kuiper, R.
Stephens, O.W.
Bertsch, U.
Broderick, P.
Campo, C.
Einsele, H.
Gregory, W.A.
Gullberg, U.
Henrion, M.
Hillengass, J.
Hoffmann, P.
Jackson, G.H.
Johnsson, E.
Jöud, M.
Kristinsson, S.Y.
Lenhoff, S.
Lenive, O.
Mellqvist, U.-.
Migliorini, G.
Nahi, H.
Nelander, S.
Nickel, J.
Nöthen, M.M.
Rafnar, T.
Ross, F.M.
da Silva Filho, M.I.
Swaminathan, B.
Thomsen, H.
Turesson, I.
Vangsted, A.
Vogel, U.
Waage, A.
Walker, B.A.
Wihlborg, A.-.
Broyl, A.
Davies, F.E.
Thorsteinsdottir, U.
Langer, C.
Hansson, M.
Kaiser, M.
Sonneveld, P.
Stefansson, K.
Morgan, G.J.
Goldschmidt, H.
Hemminki, K.
Nilsson, B.
Houlston, R.S.
(2016). Genome-wide association study identifies multiple susceptibility loci for multiple myeloma. Nature communications,
Vol.7,
pp. 12050-?.
show abstract
Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10(-8)), 6q21 (rs9372120, P=9.09 × 10(-15)), 7q36.1 (rs7781265, P=9.71 × 10(-9)), 8q24.21 (rs1948915, P=4.20 × 10(-11)), 9p21.3 (rs2811710, P=1.72 × 10(-13)), 10p12.1 (rs2790457, P=1.77 × 10(-8)), 16q23.1 (rs7193541, P=5.00 × 10(-12)) and 20q13.13 (rs6066835, P=1.36 × 10(-13)), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development..
Jarvis, D.
Mitchell, J.S.
Law, P.J.
Palin, K.
Tuupanen, S.
Gylfe, A.
Hänninen, U.A.
Cajuso, T.
Tanskanen, T.
Kondelin, J.
Kaasinen, E.
Sarin, A.-.
Kaprio, J.
Eriksson, J.G.
Rissanen, H.
Knekt, P.
Pukkala, E.
Jousilahti, P.
Salomaa, V.
Ripatti, S.
Palotie, A.
Järvinen, H.
Renkonen-Sinisalo, L.
Lepistö, A.
Böhm, J.
Meklin, J.-.
Al-Tassan, N.A.
Palles, C.
Martin, L.
Barclay, E.
Farrington, S.M.
Timofeeva, M.N.
Meyer, B.F.
Wakil, S.M.
Campbell, H.
Smith, C.G.
Idziaszczyk, S.
Maughan, T.S.
Kaplan, R.
Kerr, R.
Kerr, D.
Buchanan, D.D.
Win, A.K.
Hopper, J.L.
Jenkins, M.A.
Lindor, N.M.
Newcomb, P.A.
Gallinger, S.
Conti, D.
Schumacher, F.
Casey, G.
Taipale, J.
Aaltonen, L.A.
Cheadle, J.P.
Dunlop, M.G.
Tomlinson, I.P.
Houlston, R.S.
(2016). Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer. British journal of cancer,
Vol.115
(2),
pp. 266-272.
show abstract
Background Observational studies have associated adiposity with an increased risk of colorectal cancer (CRC). However, such studies do not establish a causal relationship. To minimise bias from confounding we performed a Mendelian randomisation (MR) analysis to examine the relationship between adiposity and CRC.Methods We used SNPs associated with adult body mass index (BMI), waist-hip ratio (WHR), childhood obesity and birth weight as instrumental variables in a MR analysis of 9254 CRC cases and 18 386 controls.Results In the MR analysis, the odds ratios (ORs) of CRC risk per unit increase in BMI, WHR and childhood obesity were 1.23 (95% CI: 1.02-1.49, P=0.033), 1.59 (95% CI: 1.08-2.34, P=0.019) and 1.07 (95% CI: 1.03-1.13, P=0.018), respectively. There was no evidence for association between birth weight and CRC (OR=1.22, 95% CI: 0.89-1.67, P=0.22). Combining these data with a concurrent MR-based analysis for BMI and WHR with CRC risk (totalling to 18 190 cases, 27 617 controls) provided increased support, ORs for BMI and WHR were 1.26 (95% CI: 1.10-1.44, P=7.7 × 10(-4)) and 1.40 (95% CI: 1.14-1.72, P=1.2 × 10(-3)), respectively.Conclusions These data provide further evidence for a strong causal relationship between adiposity and the risk of developing CRC highlighting the urgent need for prevention and treatment of adiposity..
Fehringer, G.
Kraft, P.
Pharoah, P.D.
Eeles, R.A.
Chatterjee, N.
Schumacher, F.R.
Schildkraut, J.M.
Lindström, S.
Brennan, P.
Bickeböller, H.
Houlston, R.S.
Landi, M.T.
Caporaso, N.
Risch, A.
Amin Al Olama, A.
Berndt, S.I.
Giovannucci, E.L.
Grönberg, H.
Kote-Jarai, Z.
Ma, J.
Muir, K.
Stampfer, M.J.
Stevens, V.L.
Wiklund, F.
Willett, W.C.
Goode, E.L.
Permuth, J.B.
Risch, H.A.
Reid, B.M.
Bezieau, S.
Brenner, H.
Chan, A.T.
Chang-Claude, J.
Hudson, T.J.
Kocarnik, J.K.
Newcomb, P.A.
Schoen, R.E.
Slattery, M.L.
White, E.
Adank, M.A.
Ahsan, H.
Aittomäki, K.
Baglietto, L.
Blomquist, C.
Canzian, F.
Czene, K.
Dos-Santos-Silva, I.
Eliassen, A.H.
Figueroa, J.D.
Flesch-Janys, D.
Fletcher, O.
Garcia-Closas, M.
Gaudet, M.M.
Johnson, N.
Hall, P.
Hazra, A.
Hein, R.
Hofman, A.
Hopper, J.L.
Irwanto, A.
Johansson, M.
Kaaks, R.
Kibriya, M.G.
Lichtner, P.
Liu, J.
Lund, E.
Makalic, E.
Meindl, A.
Müller-Myhsok, B.
Muranen, T.A.
Nevanlinna, H.
Peeters, P.H.
Peto, J.
Prentice, R.L.
Rahman, N.
Sanchez, M.J.
Schmidt, D.F.
Schmutzler, R.K.
Southey, M.C.
Tamimi, R.
Travis, R.C.
Turnbull, C.
Uitterlinden, A.G.
Wang, Z.
Whittemore, A.S.
Yang, X.R.
Zheng, W.
Buchanan, D.D.
Casey, G.
Conti, D.V.
Edlund, C.K.
Gallinger, S.
Haile, R.W.
Jenkins, M.
Le Marchand, L.
Li, L.
Lindor, N.M.
Schmit, S.L.
Thibodeau, S.N.
Woods, M.O.
Rafnar, T.
Gudmundsson, J.
Stacey, S.N.
Stefansson, K.
Sulem, P.
Chen, Y.A.
Tyrer, J.P.
Christiani, D.C.
Wei, Y.
Shen, H.
Hu, Z.
Shu, X.-.
Shiraishi, K.
Takahashi, A.
Bossé, Y.
Obeidat, M.
Nickle, D.
Timens, W.
Freedman, M.L.
Li, Q.
Seminara, D.
Chanock, S.J.
Gong, J.
Peters, U.
Gruber, S.B.
Amos, C.I.
Sellers, T.A.
Easton, D.F.
Hunter, D.J.
Haiman, C.A.
Henderson, B.E.
Hung, R.J.
Ovarian Cancer Association Consortium (OCAC),
PRACTICAL Consortium,
Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON),
Colorectal Transdisciplinary (CORECT) Study,
African American Breast Cancer Consortium (AABC) and African Ancestry Prostate Cancer Consortium (AAPC),
(2016). Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations. Cancer research,
Vol.76
(17),
pp. 5103-5114.
show abstract
Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14. ©2016 AACR..
Speedy, H.E.
Kinnersley, B.
Chubb, D.
Broderick, P.
Law, P.J.
Litchfield, K.
Jayne, S.
Dyer, M.J.
Dearden, C.
Follows, G.A.
Catovsky, D.
Houlston, R.S.
(2016). Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia. Blood,
Vol.128
(19),
pp. 2319-2326.
show abstract
Chronic lymphocytic leukemia (CLL) can be familial; however, thus far no rare germ line disruptive alleles for CLL have been identified. We performed whole-exome sequencing of 66 CLL families, identifying 4 families where loss-of-function mutations in protection of telomeres 1 (POT1) co-segregated with CLL. The p.Tyr36Cys mutation is predicted to disrupt the interaction between POT1 and the telomeric overhang. The c.1164-1G>A splice-site, p.Gln358SerfsTer13 frameshift, and p.Gln376Arg missense mutations are likely to impact the interaction between POT1 and adrenocortical dysplasia homolog (ACD), which is a part of the telomere-capping shelterin complex. We also identified mutations in ACD (c.752-2A>C) and another shelterin component, telomeric repeat binding factor 2, interacting protein (p.Ala104Pro and p.Arg133Gln), in 3 CLL families. In a complementary analysis of 1083 cases and 5854 controls, the POT1 p.Gln376Arg variant, which has a global minor allele frequency of 0.0005, conferred a 3.61-fold increased risk of CLL (P = .009). This study further highlights telomere dysregulation as a key process in CLL development..
Kandaswamy, R.
Sava, G.P.
Speedy, H.E.
Beà, S.
Martín-Subero, J.I.
Studd, J.B.
Migliorini, G.
Law, P.J.
Puente, X.S.
Martín-García, D.
Salaverria, I.
Gutiérrez-Abril, J.
López-Otín, C.
Catovsky, D.
Allan, J.M.
Campo, E.
Houlston, R.S.
(2016). Genetic Predisposition to Chronic Lymphocytic Leukemia Is Mediated by a BMF Super-Enhancer Polymorphism. Cell reports,
Vol.16
(8),
pp. 2061-2067.
show abstract
Chronic lymphocytic leukemia (CLL) is an adult B cell malignancy. Genome-wide association studies show that variation at 15q15.1 influences CLL risk. We deciphered the causal variant at 15q15.1 and the mechanism by which it influences tumorigenesis. We imputed all possible genotypes across the locus and then mapped highly associated SNPs to areas of chromatin accessibility, evolutionary conservation, and transcription factor binding. SNP rs539846 C>A, the most highly associated variant (p = 1.42 × 10(-13), odds ratio = 1.35), localizes to a super-enhancer defined by extensive histone H3 lysine 27 acetylation in intron 3 of B cell lymphoma 2 (BCL2)-modifying factor (BMF). The rs539846-A risk allele alters a conserved RELA-binding motif, disrupts RELA binding, and is associated with decreased BMF expression in CLL. These findings are consistent with rs539846 influencing CLL susceptibility through differential RELA binding, with direct modulation of BMF expression impacting on anti-apoptotic BCL2, a hallmark of oncogenic dependency in CLL..
Zuber, V.
Marconett, C.N.
Shi, J.
Hua, X.
Wheeler, W.
Yang, C.
Song, L.
Dale, A.M.
Laplana, M.
Risch, A.
Witoelar, A.
Thompson, W.K.
Schork, A.J.
Bettella, F.
Wang, Y.
Djurovic, S.
Zhou, B.
Borok, Z.
van der Heijden, H.F.
de Graaf, J.
Swinkels, D.
Aben, K.K.
McKay, J.
Hung, R.J.
Bikeböller, H.
Stevens, V.L.
Albanes, D.
Caporaso, N.E.
Han, Y.
Wei, Y.
Panadero, M.A.
Mayordomo, J.I.
Christiani, D.C.
Kiemeney, L.
Andreassen, O.A.
Houlston, R.
Amos, C.I.
Chatterjee, N.
Laird-Offringa, I.A.
Mills, I.G.
Landi, M.T.
(2016). Pleiotropic Analysis of Lung Cancer and Blood Triglycerides. Journal of the national cancer institute,
Vol.108
(12).
show abstract
Epidemiologically related traits may share genetic risk factors, and pleiotropic analysis could identify individual loci associated with these traits. Because of their shared epidemiological associations, we conducted pleiotropic analysis of genome-wide association studies of lung cancer (12 160 lung cancer case patients and 16 838 control subjects) and cardiovascular disease risk factors (blood lipids from 188 577 subjects, type 2 diabetes from 148 821 subjects, body mass index from 123 865 subjects, and smoking phenotypes from 74 053 subjects). We found that 6p22.1 (rs6904596, ZNF184) was associated with both lung cancer (P = 5.50x10(-6)) and blood triglycerides (P = 1.39x10(-5)). We replicated the association in 6097 lung cancer case patients and 204 657 control subjects (P = 2.40 × 10(-4)) and in 71 113 subjects with triglycerides data (P = .01). rs6904596 reached genome-wide significance in lung cancer meta-analysis (odds ratio = 1.15, 95% confidence interval = 1.10 to 1.21 ,: Pcombined = 5.20x10(-9)). The large sample size provided by the lipid GWAS data and the shared genetic risk factors between the two traits contributed to the uncovering of a hitherto unidentified genetic locus for lung cancer..
Karami, S.
Han, Y.
Pande, M.
Cheng, I.
Rudd, J.
Pierce, B.L.
Nutter, E.L.
Schumacher, F.R.
Kote-Jarai, Z.
Lindstrom, S.
Witte, J.S.
Fang, S.
Han, J.
Kraft, P.
Hunter, D.J.
Song, F.
Hung, R.J.
McKay, J.
Gruber, S.B.
Chanock, S.J.
Risch, A.
Shen, H.
Haiman, C.A.
Boardman, L.
Ulrich, C.M.
Casey, G.
Peters, U.
Amin Al Olama, A.
Berchuck, A.
Berndt, S.I.
Bezieau, S.
Brennan, P.
Brenner, H.
Brinton, L.
Caporaso, N.
Chan, A.T.
Chang-Claude, J.
Christiani, D.C.
Cunningham, J.M.
Easton, D.
Eeles, R.A.
Eisen, T.
Gala, M.
Gallinger, S.J.
Gayther, S.A.
Goode, E.L.
Grönberg, H.
Henderson, B.E.
Houlston, R.
Joshi, A.D.
Küry, S.
Landi, M.T.
Le Marchand, L.
Muir, K.
Newcomb, P.A.
Permuth-Wey, J.
Pharoah, P.
Phelan, C.
Potter, J.D.
Ramus, S.J.
Risch, H.
Schildkraut, J.
Slattery, M.L.
Song, H.
Wentzensen, N.
White, E.
Wiklund, F.
Zanke, B.W.
Sellers, T.A.
Zheng, W.
Chatterjee, N.
Amos, C.I.
Doherty, J.A.
GECCO and the GAME-ON Network: CORECT, D.R.
(2016). Telomere structure and maintenance gene variants and risk of five cancer types. International journal of cancer,
Vol.139
(12),
pp. 2655-2670.
show abstract
Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level p value cutoffs ≤3.08 × 10 -5 ). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk..
Johnson, N.
De Ieso, P.
Migliorini, G.
Orr, N.
Broderick, P.
Catovsky, D.
Matakidou, A.
Eisen, T.
Goldsmith, C.
Dudbridge, F.
Peto, J.
dos-Santos-Silva, I.
Ashworth, A.
Ross, G.
Houlston, R.S.
Fletcher, O.
(2016). Cytochrome P450 Allele CYP3A7*1C Associates with Adverse Outcomes in Chronic Lymphocytic Leukemia, Breast, and Lung Cancer. Cancer research,
Vol.76
(6),
pp. 1485-1493.
show abstract
Abstract
CYP3A enzymes metabolize endogenous hormones and chemotherapeutic agents used to treat cancer, thereby potentially affecting drug effectiveness. Here, we refined the genetic basis underlying the functional effects of a CYP3A haplotype on urinary estrone glucuronide (E1G) levels and tested for an association between CYP3A genotype and outcome in patients with chronic lymphocytic leukemia (CLL), breast, or lung cancers. The most significantly associated SNP was rs45446698, an SNP that tags the CYP3A7*1C allele; this SNP was associated with a 54% decrease in urinary E1G levels. Genotyping this SNP in 1,008 breast cancer, 1,128 lung cancer, and 347 CLL patients, we found that rs45446698 was associated with breast cancer mortality (HR, 1.74; P = 0.03), all-cause mortality in lung cancer patients (HR, 1.43; P = 0.009), and CLL progression (HR, 1.62; P = 0.03). We also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (Pinteraction = 0.06). The CYP3A7*1C allele, which results in adult expression of the fetal CYP3A7 gene, is likely to be the functional allele influencing levels of circulating endogenous sex hormones and outcome in these various malignancies. Further studies confirming these associations and determining the mechanism by which CYP3A7*1C influences outcome are required. One possibility is that standard chemotherapy regimens that include CYP3A substrates may not be optimal for the approximately 8% of cancer patients who are CYP3A7*1C carriers. Cancer Res; 76(6); 1485–93. ©2016 AACR..
Litchfield, K.
Levy, M.
Dudakia, D.
Proszek, P.
Shipley, C.
Basten, S.
Rapley, E.
Bishop, D.T.
Reid, A.
Huddart, R.
Broderick, P.
Castro, D.G.
O'Connor, S.
Giles, R.H.
Houlston, R.S.
Turnbull, C.
(2016). Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility. Nature communications,
Vol.7,
pp. 13840-?.
show abstract
Testicular germ cell tumour (TGCT) is the most common cancer in young men. Here we sought to identify risk factors for TGCT by performing whole-exome sequencing on 328 TGCT cases from 153 families, 634 sporadic TGCT cases and 1,644 controls. We search for genes that are recurrently affected by rare variants (minor allele frequency <0.01) with potentially damaging effects and evidence of segregation in families. A total of 8.7% of TGCT families carry rare disruptive mutations in the cilia-microtubule genes (CMG) as compared with 0.5% of controls (P=2.1 × 10 -8 ). The most significantly mutated CMG is DNAAF1 with biallelic inactivation and loss of DNAAF1 expression shown in tumours from carriers. DNAAF1 mutation as a cause of TGCT is supported by a dnaaf1 hu255h (+/-) zebrafish model, which has a 94% risk of TGCT. Our data implicate cilia-microtubule inactivation as a cause of TGCT and provide evidence for CMGs as cancer susceptibility genes..
Chubb, D.
Broderick, P.
Dobbins, S.E.
Frampton, M.
Kinnersley, B.
Penegar, S.
Price, A.
Ma, Y.P.
Sherborne, A.L.
Palles, C.
Timofeeva, M.N.
Bishop, D.T.
Dunlop, M.G.
Tomlinson, I.
Houlston, R.S.
(2016). Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer. Nature communications,
Vol.7,
pp. 11883-?.
show abstract
Colorectal cancer (CRC) displays a complex pattern of inheritance. It is postulated that much of the missing heritability of CRC is enshrined in high-impact rare alleles, which are mechanistically and clinically important. In this study, we assay the impact of rare germline mutations on CRC, analysing high-coverage exome sequencing data on 1,006 early-onset familial CRC cases and 1,609 healthy controls, with additional sequencing and array data on up to 5,552 cases and 6,792 controls. We identify highly penetrant rare mutations in 16% of familial CRC. Although the majority of these reside in known genes, we identify POT1, POLE2 and MRE11 as candidate CRC genes. We did not identify any coding low-frequency alleles (1-5%) with moderate effect. Our study clarifies the genetic architecture of CRC and probably discounts the existence of further major high-penetrance susceptibility genes, which individually account for >1% of the familial risk. Our results inform future study design and provide a resource for contextualizing the impact of new CRC genes..
Li, N.
Johnson, D.C.
Weinhold, N.
Studd, J.B.
Orlando, G.
Mirabella, F.
Mitchell, J.S.
Meissner, T.
Kaiser, M.
Goldschmidt, H.
Hemminki, K.
Morgan, G.J.
Houlston, R.S.
(2016). Multiple myeloma risk variant at 7p15 3 creates an IRF4-binding site and interferes with CDCA7L expression. Nature communications,
Vol.7,
pp. 13656-?.
show abstract
Genome-wide association studies have identified several risk loci for multiple myeloma (MM); however, the mechanisms by which they influence MM are unknown. Here by using genetic association data and functional characterization, we demonstrate that rs4487645 G>T, the most highly associated variant (P = 5.30 × 10-25), resides in an enhancer element 47 kb upstream of the transcription start site of c-Myc-interacting CDCA7L. The G-risk allele, associated with increased CDCA7L expression (P=1.95 × 10-36), increases IRF4 binding and the enhancer interacts with the CDCA7L promoter. We show that suppression of CDCA7L limits MM proliferation through apoptosis, and increased CDCA7L expression is associated with adverse patient survival. These findings implicate IRF4-mediated CDCA7L expression in MM biology and indicate how germline variation might confer susceptibility to MM..
Dobbins, S.E.
Broderick, P.
Chubb, D.
Kinnersley, B.
Sherborne, A.L.
Houlston, R.S.
(2016). Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes. Fam cancer,
Vol.15
(4),
pp. 593-599.
show abstract
Although family history is a major risk factor for colorectal cancer (CRC) a genetic diagnosis cannot be obtained in over 50 % of familial cases when screened for known CRC cancer susceptibility genes. The genetics of undefined-familial CRC is complex and recent studies have implied additional clinically actionable mutations for CRC in susceptibility genes for other cancers. To clarify the contribution of non-CRC susceptibility genes to undefined-familial CRC we conducted a mutational screen of 114 cancer susceptibility genes in 847 patients with early-onset undefined-familial CRC and 1609 controls by analysing high-coverage exome sequencing data. We implemented American College of Medical Genetics and Genomics standards and guidelines for assigning pathogenicity to variants. Globally across all 114 cancer susceptibility genes no statistically significant enrichment of likely pathogenic variants was shown (6.7 % cases 57/847, 5.3 % controls 85/1609; P = 0.15). Moreover there was no significant enrichment of mutations in genes such as TP53 or BRCA2 which have been proposed for clinical testing in CRC. In conclusion, while we identified genes that may be considered interesting candidates as determinants of CRC risk warranting further research, there is currently scant evidence to support a role for genes other than those responsible for established CRC syndromes in the clinical management of familial CRC..
Johnson, D.C.
Weinhold, N.
Mitchell, J.
Chen, B.
Stephens, O.W.
Försti, A.
Nickel, J.
Kaiser, M.
Gregory, W.A.
Cairns, D.
others,
(2016). Genetic factors influencing the risk of multiple myeloma bone disease. Leukemia,
Vol.30,
pp. 883-888.
Johnson, D.C.
Weinhold, N.
Mitchell, J.S.
Chen, B.
Kaiser, M.
Hillengass, J.
Bertsch, U.
Gregory, W.A.
Cairns, D.
Jackson, G.H.
others,
(2016). Genome-wide association study identifies variation at 6q25 1 associated with survival in multiple myeloma. Nature communications,
Vol.7.
Mitchell, J.S.
Li, N.
Weinhold, N.
Försti, A.
Ali, M.
Van Duin, M.
Thorleifsson, G.
Johnson, D.C.
Chen, B.
Halvarsson, B.-.
others,
(2016). Genome-wide association study identifies multiple susceptibility loci for multiple myeloma. Nature communications,
Vol.7.
Galvan, A.
Colombo, F.
Frullanti, E.
Dassano, A.
Noci, S.
Wang, Y.
Eisen, T.
Matakidou, A.
Tomasello, L.
Vezzalini, M.
Sorio, C.
Dugo, M.
Ambrogi, F.
Iacobucci, I.
Martinelli, G.
Incarbone, M.
Alloisio, M.
Nosotti, M.
Tosi, D.
Santambrogio, L.
Pelosi, G.
Pastorino, U.
Houlston, R.S.
Dragani, T.A.
(2015). Germline polymorphisms and survival of lung adenocarcinoma patients: A genome-wide study in two European patient series. International journal of cancer,
Vol.136
(5),
pp. E262-E271.
Bainbridge, M.N.
Armstrong, G.N.
Gramatges, M.M.
Bertuch, A.A.
Jhangiani, S.N.
Doddapaneni, H.
Lewis, L.
Tombrello, J.
Tsavachidis, S.
Liu, Y.
Jalali, A.
Plon, S.E.
Lau, C.C.
Parsons, D.W.
Claus, E.B.
Barnholtz-Sloan, J.
Il'yasova, D.
Schildkraut, J.
Ali-Osman, F.
Sadetzki, S.
Johansen, C.
Houlston, R.S.
Jenkins, R.B.
Lachance, D.
Olson, S.H.
Bernstein, J.L.
Merrell, R.T.
Wrensch, M.R.
Walsh, K.M.
Davis, F.G.
Lai, R.
Shete, S.
Aldape, K.
Amos, C.I.
Thompson, P.A.
Muzny, D.M.
Gibbs, R.A.
Melin, B.S.
Bondy, M.L.
Gliogene Consortium,
(2015). Germline mutations in shelterin complex genes are associated with familial glioma. J natl cancer inst,
Vol.107
(1),
p. 384.
show abstract
Gliomas are the most common brain tumor, with several histological subtypes of various malignancy grade. The genetic contribution to familial glioma is not well understood. Using whole exome sequencing of 90 individuals from 55 families, we identified two families with mutations in POT1 (p.G95C, p.E450X), a member of the telomere shelterin complex, shared by both affected individuals in each family and predicted to impact DNA binding and TPP1 binding, respectively. Validation in a separate cohort of 264 individuals from 246 families identified an additional mutation in POT1 (p.D617Efs), also predicted to disrupt TPP1 binding. All families with POT1 mutations had affected members with oligodendroglioma, a specific subtype of glioma more sensitive to irradiation. These findings are important for understanding the origin of glioma and could have importance for the future diagnostics and treatment of glioma. .
Sava, G.P.
Speedy, H.E.
Di Bernardo, M.C.
Dyer, M.J.
Holroyd, A.
Sunter, N.J.
Marr, H.
Mansouri, L.
Deaglio, S.
Karabon, L.
Frydecka, I.
Jamroziak, K.
Woszczyk, D.
Juliusson, G.
Smedby, K.E.
Jayne, S.
Majid, A.
Wang, Y.
Dearden, C.
Hall, A.G.
Mainou-Fowler, T.
Jackson, G.H.
Summerfield, G.
Harris, R.J.
Pettitt, A.R.
Allsup, D.J.
Bailey, J.R.
Pratt, G.
Pepper, C.
Fegan, C.
Rosenquist, R.
Catovsky, D.
Allan, J.M.
Houlston, R.S.
(2015). Common variation at 12q24 13 (OAS3) influences chronic lymphocytic leukemia risk. Leukemia,
Vol.29
(3),
pp. 748-751.
(2015). Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis. The lancet diabetes & endocrinology,
Vol.3
(4),
pp. 243-253.
Bartram, T.
Burkhardt, B.
Wössmann, W.
Seidemann, K.
Zimmermann, M.
Cario, G.
Lisfeld, J.
Ellinghaus, E.
Franke, A.
Houlston, R.S.
Schrappe, M.
Reiter, A.
Stanulla, M.
(2015). Childhood acute lymphoblastic leukemia-associated risk-lociIKZF1, ARID5BandCEBPEand risk of pediatric non-Hodgkin lymphoma: a report from the Berlin–Frankfurt–Münster Study Group. Leukemia & lymphoma,
Vol.56
(3),
pp. 814-816.
Jalali, A.
Amirian, E.S.
Bainbridge, M.N.
Armstrong, G.N.
Liu, Y.
Tsavachidis, S.
Jhangiani, S.N.
Plon, S.E.
Lau, C.C.
Claus, E.B.
Barnholtz-Sloan, J.S.
Il'yasova, D.
Schildkraut, J.
Ali-Osman, F.
Sadetzki, S.
Johansen, C.
Houlston, R.S.
Jenkins, R.B.
Lachance, D.
Olson, S.H.
Bernstein, J.L.
Merrell, R.T.
Wrensch, M.R.
Davis, F.G.
Lai, R.
Shete, S.
Aldape, K.
Amos, C.I.
Muzny, D.M.
Gibbs, R.A.
Melin, B.S.
Bondy, M.L.
(2015). Targeted sequencing in chromosome 17q linkage region identifies familial glioma candidates in the Gliogene Consortium. Sci rep,
Vol.5,
p. 8278.
show abstract
Glioma is a rare, but highly fatal, cancer that accounts for the majority of malignant primary brain tumors. Inherited predisposition to glioma has been consistently observed within non-syndromic families. Our previous studies, which involved non-parametric and parametric linkage analyses, both yielded significant linkage peaks on chromosome 17q. Here, we use data from next generation and Sanger sequencing to identify familial glioma candidate genes and variants on chromosome 17q for further investigation. We applied a filtering schema to narrow the original list of 4830 annotated variants down to 21 very rare (<0.1% frequency), non-synonymous variants. Our findings implicate the MYO19 and KIF18B genes and rare variants in SPAG9 and RUNDC1 as candidates worthy of further investigation. Burden testing and functional studies are planned. .
Ware, J.J.
Aveyard, P.
Broderick, P.
Houlston, R.S.
Eisen, T.
Munafò, M.R.
(2015). The association of rs1051730 genotype on adherence to and consumption of prescribed nicotine replacement therapy dose during a smoking cessation attempt. Drug and alcohol dependence,
Vol.151,
pp. 236-240.
Chubb, D.
Broderick, P.
Frampton, M.
Kinnersley, B.
Sherborne, A.
Penegar, S.
Lloyd, A.
Ma, Y.P.
Dobbins, S.E.
Houlston, R.S.
(2015). Genetic Diagnosis of High-Penetrance Susceptibility for Colorectal Cancer (CRC) Is Achievable for a High Proportion of Familial CRC by Exome Sequencing. Journal of clinical oncology,
Vol.33
(5),
pp. 426-432.
show abstract
Purpose Knowledge of the contribution of high-penetrance susceptibility to familial colorectal cancer (CRC) is relevant to the counseling, treatment, and surveillance of CRC patients and families. Patients and Methods To quantify the impact of germline mutation to familial CRC, we sequenced the mismatch repair genes (MMR) APC, MUTYH, and SMAD4/BMPR1A in 626 early-onset familial CRC cases ascertained through a population-based United Kingdom national registry. In addition, we evaluated the contribution of mutations in the exonuclease domain (exodom) of POLE and POLD1 genes that have recently been reported to confer CRC risk. Results Overall mutations (pathogenic, likely pathogenic) in MMR genes make the highest contribution to familial CRC (10.9%). Mutations in the other established CRC genes account for 3.3% of cases. POLE/POLD1 exodom mutations were identified in three patients with family histories consistent with dominant transmission of CRC. Collectively, mutations in the known genes account for 14.2% of familial CRC (89 of 626 cases; 95% CI = 11.5, 17.2). Conclusion A genetic diagnosis is feasible in a high proportion of familial CRC. Mainstreaming such analysis in clinical practice should enable the medical management of patients and their families to be optimized. Findings suggest CRC screening of POLE and POLD1 mutation carriers should be comparable to that afforded to those at risk of HNPCC. Although the risk of CRC associated with unexplained familial CRC is in general moderate, in some families the risk is substantive and likely to be the consequence of unidentified genes, as exemplified by POLE and POLD1. Our findings have utility in the design of genetic analyses to identify such novel CRC risk genes. .
Litchfield, K.
Thomsen, H.
Mitchell, J.S.
Sundquist, J.
Houlston, R.S.
Hemminki, K.
Turnbull, C.
(2015). Quantifying the heritability of testicular germ cell tumour using both population-based and genomic approaches. Scientific reports,
Vol.5
(1).
Hung, R.J.
Ulrich, C.M.
Goode, E.L.
Brhane, Y.
Muir, K.
Chan, A.T.
Marchand, L.L.
Schildkraut, J.
Witte, J.S.
Eeles, R.
Boffetta, P.
Spitz, M.R.
Poirier, J.G.
Rider, D.N.
Fridley, B.L.
Chen, Z.
Haiman, C.
Schumacher, F.
Easton, D.F.
Landi, M.T.
Brennan, P.
Houlston, R.
Christiani, D.C.
Field, J.K.
Bickeböller, H.
Risch, A.
Kote-Jarai, Z.
Wiklund, F.
Grönberg, H.
Chanock, S.
Berndt, S.I.
Kraft, P.
Lindström, S.
Al Olama, A.A.
Song, H.
Phelan, C.
Wentzensen, N.
Peters, U.
Slattery, M.L.
Sellers, T.A.
Casey, G.
Gruber, S.B.
Hunter, D.J.
Amos, C.I.
Henderson, B.
(2015). Cross Cancer Genomic Investigation of Inflammation Pathway for Five Common Cancers: Lung, Ovary, Prostate, Breast, and Colorectal Cancer. Journal of the national cancer institute,
Vol.107
(11),
pp. djv246-djv246.
Brenner, D.R.
Amos, C.I.
Brhane, Y.
Timofeeva, M.N.
Caporaso, N.
Wang, Y.
Christiani, D.C.
Bickeböller, H.
Yang, P.
Albanes, D.
Stevens, V.L.
Gapstur, S.
McKay, J.
Boffetta, P.
Zaridze, D.
Szeszenia-Dabrowska, N.
Lissowska, J.
Rudnai, P.
Fabianova, E.
Mates, D.
Bencko, V.
Foretova, L.
Janout, V.
Krokan, H.E.
Skorpen, F.
Gabrielsen, M.E.
Vatten, L.
Njølstad, I.
Chen, C.
Goodman, G.
Lathrop, M.
Vooder, T.
Välk, K.
Nelis, M.
Metspalu, A.
Broderick, P.
Eisen, T.
Wu, X.
Zhang, D.
Chen, W.
Spitz, M.R.
Wei, Y.
Su, L.
Xie, D.
She, J.
Matsuo, K.
Matsuda, F.
Ito, H.
Risch, A.
Heinrich, J.
Rosenberger, A.
Muley, T.
Dienemann, H.
Field, J.K.
Raji, O.
Chen, Y.
Gosney, J.
Liloglou, T.
Davies, M.P.
Marcus, M.
McLaughlin, J.
Orlow, I.
Han, Y.
Li, Y.
Zong, X.
Johansson, M.
Liu, G.
Tworoger, S.S.
Le Marchand, L.
Henderson, B.E.
Wilkens, L.R.
Dai, J.
Shen, H.
Houlston, R.S.
Landi, M.T.
Brennan, P.
Hung, R.J.
(2015). Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia. Carcinogenesis,
Vol.36
(11),
pp. 1314-1326.
Labreche, K.
Simeonova, I.
Kamoun, A.
Gleize, V.
Chubb, D.
Letouzé, E.
Riazalhosseini, Y.
Dobbins, S.E.
Elarouci, N.
Ducray, F.
de Reyniès, A.
Zelenika, D.
Wardell, C.P.
Frampton, M.
Saulnier, O.
Pastinen, T.
Hallout, S.
Figarella-Branger, D.
Dehais, C.
Idbaih, A.
Mokhtari, K.
Delattre, J.-.
Huillard, E.
Mark Lathrop, G.
Sanson, M.
Houlston, R.S.
(2015). TCF12 is mutated in anaplastic oligodendroglioma. Nature communications,
Vol.6
(1).
Vijayakrishnan, J.
Henrion, M.
Moorman, A.V.
Fiege, B.
Kumar, R.
Inacio da Silva Filho, M.
Holroyd, A.
Koehler, R.
Thomsen, H.
Irving, J.A.
Allan, J.M.
Lightfoot, T.
Roman, E.
Kinsey, S.E.
Sheridan, E.
Thompson, P.D.
Hoffmann, P.
Nöthen, M.M.
Mühleisen, T.W.
Eisele, L.
Bartram, C.R.
Schrappe, M.
Greaves, M.
Hemminki, K.
Harrison, C.J.
Stanulla, M.
Houlston, R.S.
(2015). The 9p21 3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A. Scientific reports,
Vol.5
(1).
Litchfield, K.
Holroyd, A.
Lloyd, A.
Broderick, P.
Nsengimana, J.
Eeles, R.
Easton, D.F.
Dudakia, D.
Bishop, D.T.
Reid, A.
Huddart, R.A.
Grotmol, T.
Wiklund, F.
Shipley, J.
Houlston, R.S.
Turnbull, C.
(2015). Identification of four new susceptibility loci for testicular germ cell tumour. Nature communications,
Vol.6
(1).
Wang, Y.
Wei, Y.
Gaborieau, V.
Shi, J.
Han, Y.
Timofeeva, M.N.
Su, L.
Li, Y.
Eisen, T.
Amos, C.I.
Landi, M.T.
Christiani, D.C.
McKay, J.D.
Houlston, R.S.
(2015). Deciphering associations for lung cancer risk through imputation and analysis of 12 316 cases and 16 831 controls. European journal of human genetics,
Vol.23
(12),
pp. 1723-1728.
Kinnersley, B.
Mitchell, J.S.
Gousias, K.
Schramm, J.
Idbaih, A.
Labussière, M.
Marie, Y.
Rahimian, A.
Wichmann, H.-.
Schreiber, S.
Hoang-Xuan, K.
Delattre, J.-.
Nöthen, M.M.
Mokhtari, K.
Lathrop, M.
Bondy, M.
Simon, M.
Sanson, M.
Houlston, R.S.
(2015). Quantifying the heritability of glioma using genome-wide complex trait analysis. Scientific reports,
Vol.5
(1).
Cheng, T.H.
Thompson, D.
Painter, J.
O’Mara, T.
Gorman, M.
Martin, L.
Palles, C.
Jones, A.
Buchanan, D.D.
Win, A.K.
Hopper, J.
Jenkins, M.
Lindor, N.M.
Newcomb, P.A.
Gallinger, S.
Conti, D.
Schumacher, F.
Casey, G.
Giles, G.G.
Pharoah, P.
Peto, J.
Cox, A.
Swerdlow, A.
Couch, F.
Cunningham, J.M.
Goode, E.L.
Winham, S.J.
Lambrechts, D.
Fasching, P.
Burwinkel, B.
Brenner, H.
Brauch, H.
Chang-Claude, J.
Salvesen, H.B.
Kristensen, V.
Darabi, H.
Li, J.
Liu, T.
Lindblom, A.
Hall, P.
de Polanco, M.E.
Sans, M.
Carracedo, A.
Castellvi-Bel, S.
Rojas-Martinez, A.
Aguiar Jnr, S.
Teixeira, M.R.
Dunning, A.M.
Dennis, J.
Otton, G.
Proietto, T.
Holliday, E.
Attia, J.
Ashton, K.
Scott, R.J.
McEvoy, M.
Dowdy, S.C.
Fridley, B.L.
Werner, H.M.
Trovik, J.
Njolstad, T.S.
Tham, E.
Mints, M.
Runnebaum, I.
Hillemanns, P.
Dörk, T.
Amant, F.
Schrauwen, S.
Hein, A.
Beckmann, M.W.
Ekici, A.
Czene, K.
Meindl, A.
Bolla, M.K.
Michailidou, K.
Tyrer, J.P.
Wang, Q.
Ahmed, S.
Healey, C.S.
Shah, M.
Annibali, D.
Depreeuw, J.
Al-Tassan, N.A.
Harris, R.
Meyer, B.F.
Whiffin, N.
Hosking, F.J.
Kinnersley, B.
Farrington, S.M.
Timofeeva, M.
Tenesa, A.
Campbell, H.
Haile, R.W.
Hodgson, S.
Carvajal-Carmona, L.
Cheadle, J.P.
Easton, D.
Dunlop, M.
Houlston, R.
Spurdle, A.
Tomlinson, I.
(2015). Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1. Scientific reports,
Vol.5
(1).
Timofeeva, M.N.
Kinnersley, B.
Farrington, S.M.
Whiffin, N.
Palles, C.
Svinti, V.
Lloyd, A.
Gorman, M.
Ooi, L.-.
Hosking, F.
Barclay, E.
Zgaga, L.
Dobbins, S.
Martin, L.
Theodoratou, E.
Broderick, P.
Tenesa, A.
Smillie, C.
Grimes, G.
Hayward, C.
Campbell, A.
Porteous, D.
Deary, I.J.
Harris, S.E.
Northwood, E.L.
Barrett, J.H.
Smith, G.
Wolf, R.
Forman, D.
Morreau, H.
Ruano, D.
Tops, C.
Wijnen, J.
Schrumpf, M.
Boot, A.
Vasen, H.F.
Hes, F.J.
van Wezel, T.
Franke, A.
Lieb, W.
Schafmayer, C.
Hampe, J.
Buch, S.
Propping, P.
Hemminki, K.
Försti, A.
Westers, H.
Hofstra, R.
Pinheiro, M.
Pinto, C.
Teixeira, M.
Ruiz-Ponte, C.
Fernández-Rozadilla, C.
Carracedo, A.
Castells, A.
Castellví-Bel, S.
Campbell, H.
Bishop, D.T.
Tomlinson, I.P.
Dunlop, M.G.
Houlston, R.S.
(2015). Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer. Scientific reports,
Vol.5
(1).
Zhang, C.
Doherty, J.A.
Burgess, S.
Hung, R.J.
Lindström, S.
Kraft, P.
Gong, J.
Amos, C.I.
Sellers, T.A.
Monteiro, A.N.
Chenevix-Trench, G.
Bickeböller, H.
Risch, A.
Brennan, P.
Mckay, J.D.
Houlston, R.S.
Landi, M.T.
Timofeeva, M.N.
Wang, Y.
Heinrich, J.
Kote-Jarai, Z.
Eeles, R.A.
Muir, K.
Wiklund, F.
Grönberg, H.
Berndt, S.I.
Chanock, S.J.
Schumacher, F.
Haiman, C.A.
Henderson, B.E.
Amin Al Olama, A.
Andrulis, I.L.
Hopper, J.L.
Chang-Claude, J.
John, E.M.
Malone, K.E.
Gammon, M.D.
Ursin, G.
Whittemore, A.S.
Hunter, D.J.
Gruber, S.B.
Knight, J.A.
Hou, L.
Le Marchand, L.
Newcomb, P.A.
Hudson, T.J.
Chan, A.T.
Li, L.
Woods, M.O.
Ahsan, H.
Pierce, B.L.
(2015). Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study. Human molecular genetics,
Vol.24
(18),
pp. 5356-5366.
Litchfield, K.
Mitchell, J.S.
Shipley, J.
Huddart, R.
Rajpert-De Meyts, E.
Skakkebæk, N.E.
Houlston, R.S.
Turnbull, C.
(2015). Polygenic susceptibility to testicular cancer: implications for personalised health care. British journal of cancer,
Vol.113
(10),
pp. 1512-1518.
show abstract
Abstract
Background:
The increasing incidence of testicular germ cell tumour (TGCT) combined with its strong heritable basis suggests that stratified screening for the early detection of TGCT may be clinically useful. We modelled the efficiency of such a personalised screening approach, based on genetic risk profiling in combination with other diagnostic tools.
Methods:
We compared the number of cases potentially detectable in the population under a number of screening models. The polygenic risk scoring (PRS) model was assumed to have a log-normal relative risk distribution across the 19 currently known TGCT susceptibility variants. The diagnostic performance of testicular biopsy and non-invasive semen analysis was also assessed, within a simulated combined screening programme.
Results:
The area under the curve for the TGCT PRS model was 0.72 with individuals in the top 1% of the PRS having a nine-fold increased TGCT risk compared with the population median. Results from population-screening simulations only achieved a maximal positive predictive value (PPV) of 60%, highlighting broader clinical factors that challenge such strategies, not least the rare nature of TGCT. In terms of future improvements, heritability estimates suggest that a significant number of additional genetic risk factors for TGCT remain to be discovered, identification of which would potentially yield improvement of the PPV to 80–90%.
Conclusions:
While personalised screening models may offer enhanced TGCT risk discrimination, presently the case for population-level testing is not compelling. However, future advances, such as more routine generation of whole genome data is likely to alter the landscape. More targeted screening programs may plausibly then offer clinical benefit, particularly given the significant survivorship issues associated with the successful treatment of TGCT.
.
Jäger, R.
Migliorini, G.
Henrion, M.
Kandaswamy, R.
Speedy, H.E.
Heindl, A.
Whiffin, N.
Carnicer, M.J.
Broome, L.
Dryden, N.
Nagano, T.
Schoenfelder, S.
Enge, M.
Yuan, Y.
Taipale, J.
Fraser, P.
Fletcher, O.
Houlston, R.S.
(2015). Capture Hi-C identifies the chromatin interactome of colorectal cancer risk loci. Nat commun,
Vol.6,
p. 6178.
show abstract
Multiple regulatory elements distant from their targets on the linear genome can influence the expression of a single gene through chromatin looping. Chromosome conformation capture implemented in Hi-C allows for genome-wide agnostic characterization of chromatin contacts. However, detection of functional enhancer-promoter interactions is precluded by its effective resolution that is determined by both restriction fragmentation and sensitivity of the experiment. Here we develop a capture Hi-C (cHi-C) approach to allow an agnostic characterization of these physical interactions on a genome-wide scale. Single-nucleotide polymorphisms associated with complex diseases often reside within regulatory elements and exert effects through long-range regulation of gene expression. Applying this cHi-C approach to 14 colorectal cancer risk loci allows us to identify key long-range chromatin interactions in cis and trans involving these loci. .
Litchfield, K.
Summersgill, B.
Yost, S.
Sultana, R.
Labreche, K.
Dudakia, D.
Renwick, A.
Seal, S.
Al-Saadi, R.
Broderick, P.
Turner, N.C.
Houlston, R.S.
Huddart, R.
Shipley, J.
Turnbull, C.
(2015). Whole-exome sequencing reveals the mutational spectrum of testicular germ cell tumours. Nat commun,
Vol.6,
p. 5973.
show abstract
Testicular germ cell tumours (TGCTs) are the most common cancer in young men. Here we perform whole-exome sequencing (WES) of 42 TGCTs to comprehensively study the cancer's mutational profile. The mutation rate is uniformly low in all of the tumours (mean 0.5 mutations per Mb) as compared with common cancers, consistent with the embryological origin of TGCT. In addition to expected copy number gain of chromosome 12p and mutation of KIT, we identify recurrent mutations in the tumour suppressor gene CDC27 (11.9%). Copy number analysis reveals recurring amplification of the spermatocyte development gene FSIP2 (15.3%) and a 0.4 Mb region at Xq28 (15.3%). Two treatment-refractory patients are shown to harbour XRCC2 mutations, a gene strongly implicated in defining cisplatin resistance. Our findings provide further insights into genes involved in the development and progression of TGCT..
Sud, A.
Cooke, R.
Swerdlow, A.J.
Houlston, R.S.
(2015). Genome-wide homozygosity signature and risk of Hodgkin lymphoma. Scientific reports,
Vol.5,
pp. 14315-?.
show abstract
Recent studies have reported that regions of homozygosity (ROH) in the genome are detectable in outbred populations and can be associated with an increased risk of malignancy. To examine whether homozygosity is associated with an increased risk of developing Hodgkin lymphoma (HL) we analysed 589 HL cases and 5,199 controls genotyped for 484,072 tag single nucleotide polymorphisms (SNPs). Across the genome the cumulative distribution of ROH was not significantly different between cases and controls. Seven ROH at 4q22.3, 4q32.2, 7p12.3-14.1, 7p22.2, 10p11.22-23, 19q13.12-2 and 19p13.2 were associated with HL risk at P < 0.01. Intriguingly 4q22.3 harbours an ROH to which the nuclear factor NF-kappa-B p105 subunit (NFKB1) maps (P = 0.002). The ROH at 19q13.12-2 has previously been implicated in B-cell precursor acute lymphoblastic leukaemia. Aside from these observations which require validation, it is unlikely that levels of measured homozygosity caused by autozygosity, uniparental isodisomy or hemizygosity play a major role in defining HL risk in predominantly outbred populations..
Al-Tassan, N.A.
Whiffin, N.
Hosking, F.J.
Palles, C.
Farrington, S.M.
Dobbins, S.E.
Harris, R.
Gorman, M.
Tenesa, A.
Meyer, B.F.
Wakil, S.M.
Kinnersley, B.
Campbell, H.
Martin, L.
Smith, C.G.
Idziaszczyk, S.
Barclay, E.
Maughan, T.S.
Kaplan, R.
Kerr, R.
Kerr, D.
Buchanan, D.D.
Win, A.K.
Hopper, J.
Jenkins, M.
Lindor, N.M.
Newcomb, P.A.
Gallinger, S.
Conti, D.
Schumacher, F.
Casey, G.
Dunlop, M.G.
Tomlinson, I.P.
Cheadle, J.P.
Houlston, R.S.
(2015). A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer. Scientific reports,
Vol.5
(1).
show abstract
AbstractGenome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project. The combined analysis identified new, significant associations with CRC at 1p36.2 marked by rs72647484 (minor allele frequency [MAF] = 0.09) near CDC42 and WNT4 (P = 1.21 × 10−8, odds ratio [OR] = 1.21 ) and at 16q24.1 marked by rs16941835 (MAF = 0.21, P = 5.06 × 10−8; OR = 1.15) within the long non-coding RNA (lncRNA) RP11-58A18.1 and ~500 kb from the nearest coding gene FOXL1. Additionally we identified a promising association at 10p13 with rs10904849 intronic to CUBN (MAF = 0.32, P = 7.01 × 10-8; OR = 1.14). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. Additionally, our analysis further demonstrates that imputation can be used to exploit GWAS data to identify novel disease-causing variants..
Li, W.
Dobbins, S.
Tomlinson, I.
Houlston, R.
Pal, D.K.
Strug, L.J.
(2015). Prioritizing Rare Variants with Conditional Likelihood Ratios. Human heredity,
Vol.79
(1),
pp. 5-13.
Mitchell, J.S.
Johnson, D.C.
Litchfield, K.
Broderick, P.
Weinhold, N.
Davies, F.E.
Gregory, W.A.
Jackson, G.H.
Kaiser, M.
Morgan, G.J.
others,
(2015). Implementation of genome-wide complex trait analysis to quantify the heritability in multiple myeloma. Scientific reports,
Vol.5.
Morris, E.J.
Penegar, S.
Whiffin, N.
Broderick, P.
Bishop, D.T.
Northwood, E.
Quirke, P.
Finan, P.
Houlston, R.S.
(2015). A retrospective observational study of the relationship between single nucleotide polymorphisms associated with the risk of developing colorectal cancer and survival. Plos one,
Vol.10
(2),
p. e0117816.
show abstract
BACKGROUND: There is variability in clinical outcome for patients with apparently the same stage colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) mapping to chromosomes 1q41, 3q26.2, 6p21, 8q23.3, 8q24.21, 10p14, 11q13, 11q23.1, 12q13.13, 14q22, 14q22.2, 15q13.3, 16q22.1, 18q21.1, 19q13.11, 20p12, 20p12.3, 20q13.33 and Xp22 have robustly been shown to be associated with the risk of developing CRC. Since germline variation can also influence patient outcome the relationship between these SNPs and patient survivorship from CRC was examined. METHODS: All enrolled into the National Study of Colorectal Cancer Genetics (NSCCG) were genotyped for 1q41, 3q26.2, 6p21, 8q23.3, 8q24.21, 10p14, 11q13, 11q23.1, 12q13.13, 14q22, 14q22.2, 15q13.3, 16q22.1, 18q21.1, 19q13.11, 20p12, 20p12.3, 20q13.33 and xp22 SNPs. Linking this information to the National Cancer Data Repository allowed patient genotype to be related to survival. RESULTS: The linked dataset consisted of 4,327 individuals. 14q22.22 genotype defined by the SNP rs4444235 showed a significant association with overall survival. Specifically, the C allele was associated with poorer observed survival (per allele hazard ratio 1.13, 95% confidence interval 1.05-1.22, P = 0.0015). CONCLUSION: The CRC susceptibility SNP rs4444235 also appears to exert an influence in modulating patient survival and warrants further evaluation as a potential prognostic marker..
Weinhold, N.
Meissner, T.
Johnson, D.C.
Seckinger, A.
Moreaux, J.
Försti, A.
Chen, B.
Nickel, J.
Chubb, D.
Rawstron, A.C.
others,
(2015). The 7p15 3 (rs4487645) association for multiple myeloma shows strong allele-specific regulation of the MYC-interacting gene CDCA7L in malignant plasma cells. Haematologica,
Vol.100,
pp. e110-e113.
Derkach, A.
Chiang, T.
Gong, J.
Addis, L.
Dobbins, S.
Tomlinson, I.
Houlston, R.
Pal, D.K.
Strug, L.J.
(2014). Association analysis using next-generation sequence data from publicly available control groups: the robust variance score statistic. Bioinformatics,
Vol.30
(15),
pp. 2179-2188.
show abstract
MOTIVATION: Sufficiently powered case-control studies with next-generation sequence (NGS) data remain prohibitively expensive for many investigators. If feasible, a more efficient strategy would be to include publicly available sequenced controls. However, these studies can be confounded by differences in sequencing platform; alignment, single nucleotide polymorphism and variant calling algorithms; read depth; and selection thresholds. Assuming one can match cases and controls on the basis of ethnicity and other potential confounding factors, and one has access to the aligned reads in both groups, we investigate the effect of systematic differences in read depth and selection threshold when comparing allele frequencies between cases and controls. We propose a novel likelihood-based method, the robust variance score (RVS), that substitutes genotype calls by their expected values given observed sequence data. RESULTS: We show theoretically that the RVS eliminates read depth bias in the estimation of minor allele frequency. We also demonstrate that, using simulated and real NGS data, the RVS method controls Type I error and has comparable power to the 'gold standard' analysis with the true underlying genotypes for both common and rare variants. AVAILABILITY AND IMPLEMENTATION: An RVS R script and instructions can be found at strug.research.sickkids.ca, and at https://github.com/strug-lab/RVS. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online..
Sava, G.P.
Speedy, H.E.
Houlston, R.S.
(2014). Candidate gene association studies and risk of chronic lymphocytic leukemia: a systematic review and meta-analysis. Leuk lymphoma,
Vol.55
(1),
pp. 160-167.
show abstract
To evaluate the contribution of association studies of candidate polymorphisms to inherited predisposition to chronic lymphocytic leukemia (CLL), we conducted a systematic review and meta-analysis of published case-control studies. We identified 36 studies which reported on polymorphic variation in 19 genes and CLL risk. Out of the 23 polymorphic variants, significant associations (p < 0.05) were seen in pooled analyses for only four variants: MDR1, rs1045642; LTA, rs2239704; CD38, rs6449182; and IFNGR1, rs4896243. These findings should be interpreted cautiously, as the estimated false positive report probabilities (FPRPs) for each association were not noteworthy (i.e. FPRP > 0.2). While studies of candidate polymorphisms may be an attractive means of identifying risk factors for CLL, the limited power of published studies to demonstrate statistically significant associations makes it essential that future analyses be based on sample sizes well-powered to identify variants having modest effects on CLL risk..
Speedy, H.E.
Di Bernardo, M.C.
Sava, G.P.
Dyer, M.J.
Holroyd, A.
Wang, Y.
Sunter, N.J.
Mansouri, L.
Juliusson, G.
Smedby, K.E.
Roos, G.
Jayne, S.
Majid, A.
Dearden, C.
Hall, A.G.
Mainou-Fowler, T.
Jackson, G.H.
Summerfield, G.
Harris, R.J.
Pettitt, A.R.
Allsup, D.J.
Bailey, J.R.
Pratt, G.
Pepper, C.
Fegan, C.
Rosenquist, R.
Catovsky, D.
Allan, J.M.
Houlston, R.S.
(2014). A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia. Nat genet,
Vol.46
(1),
pp. 56-60.
show abstract
Genome-wide association studies (GWAS) of chronic lymphocytic leukemia (CLL) have shown that common genetic variation contributes to the heritable risk of CLL. To identify additional CLL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1,739 individuals with CLL (cases) and 5,199 controls with validation in an additional 1,144 cases and 3,151 controls. A combined analysis identified new susceptibility loci mapping to 3q26.2 (rs10936599, P = 1.74 × 10(-9)), 4q26 (rs6858698, P = 3.07 × 10(-9)), 6q25.2 (IPCEF1, rs2236256, P = 1.50 × 10(-10)) and 7q31.33 (POT1, rs17246404, P = 3.40 × 10(-8)). Additionally, we identified a promising association at 5p15.33 (CLPTM1L, rs31490, P = 1.72 × 10(-7)) and validated recently reported putative associations at 5p15.33 (TERT, rs10069690, P = 1.12 × 10(-10)) and 8q22.3 (rs2511714, P = 2.90 × 10(-9)). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CLL. .
Whiffin, N.
Hosking, F.J.
Farrington, S.M.
Palles, C.
Dobbins, S.E.
Zgaga, L.
Lloyd, A.
Kinnersley, B.
Gorman, M.
Tenesa, A.
Broderick, P.
Wang, Y.
Barclay, E.
Hayward, C.
Martin, L.
Buchanan, D.D.
Win, A.K.
Hopper, J.
Jenkins, M.
Lindor, N.M.
Newcomb, P.A.
Gallinger, S.
Conti, D.
Schumacher, F.
Casey, G.
Liu, T.
Swedish Low-Risk Colorectal Cancer Study Group,
Campbell, H.
Lindblom, A.
Houlston, R.S.
Tomlinson, I.P.
Dunlop, M.G.
(2014). Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis. Hum mol genet,
Vol.23
(17),
pp. 4729-4737.
show abstract
To identify common variants influencing colorectal cancer (CRC) risk, we performed a meta-analysis of five genome-wide association studies, comprising 5626 cases and 7817 controls of European descent. We conducted replication of top ranked single nucleotide polymorphisms (SNPs) in additional series totalling 14 037 cases and 15 937 controls, identifying a new CRC risk locus at 10q24.2 [rs1035209; odds ratio (OR) = 1.13, P = 4.54 × 10(-11)]. We also performed meta-analysis of our studies, with previously published data, of several recently purported CRC risk loci. We failed to find convincing evidence for a previously reported genome-wide association at rs11903757 (2q32.3). Of the three additional loci for which evidence of an association in Europeans has been previously described we failed to show an association between rs59336 (12q24.21) and CRC risk. However, for the other two SNPs, our analyses demonstrated new, formally significant associations with CRC. These are rs3217810 intronic in CCND2 (12p13.32; OR = 1.19, P = 2.16 × 10(-10)) and rs10911251 near LAMC1 (1q25.3; OR = 1.09, P = 1.75 × 10(-8)). Additionally, we found some evidence to support a relationship between, rs647161, rs2423297 and rs10774214 and CRC risk originally identified in East Asians in our European datasets. Our findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. .
Morgan, G.J.
Johnson, D.C.
Weinhold, N.
Goldschmidt, H.
Landgren, O.
Lynch, H.T.
Hemminki, K.
Houlston, R.S.
(2014). Inherited genetic susceptibility to multiple myeloma. Leukemia,
Vol.28
(3),
pp. 518-524.
show abstract
Although the familial clustering of multiple myeloma (MM) supports the role of inherited susceptibility, only recently has direct evidence for genetic predisposition been demonstrated. A meta-analysis of two genome-wide association (GWA) studies has identified single-nucleotide polymorphisms (SNPs) localising to a number of genomic regions that are robustly associated with MM risk. In this review, we provide an overview of the evidence supporting a genetic contribution to the predisposition to MM and MGUS (monoclonal gammopathy of unknown significance), and the insight this gives into the biological basis of disease aetiology. We also highlight the promise of future approaches to identify further specific risk factors and their potential clinical utility. .
Sawyer, E.
Roylance, R.
Petridis, C.
Brook, M.N.
Nowinski, S.
Papouli, E.
Fletcher, O.
Pinder, S.
Hanby, A.
Kohut, K.
Gorman, P.
Caneppele, M.
Peto, J.
Dos Santos Silva, I.
Johnson, N.
Swann, R.
Dwek, M.
Perkins, K.-.
Gillett, C.
Houlston, R.
Ross, G.
De Ieso, P.
Southey, M.C.
Hopper, J.L.
Provenzano, E.
Apicella, C.
Wesseling, J.
Cornelissen, S.
Keeman, R.
Fasching, P.A.
Jud, S.M.
Ekici, A.B.
Beckmann, M.W.
Kerin, M.J.
Marme, F.
Schneeweiss, A.
Sohn, C.
Burwinkel, B.
Guénel, P.
Truong, T.
Laurent-Puig, P.
Kerbrat, P.
Bojesen, S.E.
Nordestgaard, B.G.
Nielsen, S.F.
Flyger, H.
Milne, R.L.
Perez, J.I.
Menéndez, P.
Benitez, J.
Brenner, H.
Dieffenbach, A.K.
Arndt, V.
Stegmaier, C.
Meindl, A.
Lichtner, P.
Schmutzler, R.K.
Lochmann, M.
Brauch, H.
Fischer, H.-.
Ko, Y.-.
GENICA Network,
Nevanlinna, H.
Muranen, T.A.
Aittomäki, K.
Blomqvist, C.
Bogdanova, N.V.
Dörk, T.
Lindblom, A.
Margolin, S.
Mannermaa, A.
Kataja, V.
Kosma, V.-.
Hartikainen, J.M.
Chenevix-Trench, G.
KConFab Investigators,
Lambrechts, D.
Weltens, C.
Van Limbergen, E.
Hatse, S.
Chang-Claude, J.
Rudolph, A.
Seibold, P.
Flesch-Janys, D.
Radice, P.
Peterlongo, P.
Bonanni, B.
Volorio, S.
Giles, G.G.
Severi, G.
Baglietto, L.
McLean, C.A.
Haiman, C.A.
Henderson, B.E.
Schumacher, F.
Le Marchand, L.
Simard, J.
Goldberg, M.S.
Labrèche, F.
Dumont, M.
Kristensen, V.
Winqvist, R.
Pylkäs, K.
Jukkola-Vuorinen, A.
Kauppila, S.
Andrulis, I.L.
Knight, J.A.
Glendon, G.
Mulligan, A.M.
Devillee, P.
Tollenaar, R.A.
Seynaeve, C.M.
Kriege, M.
Figueroa, J.
Chanock, S.J.
Sherman, M.E.
Hooning, M.J.
Hollestelle, A.
van den Ouweland, A.M.
van Deurzen, C.H.
Li, J.
Czene, K.
Humphreys, K.
Cox, A.
Cross, S.S.
Reed, M.W.
Shah, M.
Jakubowska, A.
Lubinski, J.
Jaworska-Bieniek, K.
Durda, K.
Swerdlow, A.
Ashworth, A.
Orr, N.
Schoemaker, M.
Couch, F.J.
Hallberg, E.
González-Neira, A.
Pita, G.
Alonso, M.R.
Tessier, D.C.
Vincent, D.
Bacot, F.
Bolla, M.K.
Wang, Q.
Dennis, J.
Michailidou, K.
Dunning, A.M.
Hall, P.
Easton, D.
Pharoah, P.
Schmidt, M.K.
Tomlinson, I.
Garcia-Closas, M.
(2014). Genetic predisposition to in situ and invasive lobular carcinoma of the breast. Plos genet,
Vol.10
(4),
p. e1004285.
show abstract
Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes..
Park, S.L.
Fesinmeyer, M.D.
Timofeeva, M.
Caberto, C.P.
Kocarnik, J.M.
Han, Y.
Love, S.-.
Young, A.
Dumitrescu, L.
Lin, Y.
Goodloe, R.
Wilkens, L.R.
Hindorff, L.
Fowke, J.H.
Carty, C.
Buyske, S.
Schumacher, F.R.
Butler, A.
Dilks, H.
Deelman, E.
Cote, M.L.
Chen, W.
Pande, M.
Christiani, D.C.
Field, J.K.
Bickeboeller, H.
Risch, A.
Heinrich, J.
Brennan, P.
Wang, Y.
Eisen, T.
Houlston, R.S.
Thun, M.
Albanes, D.
Caporaso, N.
Peters, U.
North, K.E.
Heiss, G.
Crawford, D.C.
Bush, W.S.
Haiman, C.A.
Landi, M.T.
Hung, R.J.
Kooperberg, C.
Amos, C.I.
Le Marchand, L.
Cheng, I.
(2014). Pleiotropic Associations of Risk Variants Identified for Other Cancers With Lung Cancer Risk: The PAGE and TRICL Consortia. Jnci-journal of the national cancer institute,
Vol.106
(4).
Ongen, H.
Andersen, C.L.
Bramsen, J.B.
Oster, B.
Rasmussen, M.H.
Ferreira, P.G.
Sandoval, J.
Vidal, E.
Whiffin, N.
Planchon, A.
Padioleau, I.
Bielser, D.
Romano, L.
Tomlinson, I.
Houlston, R.S.
Esteller, M.
Orntoft, T.F.
Dermitzakis, E.T.
(2014). Putative cis-regulatory drivers in colorectal cancer. Nature,
Vol.512
(7512),
pp. 87-90.
show abstract
The cis-regulatory effects responsible for cancer development have not been as extensively studied as the perturbations of the protein coding genome in tumorigenesis. To better characterize colorectal cancer (CRC) development we conducted an RNA-sequencing experiment of 103 matched tumour and normal colon mucosa samples from Danish CRC patients, 90 of which were germline-genotyped. By investigating allele-specific expression (ASE) we show that the germline genotypes remain important determinants of allelic gene expression in tumours. Using the changes in ASE in matched pairs of samples we discover 71 genes with excess of somatic cis-regulatory effects in CRC, suggesting a cancer driver role. We correlate genotypes and gene expression to identify expression quantitative trait loci (eQTLs) and find 1,693 and 948 eQTLs in normal samples and tumours, respectively. We estimate that 36% of the tumour eQTLs are exclusive to CRC and show that this specificity is partially driven by increased expression of specific transcription factors and changes in methylation patterns. We show that tumour-specific eQTLs are more enriched for low CRC genome-wide association study (GWAS) P values than shared eQTLs, which suggests that some of the GWAS variants are tumour specific regulatory variants. Importantly, tumour-specific eQTL genes also accumulate more somatic mutations when compared to the shared eQTL genes, raising the possibility that they constitute germline-derived cancer regulatory drivers. Collectively the integration of genome and the transcriptome reveals a substantial number of putative somatic and germline cis-regulatory cancer changes that may have a role in tumorigenesis. .
Wang, Y.
McKay, J.D.
Rafnar, T.
Wang, Z.
Timofeeva, M.N.
Broderick, P.
Zong, X.
Laplana, M.
Wei, Y.
Han, Y.
Lloyd, A.
Delahaye-Sourdeix, M.
Chubb, D.
Gaborieau, V.
Wheeler, W.
Chatterjee, N.
Thorleifsson, G.
Sulem, P.
Liu, G.
Kaaks, R.
Henrion, M.
Kinnersley, B.
Vallée, M.
LeCalvez-Kelm, F.
Stevens, V.L.
Gapstur, S.M.
Chen, W.V.
Zaridze, D.
Szeszenia-Dabrowska, N.
Lissowska, J.
Rudnai, P.
Fabianova, E.
Mates, D.
Bencko, V.
Foretova, L.
Janout, V.
Krokan, H.E.
Gabrielsen, M.E.
Skorpen, F.
Vatten, L.
Njølstad, I.
Chen, C.
Goodman, G.
Benhamou, S.
Vooder, T.
Välk, K.
Nelis, M.
Metspalu, A.
Lener, M.
Lubiński, J.
Johansson, M.
Vineis, P.
Agudo, A.
Clavel-Chapelon, F.
Bueno-de-Mesquita, H.B.
Trichopoulos, D.
Khaw, K.-.
Johansson, M.
Weiderpass, E.
Tjønneland, A.
Riboli, E.
Lathrop, M.
Scelo, G.
Albanes, D.
Caporaso, N.E.
Ye, Y.
Gu, J.
Wu, X.
Spitz, M.R.
Dienemann, H.
Rosenberger, A.
Su, L.
Matakidou, A.
Eisen, T.
Stefansson, K.
Risch, A.
Chanock, S.J.
Christiani, D.C.
Hung, R.J.
Brennan, P.
Landi, M.T.
Houlston, R.S.
Amos, C.I.
(2014). Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer. Nat genet,
Vol.46
(7),
pp. 736-741.
show abstract
We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 × 10(-20)) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10(-13)). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10(-10)) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data. .
Andersson, U.
Wibom, C.
Cederquist, K.
Aradottir, S.
Borg, A.
Armstrong, G.N.
Shete, S.
Lau, C.C.
Bainbridge, M.N.
Claus, E.B.
Barnholtz-Sloan, J.
Lai, R.
Il'yasova, D.
Houlston, R.S.
Schildkraut, J.
Bernstein, J.L.
Olson, S.H.
Jenkins, R.B.
Lachance, D.H.
Wrensch, M.
Davis, F.G.
Merrell, R.
Johansen, C.
Sadetzki, S.
Gliogene Consortium,
Bondy, M.L.
Melin, B.S.
(2014). Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer. Neuro oncol,
Vol.16
(10),
pp. 1333-1340.
show abstract
BACKGROUND: Although familial susceptibility to glioma is known, the genetic basis for this susceptibility remains unidentified in the majority of glioma-specific families. An alternative approach to identifying such genes is to examine cancer pedigrees, which include glioma as one of several cancer phenotypes, to determine whether common chromosomal modifications might account for the familial aggregation of glioma and other cancers. METHODS: Germline rearrangements in 146 glioma families (from the Gliogene Consortium; http://www.gliogene.org/) were examined using multiplex ligation-dependent probe amplification. These families all had at least 2 verified glioma cases and a third reported or verified glioma case in the same family or 2 glioma cases in the family with at least one family member affected with melanoma, colon, or breast cancer.The genomic areas covering TP53, CDKN2A, MLH1, and MSH2 were selected because these genes have been previously reported to be associated with cancer pedigrees known to include glioma. RESULTS: We detected a single structural rearrangement, a deletion of exons 1-6 in MSH2, in the proband of one family with 3 cases with glioma and one relative with colon cancer. CONCLUSIONS: Large deletions and duplications are rare events in familial glioma cases, even in families with a strong family history of cancers that may be involved in known cancer syndromes..
Labussière, M.
Di Stefano, A.L.
Gleize, V.
Boisselier, B.
Giry, M.
Mangesius, S.
Bruno, A.
Paterra, R.
Marie, Y.
Rahimian, A.
Finocchiaro, G.
Houlston, R.S.
Hoang-Xuan, K.
Idbaih, A.
Delattre, J.-.
Mokhtari, K.
Sanson, M.
(2014). TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations. Br j cancer,
Vol.111
(10),
pp. 2024-2032.
show abstract
BACKGROUND: The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF transcription factors, whereas the common rs2853669 polymorphism disrupts another Ets/TCF site on TERT promoter. METHODS: We sequenced for TERTp-mut in 807 glioma DNAs and in 235 blood DNAs and analysed TERT expression by RT-PCR in 151 samples. TERTp-mut status and TERTp polymorphism rs2853669 were correlated with histology, genomic profile, TERT mRNA expression, clinical outcome and rs2736100 genotype. RESULTS: TERTp-mut identified in 60.8% of gliomas (491 out of 807) was globally associated with poorer outcome (Hazard ratio (HR)=1.50). We defined, based on TERTp-mut and IDH mutation status, four prognostic groups: (1) TERTp-mut and IDH-mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2) TERTp-wt and IDH-mut, associated with TP53 mutation, OS=97.5 months; (3) TERTp-wt and IDH-wt, with no specific association, OS=31.6 months; (4) TERTp-mut and IDH-wt, associated with EGFR amplification, OS=15.4 months. TERTp-mut was associated with higher TERT mRNA expression, whereas the rs2853669 variant was associated with lower TERT mRNA expression. The mutation of CIC (a repressor of ETV1-5 belonging to the Ets/TCF family) was also associated with TERT mRNA upregulation. CONCLUSIONS: In addition to IDH mutation status, defining the TERTp-mut status of glial tumours should afford enhanced prognostic stratification of patients with glioma. We also show that TERTp-mut, rs2853669 variant and CIC mutation influence Tert expression. This effect could be mediated by Ets/TCF transcription factors..
Jaeger, R.
Harutyunyan, A.S.
Rumi, E.
Pietra, D.
Berg, T.
Olcaydu, D.
Houlston, R.S.
Cazzola, M.
Kralovics, R.
(2014). Common germline variation at the TERT locus contributes to familial clustering of myeloproliferative neoplasms. American journal of hematology,
Vol.89
(12),
pp. 1107-1110.
Hemminki, K.
Houlston, R.S.
(2014). Special section editorial. International journal of cancer,
Vol.135
(8),
pp. 1755-1755.
Weinhold, N.
Johnson, D.C.
Rawstron, A.C.
Foersti, A.
Doughty, C.
Vijayakrishnan, J.
Broderick, P.
Dahir, N.B.
Begum, D.B.
Hosking, F.J.
Yong, K.
Walker, B.A.
Hoffmann, P.
Muehleisen, T.W.
Langer, C.
Doerner, E.
Joeckel, K.-.
Eisele, L.
Noethen, M.M.
Hose, D.
Davies, F.E.
Goldschmidt, H.
Morgan, G.J.
Hemminki, K.
Houlston, R.S.
(2014). Inherited genetic susceptibility to monoclonal gammopathy of unknown significance. Blood,
Vol.123
(16),
pp. 2513-2517.
Lucassen, A.
Houlston, R.S.
(2014). The challenges of genome analysis in the health care setting. Genes (basel),
Vol.5
(3),
pp. 576-585.
show abstract
Genome sequencing is now a sufficiently mature and affordable technology for clinical use. Its application promises not only to transform clinicians' diagnostic and predictive ability, but also to improve preventative therapies, surveillance regimes, and tailor patient treatment to an individual's genetic make-up. However, as with any technological advance, there are associated fresh challenges. While some of the ethical, legal and social aspects resulting from the generation of data from genome sequencing are generic, several nuances are unique. Since the UK government recently announced plans to sequence the genomes of 100,000 Health Service patients, and similar initiatives are being considered elsewhere, a discussion of these nuances is timely and needs to go hand in hand with formulation of guidelines and public engagement activities around implementation of sequencing in clinical practice. .
Whiffin, N.
Houlston, R.S.
(2014). Architecture of inherited susceptibility to colorectal cancer: a voyage of discovery. Genes (basel),
Vol.5
(2),
pp. 270-284.
show abstract
This review looks back at five decades of research into genetic susceptibility to colorectal cancer (CRC) and the insights these studies have provided. Initial evidence of a genetic basis of CRC stems from epidemiological studies in the 1950s and is further provided by the existence of multiple dominant predisposition syndromes. Genetic linkage and positional cloning studies identified the first high-penetrance genes for CRC in the 1980s and 1990s. More recent genome-wide association studies have identified common low-penetrance susceptibility loci and provide support for a polygenic model of disease susceptibility. These observations suggest a high proportion of CRC may arise in a group of susceptible individuals as a consequence of the combined effects of common low-penetrance risk alleles and rare variants conferring moderate CRC risks. Despite these advances, however, currently identified loci explain only a small fraction of the estimated heritability to CRC. It is hoped that a new generation of sequencing projects will help explain this missing heritability. .
Scales, M.
Jäger, R.
Migliorini, G.
Houlston, R.S.
Henrion, M.Y.
(2014). visPIG--a web tool for producing multi-region, multi-track, multi-scale plots of genetic data. Plos one,
Vol.9
(9),
p. e107497.
show abstract
We present VISual Plotting Interface for Genetics (visPIG; http://vispig.icr.ac.uk), a web application to produce multi-track, multi-scale, multi-region plots of genetic data. visPIG has been designed to allow users not well versed with mathematical software packages and/or programming languages such as R, Matlab®, Python, etc., to integrate data from multiple sources for interpretation and to easily create publication-ready figures. While web tools such as the UCSC Genome Browser or the WashU Epigenome Browser allow custom data uploads, such tools are primarily designed for data exploration. This is also true for the desktop-run Integrative Genomics Viewer (IGV). Other locally run data visualisation software such as Circos require significant computer skills of the user. The visPIG web application is a menu-based interface that allows users to upload custom data tracks and set track-specific parameters. Figures can be downloaded as PDF or PNG files. For sensitive data, the underlying R code can also be downloaded and run locally. visPIG is multi-track: it can display many different data types (e.g association, functional annotation, intensity, interaction, heat map data,…). It also allows annotation of genes and other custom features in the plotted region(s). Data tracks can be plotted individually or on a single figure. visPIG is multi-region: it supports plotting multiple regions, be they kilo- or megabases apart or even on different chromosomes. Finally, visPIG is multi-scale: a sub-region of particular interest can be 'zoomed' in. We describe the various features of visPIG and illustrate its utility with examples. visPIG is freely available through http://vispig.icr.ac.uk under a GNU General Public License (GPLv3)..
Kinnersley, B.
Buch, S.
Castellví-Bel, S.
Farrington, S.M.
Forsti, A.
Hampe, J.
Hemminki, K.
Hofstra, R.M.
Northwood, E.
Palles, C.
Pinheiro, M.
Ruiz-Ponte, C.
Schafmayer, C.
Teixeira, M.R.
Westers, H.
Wezel, T.V.
Bishop, D.T.
Tomlinson, I.
Dunlop, M.G.
Houlston, R.S.
(2014). Re: Role of the Oxidative DNA Damage Repair Gene OGG1 in Colorectal Tumorigenesis. Journal of the national cancer institute,
.
Chiara Di Bernardo, M.
Broderick, P.
Catovsky, D.
Houlston, R.S.
(2013). Common genetic variation contributes significantly to the risk of developing chronic lymphocytic leukemia. Haematologica,
Vol.98
(3),
pp. e23-e24.
Di Bernardo, M.C.
Broderick, P.
Harris, S.
Dyer, M.J.
Matutes, E.
Dearden, C.
Catovsky, D.
Houlston, R.S.
(2013). Risk of developing chronic lymphocytic leukemia is influenced by HLA-A class I variation. Leukemia,
Vol.27
(1),
pp. 255-258.
Wang, J.
Carvajal-Carmona, L.G.
Chu, J.-.
Zauber, A.G.
APC Trial Collaborators,
Kubo, M.
Matsuda, K.
Dunlop, M.
Houlston, R.S.
Sieber, O.
Lipton, L.
Gibbs, P.
Martin, N.G.
Montgomery, G.W.
Young, J.
Baird, P.N.
Ratain, M.J.
Nakamura, Y.
Weiss, S.T.
Tomlinson, I.
Bertagnolli, M.M.
(2013). Germline variants and advanced colorectal adenomas: adenoma prevention with celecoxib trial genome-wide association study. Clin cancer res,
Vol.19
(23),
pp. 6430-6437.
show abstract
PURPOSE: Identification of single-nucleotide polymorphisms (SNP) associated with development of advanced colorectal adenomas. EXPERIMENTAL DESIGN: Discovery phase: 1,406 Caucasian patients (139 advanced adenoma cases and 1,267 controls) from the Adenoma Prevention with Celecoxib (APC) trial were included in a genome-wide association study (GWAS) to identify variants associated with postpolypectomy disease recurrence. Genome-wide significance was defined as false discovery rate less than 0.05, unadjusted P = 7.4 × 10(-7). Validation phase: results were further evaluated using 4,175 familial colorectal adenoma cases and 5,036 controls from patients of European ancestry [COloRectal Gene Identification consortium (CORGI), Scotland, Australia, and VQ58]. RESULTS: Our study identified eight SNPs associated with advanced-adenoma risk in the APC trial (rs2837156, rs7278863, rs2837237, rs2837241, rs2837254, rs741864 at 21q22.2, and rs1381392 and rs17651822 at 3p24.1, at P < 10(-7) level with OR > 2). Five variants in strong pairwise linkage disequilibrium (rs7278863, rs2837237, rs741864, rs741864, and rs2837241; r(2) = 0.8-1) are in or near the coding region for the tight junction adhesion protein, IGSF5. An additional variant associated with advanced adenomas, rs1535989 [minor allele frequency, 0.11; OR, 2.09; 95% confidence interval (CI), 1.50-2.91], also predicted colorectal cancer development in a validation analysis (P = 0.019) using a series of adenoma cases or colorectal cancer (CORGI study) and 3 sets of colorectal cancer cases and controls (Scotland, VQ58, and Australia; N = 9,211). CONCLUSIONS: Our results suggest that common polymorphisms contribute to the risk of developing advanced adenomas and might also contribute to the risk of developing colorectal cancer. The variant at rs1535989 may identify patients whose risk for neoplasia warrants increased colonoscopic surveillance..
Enciso-Mora, V.
Hosking, F.J.
Kinnersley, B.
Wang, Y.
Shete, S.
Zelenika, D.
Broderick, P.
Idbaih, A.
Delattre, J.-.
Hoang-Xuan, K.
Marie, Y.
Di Stefano, A.L.
Labussière, M.
Dobbins, S.
Boisselier, B.
Ciccarino, P.
Rossetto, M.
Armstrong, G.
Liu, Y.
Gousias, K.
Schramm, J.
Lau, C.
Hepworth, S.J.
Strauch, K.
Müller-Nurasyid, M.
Schreiber, S.
Franke, A.
Moebus, S.
Eisele, L.
Forsti, A.
Hemminki, K.
Tomlinson, I.P.
Swerdlow, A.
Lathrop, M.
Simon, M.
Bondy, M.
Sanson, M.
Houlston, R.S.
(2013). Deciphering the 8q24 21 association for glioma. Hum mol genet,
Vol.22
(11),
pp. 2293-2302.
show abstract
We have previously identified tagSNPs at 8q24.21 influencing glioma risk. We have sought to fine-map the location of the functional basis of this association using data from four genome-wide association studies, comprising a total of 4147 glioma cases and 7435 controls. To improve marker density across the 700 kb region, we imputed genotypes using 1000 Genomes Project data and high-coverage sequencing data generated on 253 individuals. Analysis revealed an imputed low-frequency SNP rs55705857 (P = 2.24 × 10(-38)) which was sufficient to fully capture the 8q24.21 association. Analysis by glioma subtype showed the association with rs55705857 confined to non-glioblastoma multiforme (non-GBM) tumours (P = 1.07 × 10(-67)). Validation of the non-GBM association was shown in three additional datasets (625 non-GBM cases, 2412 controls; P = 1.41 × 10(-28)). In the pooled analysis, the odds ratio for low-grade glioma associated with rs55705857 was 4.3 (P = 2.31 × 10(-94)). rs55705857 maps to a highly evolutionarily conserved sequence within the long non-coding RNA CCDC26 raising the possibility of direct functionality. These data provide additional insights into the aetiological basis of glioma development..
Palles, C.
Cazier, J.-.
Howarth, K.M.
Domingo, E.
Jones, A.M.
Broderick, P.
Kemp, Z.
Spain, S.L.
Almeida, E.G.
Salguero, I.
Sherborne, A.
Chubb, D.
Carvajal-Carmona, L.G.
Ma, Y.
Kaur, K.
Dobbins, S.
Barclay, E.
Gorman, M.
Martin, L.
Kovac, M.B.
Humphray, S.
Lucassen, A.
Holmes, C.C.
Bentley, D.
Donnelly, P.
Taylor, J.
Petridis, C.
Roylance, R.
Sawyer, E.J.
Kerr, D.J.
Clark, S.
Grimes, J.
Kearsey, S.E.
Thomas, H.J.
McVean, G.
Houlston, R.S.
Tomlinson, I.
Consortium, C.O.
Consortium, W.
(2013). Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nature genetics,
Vol.45
(2),
pp. 136-144.
Sadetzki, S.
Bruchim, R.
Oberman, B.
Armstrong, G.N.
Lau, C.C.
Claus, E.B.
Barnholtz-Sloan, J.S.
Il'yasova, D.
Schildkraut, J.
Johansen, C.
Houlston, R.S.
Shete, S.
Amos, C.I.
Bernstein, J.L.
Olson, S.H.
Jenkins, R.B.
Lachance, D.
Vick, N.A.
Merrell, R.
Wrensch, M.
Davis, F.G.
McCarthy, B.J.
Lai, R.
Melin, B.S.
Bondy, M.L.
Consortium, G.
(2013). Description of selected characteristics of familial glioma patients - Results from the Gliogene Consortium. European journal of cancer,
Vol.49
(6),
pp. 1335-1345.
Di Stefano, A.L.
Enciso-Mora, V.
Marie, Y.
Desestret, V.
Labussire, M.
Boisselier, B.
Mokhtari, K.
Idbaih, A.
Hoang-Xuan, K.
Delattre, J.-.
Houlston, R.S.
Sanson, M.
(2013). Association between glioma susceptibility loci and tumour pathology defines specific molecular etiologies. Neuro-oncology,
Vol.15
(5),
pp. 542-547.
Dunlop, M.G.
Tenesa, A.
Farrington, S.M.
Ballereau, S.
Brewster, D.H.
Koessler, T.
Pharoah, P.
Schafmayer, C.
Hampe, J.
Voelzke, H.
Chang-Claude, J.
Hoffmeister, M.
Brenner, H.
von Holst, S.
Picelli, S.
Lindblom, A.
Jenkins, M.A.
Hopper, J.L.
Casey, G.
Duggan, D.
Newcomb, P.A.
Abuli, A.
Bessa, X.
Ruiz-Ponte, C.
Castellvi-Bel, S.
Niittymaeki, I.
Tuupanen, S.
Karhu, A.
Aaltonen, L.
Zanke, B.
Hudson, T.
Gallinger, S.
Barclay, E.
Martin, L.
Gorman, M.
Carvajal-Carmona, L.
Walther, A.
Kerr, D.
Lubbe, S.
Broderick, P.
Chandler, I.
Pittman, A.
Penegar, S.
Campbell, H.
Tomlinson, I.
Houlston, R.S.
(2013). Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42 103 individuals. Gut,
Vol.62
(6),
pp. 871-881.
Migliorini, G.
Fiege, B.
Hosking, F.J.
Ma, Y.
Kumar, R.
Sherborne, A.L.
da Silva Filho, M.I.
Vijayakrishnan, J.
Koehler, R.
Thomsen, H.
Irving, J.A.
Allan, J.M.
Lightfoot, T.
Roman, E.
Kinsey, S.E.
Sheridan, E.
Thompson, P.
Hoffmann, P.
Nöthen, M.M.
Mühleisen, T.W.
Eisele, L.
Zimmermann, M.
Bartram, C.R.
Schrappe, M.
Greaves, M.
Stanulla, M.
Hemminki, K.
Houlston, R.S.
(2013). Variation at 10p12 2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype. Blood,
Vol.122
(19),
pp. 3298-3307.
show abstract
Acute lymphoblastic leukemia (ALL) is the major pediatric cancer diagnosed in economically developed countries with B-cell precursor (BCP)-ALL, accounting for approximately 70% of ALL. Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence for common inherited susceptibility to BCP-ALL, identifying susceptibility loci at 7p12.2, 9p21.3, 10q21.2, and 14q11.2. To identify additional BCP-ALL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1658 cases and 4723 controls, with validation in 1449 cases and 1488 controls. Combined analysis identified novel loci mapping to 10p12.2 (rs10828317, odds ratio [OR] = 1.23; P = 2.30 × 10(-9)) and 10p14 marked by rs3824662 (OR = 1.31; P = 8.62 × 10(-12)). The single nucleotide polymorphism rs10828317 is responsible for the N215S polymorphism in exon 7 of PIP4K2A, and rs3824662 localizes to intron 3 of the transcription factor and putative tumor suppressor gene GATA3. The rs10828317 association was shown to be specifically associated with hyperdiploid ALL, whereas the rs3824662-associated risk was confined to nonhyperdiploid non-TEL-AML1 + ALL. The risk allele of rs3824662 was correlated with older age at diagnosis (P < .001) and significantly worse event-free survivorship (P < .0001). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to BCP-ALL and the influence of constitutional genotype on disease development. .
Sava, G.P.
Speedy, H.E.
Di Bernardo, M.C.
Deaglio, S.
Karabon, L.
Frydecka, I.
Woszczyk, D.
Rossi, D.
Gaidano, G.
Mansouri, L.
Smedby, K.E.
Juliusson, G.
Rosenquist, R.
Catovsky, D.
Houlston, R.S.
(2013). rs2072135, a low-penetrance variant for chronic lymphocytic leukaemia?. Br j haematol,
Vol.162
(2),
pp. 221-228.
show abstract
Recent multi-stage genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) that are robustly associated with chronic lymphocytic leukaemia (CLL) risk. Given that most of these SNPs map to non-coding regions of the genome, it suggests that the functional basis of many GWAS signals will be through differential gene expression. By referencing publically accessible expression quantitative trait loci (eQTL) data on lymphoblastoid cells lines (LCLs) we have globally demonstrated an association between GWAS P-values and eQTLs, consistent with much of the variation in CLL risk being defined by variants impacting on gene expression. To explore using eQTL data to select GWAS SNPs for replication, we genotyped rs2072135 (GWAS P-value = 0·0024, eQTL P-value = 1·510(-19)) in five independent case-control series totalling 1968 cases and 3538 controls. While not attaining statistical significance (combined P-value = 1 × 10(-4)), rs2072135 defines a promising risk locus for CLL. Incorporating eQTL information offers an attractive strategy for selecting SNPs from GWAS for validation..
Dobbins, S.E.
Sherborne, A.L.
Ma, Y.P.
Bardini, M.
Biondi, A.
Cazzaniga, G.
Lloyd, A.
Chubb, D.
Greaves, M.F.
Houlston, R.S.
(2013). The silent mutational landscape of infant MLL-AF4 pro-B acute lymphoblastic leukemia. Genes chromosomes cancer,
Vol.52
(10),
pp. 954-960.
show abstract
Over 90% of infants (< 1-year-old) diagnosed with leukemia have pro-B acute lymphoblastic leukemia (ALL) containing the MLL-AF4 fusion. When compared with other forms of paediatric ALL affecting later B-cell differentiation, MLL-AF4 pro-B is associated with a dismal prognosis with a typical 5-year disease-free survival of <20%. MLL-AF4 may be sufficient on its own for leukemogenesis or the gene-fusion product may alternatively predispose transformed cells to global genetic instability, enhancing the acquisition of additional key mutations. To gain insight into the genomic landscape of infant MLL-AF4 pro-B ALL we performed whole genome sequencing of diagnostic leukemic blasts and matched germline samples from three MLL-AF4 pro-B ALL infants. Our analysis revealed few somatic changes (copy number abnormalities, loss of heterozygosity, or single nucleotide variants), demonstrating that only a very small number of mutations are necessary to generate infant MLL-leukemia..
Chubb, D.
Weinhold, N.
Broderick, P.
Chen, B.
Johnson, D.C.
Försti, A.
Vijayakrishnan, J.
Migliorini, G.
Dobbins, S.E.
Holroyd, A.
Hose, D.
Walker, B.A.
Davies, F.E.
Gregory, W.A.
Jackson, G.H.
Irving, J.A.
Pratt, G.
Fegan, C.
Fenton, J.A.
Neben, K.
Hoffmann, P.
Nöthen, M.M.
Mühleisen, T.W.
Eisele, L.
Ross, F.M.
Straka, C.
Einsele, H.
Langer, C.
Dörner, E.
Allan, J.M.
Jauch, A.
Morgan, G.J.
Hemminki, K.
Houlston, R.S.
Goldschmidt, H.
(2013). Common variation at 3q26 2, 6p21 33, 17p11 2 and 22q13 1 influences multiple myeloma risk. Nat genet,
Vol.45
(10),
pp. 1221-1225.
show abstract
To identify variants for multiple myeloma risk, we conducted a genome-wide association study with validation in additional series totaling 4,692 individuals with multiple myeloma (cases) and 10,990 controls. We identified four risk loci at 3q26.2 (rs10936599, P = 8.70 × 10(-14)), 6p21.33 (rs2285803, PSORS1C2, P = 9.67 × 10(-11)), 17p11.2 (rs4273077, TNFRSF13B, P = 7.67 × 10(-9)) and 22q13.1 (rs877529, CBX7, P = 7.63 × 10(-16)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy, as well as insight into the biological basis of predisposition. .
Köhler, A.
Chen, B.
Gemignani, F.
Elisei, R.
Romei, C.
Figlioli, G.
Cipollini, M.
Cristaudo, A.
Bambi, F.
Hoffmann, P.
Herms, S.
Kalemba, M.
Kula, D.
Harris, S.
Broderick, P.
Houlston, R.
Pastor, S.
Marcos, R.
Velázquez, A.
Jarzab, B.
Hemminki, K.
Landi, S.
Försti, A.
(2013). Genome-wide association study on differentiated thyroid cancer. J clin endocrinol metab,
Vol.98
(10),
pp. E1674-E1681.
show abstract
CONTEXT: Genome-wide association studies (GWASs) of differentiated thyroid cancer (DTC) have identified associations with polymorphisms at 2q35 (DIRC3), 8p12 (NRG1), 9q22.33 (FOXE1), and 14q13.2 (NKX2-1). However, most of the inherited genetic risk factors of DTC remain to be discovered. OBJECTIVE: Our objective was to identify additional common DTC susceptibility loci. DESIGN: We conducted a GWAS in a high-incidence Italian population of 690 cases and 497 controls and followed up the most significant polymorphisms in 2 additional Italian series and in 3 low-incidence populations totaling 2958 cases and 3727 controls. RESULTS: After excluding the most robust previously identified locus (9q22.33), the strongest association was shown by rs6759952, confirming the recently published association in DIRC3 (odds ratio [OR] = 1.21, P = 6.4 × 10(-10), GWAS and all replications combined). Additionally, in the combined analysis of the Italian series, suggestive associations were attained with rs10238549 and rs7800391 in IMMP2L (OR = 1.27, P = 4.1 × 10(-6); and OR = 1.25, P = 5.7 × 10(-6)), rs7617304 in RARRES1 (OR = 1.25, P = 4.6 × 10(-5)) and rs10781500 in SNAPC4/CARD9 (OR = 1.23, P = 3.5 × 10(-5)). CONCLUSIONS: Our findings provide additional insights into the genetic and biological basis of inherited genetic susceptibility to DTC. Additional studies are needed to determine the role of the identified polymorphisms in the development of DTC and their possible use in the clinical practice..
Henrion, M.
Frampton, M.
Scelo, G.
Purdue, M.
Ye, Y.
Broderick, P.
Ritchie, A.
Kaplan, R.
Meade, A.
McKay, J.
Johansson, M.
Lathrop, M.
Larkin, J.
Rothman, N.
Wang, Z.
Chow, W.-.
Stevens, V.L.
Ryan Diver, W.
Gapstur, S.M.
Albanes, D.
Virtamo, J.
Wu, X.
Brennan, P.
Chanock, S.
Eisen, T.
Houlston, R.S.
(2013). Common variation at 2q22 3 (ZEB2) influences the risk of renal cancer. Hum mol genet,
Vol.22
(4),
pp. 825-831.
show abstract
Genome-wide association studies (GWASs) of renal cell cancer (RCC) have identified four susceptibility loci thus far. To identify an additional RCC common susceptibility locus, we conducted a GWAS and performed a meta-analysis with published GWASs (totalling 2215 cases and 8566 controls of European background) and followed up the most significant association signals [nine single nucleotide polymorphisms (SNPs) in eight genomic regions] in 3739 cases and 8786 controls. A combined analysis identified a novel susceptibility locus mapping to 2q22.3 marked by rs12105918 (P = 1.80 × 10(-8); odds ratio 1.29, 95% CI: 1.18-1.41). The signal localizes to intron 2 of the ZEB2 gene (zinc finger E box-binding homeobox 2). Our findings suggest that genetic variation in ZEB2 influences the risk of RCC. This finding provides further insights into the genetic and biological basis of inherited genetic susceptibility to RCC..
Whiffin, N.
Dobbins, S.E.
Hosking, F.J.
Palles, C.
Tenesa, A.
Wang, Y.
Farrington, S.M.
Jones, A.M.
Broderick, P.
Campbell, H.
Newcomb, P.A.
Casey, G.
Conti, D.V.
Schumacher, F.
Gallinger, S.
Lindor, N.M.
Hopper, J.
Jenkins, M.
Dunlop, M.G.
Tomlinson, I.P.
Houlston, R.S.
(2013). Deciphering the genetic architecture of low-penetrance susceptibility to colorectal cancer. Hum mol genet,
Vol.22
(24),
pp. 5075-5082.
show abstract
Recent genome-wide association studies (GWASs) have identified common variants at 16 autosomal regions influencing the risk of developing colorectal cancer (CRC). To decipher the genetic basis of the association signals at these loci, we performed a meta-analysis of data from five GWASs, totalling 5626 cases and 7817 controls, using imputation to recover un-typed genotypes. To enhance our ability to discover low-frequency risk variants, in addition to using 1000 Genomes Project data as a reference panel, we made use of high-coverage sequencing data on 253 individuals, 199 with early-onset familial CRC. For 13 of the regions, it was possible to refine the association signal identifying a smaller region of interest likely to harbour the functional variant. Our analysis did not provide evidence that any of the associations at the 16 loci being a consequence of synthetic associations rather than linkage disequilibrium with a common risk variant. .
Morris, E.J.
Penegar, S.
Whitehouse, L.E.
Quirke, P.
Finan, P.
Bishop, D.T.
Wilkinson, J.
Houlston, R.S.
(2013). A retrospective observational study of the relationship between family history and survival from colorectal cancer. British journal of cancer,
Vol.108
(7),
pp. 1502-1507.
Ruark, E.
Snape, K.
Humburg, P.
Loveday, C.
Bajrami, I.
Brough, R.
Rodrigues, D.N.
Renwick, A.
Seal, S.
Ramsay, E.
Duarte, S.D.
Rivas, M.A.
Warren-Perry, M.
Zachariou, A.
Campion-Flora, A.
Hanks, S.
Murray, A.
Ansari Pour, N.
Douglas, J.
Gregory, L.
Rimmer, A.
Walker, N.M.
Yang, T.-.
Adlard, J.W.
Barwell, J.
Berg, J.
Brady, A.F.
Brewer, C.
Brice, G.
Chapman, C.
Cook, J.
Davidson, R.
Donaldson, A.
Douglas, F.
Eccles, D.
Evans, D.G.
Greenhalgh, L.
Henderson, A.
Izatt, L.
Kumar, A.
Lalloo, F.
Miedzybrodzka, Z.
Morrison, P.J.
Paterson, J.
Porteous, M.
Rogers, M.T.
Shanley, S.
Walker, L.
Gore, M.
Houlston, R.
Brown, M.A.
Caufield, M.J.
Deloukas, P.
McCarthy, M.I.
Todd, J.A.
Breast and Ovarian Cancer Susceptibility Collaboration,
Wellcome Trust Case Control Consortium,
Turnbull, C.
Reis-Filho, J.S.
Ashworth, A.
Antoniou, A.C.
Lord, C.J.
Donnelly, P.
Rahman, N.
(2013). Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature,
Vol.493
(7432),
pp. 406-410.
show abstract
Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10(-9)). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification..
Enciso-Mora, V.
Hosking, F.J.
Di Stefano, A.L.
Zelenika, D.
Shete, S.
Broderick, P.
Idbaih, A.
Delattre, J.-.
Hoang-Xuan, K.
Marie, Y.
Labussière, M.
Alentorn, A.
Ciccarino, P.
Rossetto, M.
Armstrong, G.
Liu, Y.
Gousias, K.
Schramm, J.
Lau, C.
Hepworth, S.J.
Schoemaker, M.
Strauch, K.
Müller-Nurasyid, M.
Schreiber, S.
Franke, A.
Moebus, S.
Eisele, L.
Swerdlow, A.
Simon, M.
Bondy, M.
Lathrop, M.
Sanson, M.
Houlston, R.S.
(2013). Low penetrance susceptibility to glioma is caused by the TP53 variant rs78378222. Br j cancer,
Vol.108
(10),
pp. 2178-2185.
show abstract
BACKGROUND: Most of the heritable risk of glioma is presently unaccounted for by mutations in known genes. In addition to rare inactivating germline mutations in TP53 causing glioma in the context of the Li-Fraumeni syndrome, polymorphic variation in TP53 may also contribute to the risk of developing glioma. METHODS: To comprehensively evaluate the impact of variation in TP53 on risk, we analysed 23 tagSNPs and imputed 2377 unobserved genotypes in four series totaling 4147 glioma cases and 7435 controls. RESULTS: The strongest validated association signal was shown by the imputed single-nucleotide polymorphism (SNP) rs78378222 (P=6.86 × 10(-24), minor allele frequency ~0.013). Confirmatory genotyping confirmed the high quality of the imputation. The association between rs78378222 and risk was seen for both glioblastoma multiforme (GBM) and non-GBM tumours. We comprehensively examined the relationship between rs78378222 and overall survival in two of the case series totaling 1699 individuals. Despite employing statistical tests sensitive to the detection of differences in early survival, no association was shown. CONCLUSION: Our data provided strong validation of rs78378222 as a risk factor for glioma but do not support the tenet that the polymorphism being a clinically useful prognostic marker. Acquired TP53 inactivation is a common feature of glioma. As rs78378222 changes the polyadenylation signal of TP53 leading to impaired 3'-end processing of TP53 mRNA, the SNP has strong plausibility for being directly functional contributing to the aetiological basis of glioma..
Ma, Y.
Dobbins, S.E.
Sherborne, A.L.
Chubb, D.
Galbiati, M.
Cazzaniga, G.
Micalizzi, C.
Tearle, R.
Lloyd, A.L.
Hain, R.
Greaves, M.
Houlston, R.S.
(2013). Developmental timing of mutations revealed by whole-genome sequencing of twins with acute lymphoblastic leukemia. Proc natl acad sci u s a,
Vol.110
(18),
pp. 7429-7433.
show abstract
Acute lymphoblastic leukemia (ALL) is the major pediatric cancer. At diagnosis, the developmental timing of mutations contributing critically to clonal diversification and selection can be buried in the leukemia's covert natural history. Concordance of ALL in monozygotic, monochorionic twins is a consequence of intraplacental spread of an initiated preleukemic clone. Studying monozygotic twins with ALL provides a unique means of uncovering the timeline of mutations contributing to clonal evolution, pre- and postnatally. We sequenced the whole genomes of leukemic cells from two twin pairs with ALL to comprehensively characterize acquired somatic mutations in ALL, elucidating the developmental timing of all genetic lesions. Shared, prenatal, coding-region single-nucleotide variants were limited to the putative initiating lesions. All other nonsynonymous single-nucleotide variants were distinct between tumors and, therefore, secondary and postnatal. These changes occurred in a background of noncoding mutational changes that were almost entirely discordant in twin pairs and likely passenger mutations acquired during leukemic cell proliferation..
Speedy, H.E.
Sava, G.
Houlston, R.S.
(2013). Inherited susceptibility to CLL. Adv exp med biol,
Vol.792,
pp. 293-308.
show abstract
Chronic lymphocytic leukaemia (CLL) is the most common lymphoid malignancy in Western countries, accounting for around a quarter of all leukaemias. Despite a strong familial basis to CLL, with risks in first-degree relatives of CLL cases being increased around sevenfold, the inherited genetic basis of CLL is currently largely unknown. The failure of genetic studies of CLL families to provide support for a major disease-causing locus has suggested a model of susceptibility based on the co-inheritance of multiple low-risk variants, some of which will be common. Recent genome-wide association studies of CLL have vindicated this model of inherited susceptibility to CLL, identifying common variants at multiple independent loci influencing risk. Here we review the evidence for inherited genetic predisposition to CLL and what the currently identified risk loci are telling us about the biology of CLL development. .
Frampton, M.
da Silva Filho, M.I.
Broderick, P.
Thomsen, H.
Försti, A.
Vijayakrishnan, J.
Cooke, R.
Enciso-Mora, V.
Hoffmann, P.
Nöthen, M.M.
Lloyd, A.
Holroyd, A.
Eisele, L.
Jöckel, K.-.
Ponader, S.
von Strandmann, E.P.
Lightfoot, T.
Roman, E.
Lake, A.
Montgomery, D.
Jarrett, R.F.
Swerdlow, A.J.
Engert, A.
Hemminki, K.
Houlston, R.S.
(2013). Variation at 3p24 1 and 6q23 3 influences the risk of Hodgkin's lymphoma. Nat commun,
Vol.4,
p. 2549.
show abstract
In addition to HLA, recent genome-wide association studies (GWASs) of Hodgkin's lymphoma (HL) have identified susceptibility loci for HL at 2p16.1, 8q24.21 and 10p14. In this study, we perform a GWAS meta-analysis with published GWAS (totalling 1,465 cases and 6,417 controls of European background), and follow-up the most significant association signals in 2,024 cases and 1,853 controls. A combined analysis identifies new HL susceptibility loci mapping to 3p24.1 (rs3806624; P=1.14 × 10(-12), odds ratio (OR)=1.26) and 6q23.3 (rs7745098; P=3.42 × 10(-9), OR=1.21). rs3806624 localizes 5' to the EOMES (eomesodermin) gene within a p53 response element affecting p53 binding. rs7745098 maps intergenic to HBS1L and MYB, a region previously associated with haematopoiesis. These findings provide further insight into the genetic and biological basis of inherited susceptibility to HL. .
Lubbe, S.J.
Di Bernardo, M.C.
Broderick, P.
Chandler, I.
Houlston, R.S.
(2012). Comprehensive evaluation of the impact of 14 genetic variants on colorectal cancer phenotype and risk. Am j epidemiol,
Vol.175
(1),
pp. 1-10.
show abstract
To comprehensively evaluate the impact of recently identified colorectal cancer (CRC) variants at 1q41, 3q26.2, 8q23.3, 8q24.21, 10p14, 11q23.1, 12q13.13, 14q22.2, 15q13.3, 16q22.1, 18q21.1, 19q13.11, 20p12.3, and 20q13.33 on risk and CRC phenotype, the authors analyzed 8,878 cases and 6,051 controls from the United Kingdom ascertained in 1999-2007. The impact of variants on the familial CRC risk was enumerated from age-, sex-, and calendar-specific CRC rates in the 50,924 first-degree relatives of cases. Each of the 14 susceptibility loci independently influences CRC with the risk increasing with increasing number of risk alleles carried (per allele odds ratio = 1.13; P = 2.99 × 10(-58)) and, for those within the upper quintile, there is a 2.3-fold increased risk. In first-degree relatives of cases with ≤17, 18-21, and ≥22 risk alleles, standardized incidence ratios were 1.76, 2.08, and 2.25, respectively. Although the discriminatory attributes of the 14 CRC susceptibility loci for individual risk prediction are poor (area under the curve = 0.58), they may allow subgroups of the population at different CRC risks to be distinguished..
Lubbe, S.J.
Whiffin, N.
Chandler, I.
Broderick, P.
Houlston, R.S.
(2012). Relationship between 16 susceptibility loci and colorectal cancer phenotype in 3146 patients. Carcinogenesis,
Vol.33
(1),
pp. 108-112.
show abstract
Recent genome-wide association studies have identified single-nucleotide polymorphisms at 16 genetic loci associated with colorectal cancer risk: rs6691170 (1q41), rs10936599 (3q26.2), rs16892766 (8q23.3), rs6983267 (8q24.21), rs10795668 (10p14), rs3802842 (11q23.1), rs11169552 (12q13.13), rs4444235, rs1957636 (14q22.2), rs4779584 (15q13.3), rs9929218 (16q22.1), rs4939827 (18q21.1), rs10411210 (19q13.11), rs961253 and rs4813802 (20p12.3) and rs4925386 (20q13.33). In the present study, we examined whether these variants are preferentially associated with tumour subtype-tumour site, stage, degree of differentiation and microsatellite instability status-in 3146 patients. Several loci showed statistically significant associations with specific phenotypes notably rs6691170 and rs3802842 associated with microsatellite stable rectal disease; rs4779584, rs961253 and rs4813802 associated with microsatellite stable colonic disease and rs4444235 and rs4925386 with microsatellite instability colonic disease. These findings are consistent with pathogenic variants in loci differentially impacting on distinct morphogenetic pathways consistent with aetiologically different risk factors in the development of colorectal cancer..
Johnson, N.
Walker, K.
Gibson, L.J.
Orr, N.
Folkerd, E.
Haynes, B.
Palles, C.
Coupland, B.
Schoemaker, M.
Jones, M.
Broderick, P.
Sawyer, E.
Kerin, M.
Tomlinson, I.P.
Zvelebil, M.
Chilcott-Burns, S.
Tomczyk, K.
Simpson, G.
Williamson, J.
Hillier, S.G.
Ross, G.
Houlston, R.S.
Swerdlow, A.
Ashworth, A.
Dowsett, M.
Peto, J.
Dos Santos Silva, I.
Fletcher, O.
(2012). CYP3A variation, premenopausal estrone levels, and breast cancer risk. J natl cancer inst,
Vol.104
(9),
pp. 657-669.
show abstract
BACKGROUND: Epidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women. METHODS: We measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided. RESULTS: rs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in E1G levels (95% confidence interval [CI] = 27.8% to 15.3% reduction; P = 2.7 × 10(-9)) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95% CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95% CI = 0.93 to 1.10; P = .82). CONCLUSIONS: Genetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer..
Shi, J.
Chatterjee, N.
Rotunno, M.
Wang, Y.
Pesatori, A.C.
Consonni, D.
Li, P.
Wheeler, W.
Broderick, P.
Henrion, M.
Eisen, T.
Wang, Z.
Chen, W.
Dong, Q.
Albanes, D.
Thun, M.
Spitz, M.R.
Bertazzi, P.A.
Caporaso, N.E.
Chanock, S.J.
Amos, C.I.
Houlston, R.S.
Landi, M.T.
(2012). Inherited Variation at Chromosome 12p13 33, Including RAD52, Influences the Risk of Squamous Cell Lung Carcinoma. Cancer discovery,
Vol.2
(2),
pp. 131-139.
Tomlinson, I.P.
Houlston, R.S.
Montgomery, G.W.
Sieber, O.M.
Dunlop, M.G.
(2012). Investigation of the effects of DNA repair gene polymorphisms on the risk of colorectal cancer. Mutagenesis,
Vol.27
(2),
pp. 219-223.
Wibom, C.
Sjöström, S.
Henriksson, R.
Brännström, T.
Broholm, H.
Rydén, P.
Johansen, C.
Collatz-Laier, H.
Hepworth, S.
McKinney, P.A.
Bethke, L.
Houlston, R.S.
Andersson, U.
Melin, B.S.
(2012). DNA-repair gene variants are associated with glioblastoma survival. Acta oncol,
Vol.51
(3),
pp. 325-332.
show abstract
Patient outcome from glioma may be influenced by germline variation. Considering the importance of DNA repair in cancer biology as well as in response to treatment, we studied the relationship between 1458 SNPs, which captured the majority of the common genetic variation in 136 DNA repair genes, in 138 glioblastoma samples from Sweden and Denmark. We confirmed our findings in an independent cohort of 121 glioblastoma patients from the UK. Our analysis revealed nine SNPs annotating MSH2, RAD51L1 and RECQL4 that were significantly (p < 0.05) associated with glioblastoma survival..
Houlston, R.S.
members of COGENT,
(2012). COGENT (COlorectal cancer GENeTics) revisited. Mutagenesis,
Vol.27
(2),
pp. 143-151.
show abstract
Many colorectal cancers (CRCs) develop in genetically susceptible individuals most of whom are not carriers of germ line mismatch repair or APC gene mutations and much of the heritable risk of CRC appears to be attributable to the co-inheritance of multiple low-risk variants. The accumulated experience to date in identifying this class of susceptibility allele has highlighted the need to conduct statistically and methodologically rigorous studies and the need for the multi-centre collaboration. This has been the motivation for establishing the COGENT (COlorectal cancer GENeTics) consortium which now includes over 20 research groups in Europe, Australia, the Americas, China and Japan actively working on CRC genetics. Here, we review the rationale for identifying low-penetrance variants for CRC and the current and future challenges for COGENT..
Kinnersley, B.
Migliorini, G.
Broderick, P.
Whiffin, N.
Dobbins, S.E.
Casey, G.
Hopper, J.
Sieber, O.
Lipton, L.
Kerr, D.J.
Dunlop, M.G.
Tomlinson, I.P.
Houlston, R.S.
Colon Cancer Family Registry,
(2012). The TERT variant rs2736100 is associated with colorectal cancer risk. Br j cancer,
Vol.107
(6),
pp. 1001-1008.
show abstract
BACKGROUND: Polymorphic variation at the 5p15.33 (TERT-CLPTM1L) locus is associated with the risk of many cancers but a relationship with colorectal cancer (CRC) risk has yet to be defined. METHODS: We used data from six genome-wide association studies (GWAS) of CRC, linkage disequilibrium mapping and imputation, to examine the relationship between 73 single-nucleotide polymorphisms at 5p15.33 and CRC risk in detail. RESULTS: rs2736100, which localises to intron 2 of TERT, provided the strongest evidence of an association with CRC (P=2.28 × 10⁻⁴). The association was also shown in an independent series of 10 047 CRC cases and 6918 controls (P=0.02). A meta-analysis of all seven studies (totalling 16 039 cases, 16 430 controls) provided increased evidence of association (P=2.49 × 10⁻⁵; per allele odds ratio=1.07). The association of rs2736100 on CRC risk was shown to be independent of 15 low-penetrance variants previously identified. CONCLUSION: The rs2736100 association demonstrates an influence of variation at 5p15.33 on CRC risk and further evidence that the 5p15.33 (TERT-CLPTM1L) locus has pleiotropic effects (reflecting generic or lineage-specific effects) on cancer risk..
Morgan, G.
Johnsen, H.E.
Goldschmidt, H.
Palumbo, A.
Cavo, M.
Sonneveld, P.
Miguel, J.S.
Chim, C.S.
Browne, P.
Einsele, H.
Waage, A.
Turesson, I.
Spencer, A.
Hajek, R.
Ludwig, H.
Hemminki, K.
Houlston, R.
(2012). MyelomA Genetics International Consortium. Leuk lymphoma,
Vol.53
(5),
pp. 796-800.
show abstract
While the etiology of multiple myeloma (MM) is largely unknown, evidence for an inherited genetic susceptibility is provided by the two-fold increased risk of the disease seen in first-degree relatives of cases of MM. It is likely that part of this heritable risk is a consequence of the co-inheritance of low-risk genetic variants. The accumulated experience to date in identifying risk variants for other tumors has highlighted difficulties in conducting statistically and methodologically rigorous studies. The MyelomA Genetics International Consortium (MAGIC) includes 16 research groups in Europe, Asia, Australasia, the Middle East and the Americas engaged in studying the genetics of MM. The first goal of MAGIC is to identify and characterize common genetic variants for MM through association-based analyses. Here, we review the rationale for identifying genetic risk variants for MM and our proposed strategy for establishing MAGIC..
Davies, J.L.
Cazier, J.-.
Dunlop, M.G.
Houlston, R.S.
Tomlinson, I.P.
Holmes, C.C.
(2012). A Novel Test for Gene-Ancestry Interactions in Genome-Wide Association Data. Plos one,
Vol.7
(12).
Liu, Y.
Melin, B.S.
Rajaraman, P.
Wang, Z.
Linet, M.
Shete, S.
Amos, C.I.
Lau, C.C.
Scheurer, M.E.
Tsavachidis, S.
Armstrong, G.N.
Houlston, R.S.
Hosking, F.J.
Claus, E.B.
Barnholtz-Sloan, J.
Lai, R.
Il'yasova, D.
Schildkraut, J.
Sadetzki, S.
Johansen, C.
Bernstein, J.L.
Olson, S.H.
Jenkins, R.B.
LaChance, D.
Vick, N.A.
Wrensch, M.
Davis, F.
McCarthy, B.J.
Andersson, U.
Thompson, P.A.
Chanock, S.
Bondy, M.L.
(2012). Insight in glioma susceptibility through an analysis of 6p22 3, 12p13 33-12 1, 17q22-23 2 and 18q23 SNP genotypes in familial and non-familial glioma. Human genetics,
Vol.131
(9),
pp. 1507-1517.
Gorlova, O.
Broderick, P.
Field, J.
Schwartz, A.
Houlston, R.
Ying, J.
Yu, X.
Zhao, Y.
Wenzlaff, A.
Zhang, R.
Oloide, R.
Petterson, T.
Wang, L.
Ruterbush, J.
Wang, Y.
Zhang, D.
Liu, G.
Wu, X.
Amos, C.
Christiani, D.
Hung, R.
Yang, P.
Spitz, M.
(2012). GENOME-WIDE ASSOCIATION STUDY OF LUNG CANCER IN NEVER SMOKERS. Journal of thoracic oncology,
Vol.7
(9),
pp. S169-S169.
Enciso-Mora, V.
Hosking, F.J.
Sheridan, E.
Kinsey, S.E.
Lightfoot, T.
Roman, E.
Irving, J.A.
Tomlinson, I.P.
Allan, J.M.
Taylor, M.
Greaves, M.
Houlston, R.S.
(2012). Common genetic variation contributes significantly to the risk of childhood B-cell precursor acute lymphoblastic leukemia. Leukemia,
Vol.26
(10),
pp. 2212-2215.
show abstract
Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence that common genetic variation influences the risk of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), identifying risk single-nucleotide polymorphisms (SNPs) localizing to 7p12.2, 9p21.3, 10q21.2 and 14q11.2. The testing of SNPs individually for an association in GWA studies necessitates the imposition of a very stringent P-value to address the issue of multiple testing. While this reduces false positives, real associations may be missed and therefore any estimate of the total heritability will be negatively biased. Using GWAS data on 823 BCP-ALL cases by considering all typed SNPs simultaneously, we have calculated that 24% of the total variation in BCP-ALL risk is accounted for common genetic variation (95% confidence interval 6-42%). Our findings provide support for a polygenic basis for susceptibility to BCP-ALL and have wider implications for future searches for novel disease-causing risk variants..
Huang, X.
Kushekhar, K.
Nolte, I.
Kooistra, W.
Visser, L.
Bouwman, I.
Kouprie, N.
Veenstra, R.
van Imhoff, G.
Olver, B.
Houlston, R.S.
Poppema, S.
Diepstra, A.
Hepkema, B.
van den Berg, A.
(2012). HLA Associations in Classical Hodgkin Lymphoma: EBV Status Matters. Plos one,
Vol.7
(7).
Sun, X.
Vengoechea, J.
Elston, R.
Chen, Y.
Amos, C.I.
Armstrong, G.
Bernstein, J.L.
Claus, E.
Davis, F.
Houlston, R.S.
Il'yasova, D.
Jenkins, R.B.
Johansen, C.
Lai, R.
Lau, C.C.
Liu, Y.
McCarthy, B.J.
Olson, S.H.
Sadetzki, S.
Schildkraut, J.
Shete, S.
Yu, R.
Vick, N.A.
Merrell, R.
Wrensch, M.
Yang, P.
Melin, B.
Bondy, M.L.
Barnholtz-Sloan, J.S.
Consortium, G.
(2012). A Variable Age of Onset Segregation Model for Linkage Analysis, with Correction for Ascertainment, Applied to Glioma. Cancer epidemiology biomarkers & prevention,
Vol.21
(12),
pp. 2242-2251.
Rajaraman, P.
Melin, B.S.
Wang, Z.
McKean-Cowdin, R.
Michaud, D.S.
Wang, S.S.
Bondy, M.
Houlston, R.
Jenkins, R.B.
Wrensch, M.
Yeager, M.
Ahlbom, A.
Albanes, D.
Andersson, U.
Freeman, L.E.
Buring, J.E.
Butler, M.A.
Braganza, M.
Carreon, T.
Feychting, M.
Fleming, S.J.
Gapstur, S.M.
Gaziano, J.M.
Giles, G.G.
Hallmans, G.
Henriksson, R.
Hoffman-Bolton, J.
Inskip, P.D.
Johansen, C.
Kitahara, C.M.
Lathrop, M.
Liu, C.
Le Marchand, L.
Linet, M.S.
Lonn, S.
Peters, U.
Purdue, M.P.
Rothman, N.
Ruder, A.M.
Sanson, M.
Sesso, H.D.
Severi, G.
Shu, X.-.
Simon, M.
Stampfer, M.
Stevens, V.L.
Visvanathan, K.
White, E.
Wolk, A.
Zeleniuch-Jacquotte, A.
Zheng, W.
Decker, P.
Enciso-Mora, V.
Fridley, B.
Gao, Y.-.
Kosel, M.
Lachance, D.H.
Lau, C.
Rice, T.
Swerdlow, A.
Wiemels, J.L.
Wiencke, J.K.
Shete, S.
Xiang, Y.-.
Xiao, Y.
Hoover, R.N.
Jr, F.J.
Chatterjee, N.
Hartge, P.
Chanock, S.J.
(2012). Genome-wide association study of glioma and meta-analysis. Human genetics,
Vol.131
(12),
pp. 1877-1888.
Robertson, L.
Hanson, H.
Seal, S.
Warren-Perry, M.
Hughes, D.
Howell, I.
Turnbull, C.
Houlston, R.
Shanley, S.
Butler, S.
Evans, D.G.
Ross, G.
Eccles, D.
Tutt, A.
Rahman, N.
TNT Trial TMG,
BCSC (UK),
(2012). BRCA1 testing should be offered to individuals with triple-negative breast cancer diagnosed below 50 years. Br j cancer,
Vol.106
(6),
pp. 1234-1238.
show abstract
BACKGROUND: Triple-negative (TN) tumours are the predominant breast cancer subtype in BRCA1 mutation carriers. Recently, it was proposed that all individuals below 50 years of age with TN breast cancer should be offered BRCA testing. We have evaluated the BRCA1 mutation frequency and the implications for clinical practice of undertaking genetic testing in women with TN breast cancer. METHODS: We undertook BRCA1 mutation analysis in 308 individuals with TN breast cancer, 159 individuals from unselected series of breast cancer and 149 individuals from series ascertained on the basis of young age and/or family history. RESULTS: BRCA1 mutations were present in 45 out of 308 individuals. Individuals with TN cancer <50 years had >10% likelihood of carrying a BRCA1 mutation in both the unselected (11 out of 58, 19%) and selected (26 out of 111, 23%) series. However, over a third would not have been offered testing using existing criteria. We estimate that testing all individuals with TN breast cancer <50 years would generate an extra 1200 tests annually in England. CONCLUSION: Women with TN breast cancer diagnosed below 50 years have >10% likelihood of carrying a BRCA1 mutation and are therefore eligible for testing in most centres. However, implementation may place short-term logistical and financial burdens on genetic services..
Ross, G.M.
Johnson, N.
Orr, N.
Walker, K.
Gibson, L.
Folkerd, E.
Haynes, B.
Palles, C.
Coupland, B.
Shoemaker, M.
Jones, M.
Broderick, P.
Sawyer, E.
Kerin, M.
Tomlinson, I.
Zvelebil, M.
Chilcott-Burns, S.
Tomczyk, K.
Simpson, G.
Willianson, J.
Hillier, S.
Houlston, R.
Swerdlow, A.
Ashworth, A.
Dowsett, M.
Peto, J.
dos Santos, I.
Fletcher, O.
(2012). Abstract P3-08-04: Impact of CYP3A variation on estrone levels and breast cancer risk. Poster session abstracts,
.
Timofeeva, M.N.
Hung, R.J.
Rafnar, T.
Christiani, D.C.
Field, J.K.
Bickeboeller, H.
Risch, A.
McKay, J.D.
Wang, Y.
Dai, J.
Gaborieau, V.
McLaughlin, J.
Brenner, D.
Narod, S.A.
Caporaso, N.E.
Albanes, D.
Thun, M.
Eisen, T.
Wichmann, H.-.
Rosenberger, A.
Han, Y.
Chen, W.
Zhu, D.
Spitz, M.
Wu, X.
Pande, M.
Zhao, Y.
Zaridze, D.
Szeszenia-Dabrowska, N.
Lissowska, J.
Rudnai, P.
Fabianova, E.
Mates, D.
Bencko, V.
Foretova, L.
Janout, V.
Krokan, H.E.
Gabrielsen, M.E.
Skorpen, F.
Vatten, L.
Njolstad, I.
Chen, C.
Goodman, G.
Lathrop, M.
Benhamou, S.
Vooder, T.
Vaelk, K.
Nelis, M.
Metspalu, A.
Raji, O.
Chen, Y.
Gosney, J.
Liloglou, T.
Muley, T.
Dienemann, H.
Thorleifsson, G.
Shen, H.
Stefansson, K.
Brennan, P.
Amos, C.I.
Houlston, R.
Landi, M.T.
Team, T.R.
(2012). Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls. Human molecular genetics,
Vol.21
(22),
pp. 4980-4995.
Spain, S.L.
Carvajal-Carmona, L.G.
Howarth, K.M.
Jones, A.M.
Su, Z.
Cazier, J.-.
Williams, J.
Aaltonen, L.A.
Pharoah, P.
Kerr, D.J.
Cheadle, J.
Li, L.
Casey, G.
Vodicka, P.
Sieber, O.
Lipton, L.
Gibbs, P.
Martin, N.G.
Montgomery, G.W.
Young, J.
Baird, P.N.
Morreau, H.
van Wezel, T.
Ruiz-Ponte, C.
Fernandez-Rozadilla, C.
Carracedo, A.
Castells, A.
Castellvi-Bel, S.
Dunlop, M.
Houlston, R.S.
Tomlinson, I.P.
(2012). Refinement of the associations between risk of colorectal cancer and polymorphisms on chromosomes 1q41 and 12q13 13. Hum mol genet,
Vol.21
(4),
pp. 934-946.
show abstract
In genome-wide association studies (GWASs) of colorectal cancer, we have identified two genomic regions in which pairs of tagging-single nucleotide polymorphisms (tagSNPs) are associated with disease; these comprise chromosomes 1q41 (rs6691170, rs6687758) and 12q13.13 (rs7163702, rs11169552). We investigated these regions further, aiming to determine whether they contain more than one independent association signal and/or to identify the SNPs most strongly associated with disease. Genotyping of additional sample sets at the original tagSNPs showed that, for both regions, the two tagSNPs were unlikely to identify a single haplotype on which the functional variation lay. Conversely, one of the pair of SNPs did not fully capture the association signal in each region. We therefore undertook more detailed analyses, using imputation, logistic regression, genealogical analysis using the GENECLUSTER program and haplotype analysis. In the 1q41 region, the SNP rs11118883 emerged as a strong candidate based on all these analyses, sufficient to account for the signals at both rs6691170 and rs6687758. rs11118883 lies within a region with strong evidence of transcriptional regulatory activity and has been associated with expression of PDGFRB mRNA. For 12q13.13, a complex situation was found: SNP rs7972465 showed stronger association than either rs11169552 or rs7136702, and GENECLUSTER found no good evidence for a two-SNP model. However, logistic regression and haplotype analyses supported a two-SNP model, in which a signal at the SNP rs706793 was added to that at rs11169552. Post-GWAS fine-mapping studies are challenging, but the use of multiple tools can assist in identifying candidate functional variants in at least some cases..
Lubbe, S.J.
Pittman, A.M.
Olver, B.
Lloyd, A.
Vijayakrishnan, J.
Naranjo, S.
Dobbins, S.
Broderick, P.
Gómez-Skarmeta, J.L.
Houlston, R.S.
(2012). The 14q22 2 colorectal cancer variant rs4444235 shows cis-acting regulation of BMP4. Oncogene,
Vol.31
(33),
pp. 3777-3784.
show abstract
Common genetic variation at human 14q22.2 tagged by rs4444235 is significantly associated with colorectal cancer (CRC) risk. Re-sequencing was used to comprehensively annotate the 17kb region of strong linkage disequilibrium encompassing rs4444235. Through bioinformatic analyses using H3K4Me1, H3K4Me3, and DNase-I hypersensitivity chromatin signatures and evolutionary conservation we identified seven candidate disease-causing single-nucleotide polymorphisms mapping to six regions within the 17-kb region predicted to have regulatory potential. Reporter gene studies of these regions demonstrated that the element to which rs4444235 maps acts as an allele-specific transcriptional enhancer. Allele-specific expression studies in CRC cell lines heterozygous for rs4444235 showed significantly increased expression of bone morphogenetic protein-4 (BMP4) associated with the risk allele (P<0.001). These data provide evidence for a functional basis for the non-coding risk variant rs4444235 at 14q22.2 and emphasizes the importance of genetic variation in the BMP pathway genes as determinants of CRC risk..
Hemminki, K.
Houlston, R.
Sundquist, J.
Sundquist, K.
Shu, X.
(2012). Co-Morbidity between Early-Onset Leukemia and Type 1 Diabetes - Suggestive of a Shared Viral Etiology?. Plos one,
Vol.7
(6).
Ma, Y.P.
van Leeuwen, F.E.
Cooke, R.
Broeks, A.
Enciso-Mora, V.
Olver, B.
Lloyd, A.
Broderick, P.
Russell, N.S.
Janus, C.
Ashworth, A.
Houlston, R.S.
Swerdlow, A.J.
(2012). FGFR2 genotype and risk of radiation-associated breast cancer in Hodgkin lymphoma. Blood,
Vol.119
(4),
pp. 1029-1031.
show abstract
Women treated at young ages with supradiaphragmatic radiotherapy for Hodgkin lymphoma (HL) have a highly increased risk of breast cancer. For personalized advice and follow-up regimens for patients, information is needed on how the radiotherapy-related risk is affected by other breast cancer risk factors. Genome-wide association studies have identified 14 independently replicated common single nucleotide polymorphisms that influence breast cancer risk. To examine whether these variants contribute to risk of radiation-associated breast cancer in HL, we analyzed 2 independent case-control series, from the United Kingdom and The Netherlands, totaling 693 HL patients, 232 with breast cancer and 461 without. rs1219648, which annotates the FGFR2 gene, was associated with risk in both series (combined per-allele odds ratio = 1.59, 95% confidence interval: 1.26-2.02; P = .000111). These data provide evidence that genetic variation in FGFR2 influences radiation-induced breast cancer risk..
Slager, S.L.
Skibola, C.F.
Di Bernardo, M.C.
Conde, L.
Broderick, P.
McDonnell, S.K.
Goldin, L.R.
Croft, N.
Holroyd, A.
Harris, S.
Riby, J.
Serie, D.J.
Kay, N.E.
Call, T.G.
Bracci, P.M.
Halperin, E.
Lanasa, M.C.
Cunningham, J.M.
Leis, J.F.
Morrison, V.A.
Spector, L.G.
Vachon, C.M.
Shanafelt, T.D.
Strom, S.S.
Camp, N.J.
Weinberg, J.B.
Matutes, E.
Caporaso, N.E.
Wade, R.
Dyer, M.J.
Dearden, C.
Cerhan, J.R.
Catovsky, D.
Houlston, R.S.
(2012). Common variation at 6p21 31 (BAK1) influences the risk of chronic lymphocytic leukemia. Blood,
Vol.120
(4),
pp. 843-846.
Dunlop, M.G.
Dobbins, S.E.
Farrington, S.M.
Jones, A.M.
Palles, C.
Whiffin, N.
Tenesa, A.
Spain, S.
Broderick, P.
Ooi, L.-.
Domingo, E.
Smillie, C.
Henrion, M.
Frampton, M.
Martin, L.
Grimes, G.
Gorman, M.
Semple, C.
Ma, Y.P.
Barclay, E.
Prendergast, J.
Cazier, J.-.
Olver, B.
Penegar, S.
Lubbe, S.
Chander, I.
Carvajal-Carmona, L.G.
Ballereau, S.
Lloyd, A.
Vijayakrishnan, J.
Zgaga, L.
Rudan, I.
Theodoratou, E.
Colorectal Tumour Gene Identification (CORGI) Consortium,
Starr, J.M.
Deary, I.
Kirac, I.
Kovacević, D.
Aaltonen, L.A.
Renkonen-Sinisalo, L.
Mecklin, J.-.
Matsuda, K.
Nakamura, Y.
Okada, Y.
Gallinger, S.
Duggan, D.J.
Conti, D.
Newcomb, P.
Hopper, J.
Jenkins, M.A.
Schumacher, F.
Casey, G.
Easton, D.
Shah, M.
Pharoah, P.
Lindblom, A.
Liu, T.
Swedish Low-Risk Colorectal Cancer Study Group,
Smith, C.G.
West, H.
Cheadle, J.P.
COIN Collaborative Group,
Midgley, R.
Kerr, D.J.
Campbell, H.
Tomlinson, I.P.
Houlston, R.S.
(2012). Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk. Nat genet,
Vol.44
(7),
pp. 770-776.
show abstract
We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10(-10)), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10(-10)) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10(-10)) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC..
Frampton, M.
Houlston, R.
(2012). Generation of artificial FASTQ files to evaluate the performance of next-generation sequencing pipelines. Plos one,
Vol.7
(11),
p. e49110.
show abstract
Pipelines for the analysis of Next-Generation Sequencing (NGS) data are generally composed of a set of different publicly available software, configured together in order to map short reads of a genome and call variants. The fidelity of pipelines is variable. We have developed ArtificialFastqGenerator, which takes a reference genome sequence as input and outputs artificial paired-end FASTQ files containing Phred quality scores. Since these artificial FASTQs are derived from the reference genome, it provides a gold-standard for read-alignment and variant-calling, thereby enabling the performance of any NGS pipeline to be evaluated. The user can customise DNA template/read length, the modelling of coverage based on GC content, whether to use real Phred base quality scores taken from existing FASTQ files, and whether to simulate sequencing errors. Detailed coverage and error summary statistics are outputted. Here we describe ArtificialFastqGenerator and illustrate its implementation in evaluating a typical bespoke NGS analysis pipeline under different experimental conditions. ArtificialFastqGenerator was released in January 2012. Source code, example files and binaries are freely available under the terms of the GNU General Public License v3.0. from https://sourceforge.net/projects/artfastqgen/..
Orr, N.
Lemnrau, A.
Cooke, R.
Fletcher, O.
Tomczyk, K.
Jones, M.
Johnson, N.
Lord, C.J.
Mitsopoulos, C.
Zvelebil, M.
McDade, S.S.
Buck, G.
Blancher, C.
Consortium, K.C.
Trainer, A.H.
James, P.A.
Bojesen, S.E.
Bokmand, S.
Nevanlinna, H.
Mattson, J.
Friedman, E.
Laitman, Y.
Palli, D.
Masala, G.
Zanna, I.
Ottini, L.
Giannini, G.
Hollestelle, A.
Ouweland, A.M.
Novakovic, S.
Krajc, M.
Gago-Dominguez, M.
Castelao, J.E.
Olsson, H.
Hedenfalk, I.
Easton, D.F.
Pharoah, P.D.
Dunning, A.M.
Bishop, D.T.
Neuhausen, S.L.
Steele, L.
Houlston, R.S.
Garcia-Closas, M.
Ashworth, A.
Swerdlow, A.J.
(2012). Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk. Nat genet,
Vol.44,
pp. 1182-1184.
show abstract
We conducted a genome-wide association study of male breast cancer comprising 823 cases and 2,795 controls of European ancestry, with validation in independent sample sets totaling 438 cases and 474 controls. A SNP in RAD51B at 14q24.1 was significantly associated with male breast cancer risk (P = 3.02 x 10(-13); odds ratio (OR) = 1.57). We also refine association at 16q12.1 to a SNP within TOX3 (P = 3.87 x 10(-15); OR = 1.50)..
Dobbins, S.E.
Hosking, F.J.
Shete, S.
Armstrong, G.
Swerdlow, A.
Liu, Y.
Yu, R.
Lau, C.
Schoemaker, M.J.
Hepworth, S.J.
Muir, K.
Bondy, M.
Houlston, R.S.
(2011). Allergy and glioma risk: test of association by genotype. Int j cancer,
Vol.128
(7),
pp. 1736-1740.
show abstract
Although epidemiological studies have suggested an association between atopy and glioma risk, these observations have been based on self-reporting of allergic conditions raising the possibility that associations may be noncausal and arise as a consequence of bias, reverse causation or other artifacts. Genetic information provides an alternative approach to investigate the relationship avoiding such biases. We analyzed 1,878 glioma cases and 3,670 controls for variants at 2q12, 5q12.1, 11q13 and 17q21 that are associated with asthma or eczema risk at p < 5.0 × 10(-7) . The SNP rs7216389, which tags the 3' flanking region of ORMDL3 at 17q21 and has been associated with childhood asthma, was correlated with increased glioma risk (OR = 1.10; 95% CI: 1.01-1.19). These data provide evidence for a correlation between asthma susceptibility and glioma risk and illustrate the value of using genetics as an investigative tool for developing etiological hypotheses..
Lubbe, S.J.
Pittman, A.M.
Matijssen, C.
Twiss, P.
Olver, B.
Lloyd, A.
Qureshi, M.
Brown, N.
Nye, E.
Stamp, G.
Blagg, J.
Houlston, R.S.
(2011). Evaluation of germline BMP4 mutation as a cause of colorectal cancer. Hum mutat,
Vol.32
(1),
pp. E1928-E1938.
show abstract
Transforming growth factor-β (TGF-β) signalling plays a key role in colorectal cancer (CRC). Bone morphogenetic protein-4 (BMP4) is a member of the TGF-β family of signal transduction molecules. To examine if germline mutation in BMP4 causes CRC we analysed 504 genetically enriched CRC cases (by virtue of early-onset disease, family history of CRC) for mutations in the coding sequence of BMP4. We identified three pathogenic mutations, p.R286X (g.8330C>T), p.W325C (g.8449G>T) and p.C373S (g.8592G>C), amongst the CRC cases which were not observed in 524 healthy controls. p.R286X localizes to the N-terminal of the TGF-β1 prodomain truncating the protein prior to the active domain. p.W325C and p.C373S mutations are predicted from protein homology modelling with BMP2 to impact deleteriously on BMP4 function. Segregation of p.C373S with adenoma and hyperplastic polyp in first-degree relatives of the case suggests germline mutations may confer a juvenile polyposis-type phenotype. These findings suggest mutation of BMP4is a cause of CRC and the value of protein-based modelling in the elucidation of rare disease-causing variants..
Fletcher, O.
Johnson, N.
Orr, N.
Hosking, F.J.
Gibson, L.J.
Walker, K.
Zelenika, D.
Gut, I.
Heath, S.
Palles, C.
Coupland, B.
Broderick, P.
Schoemaker, M.
Jones, M.
Williamson, J.
Chilcott-Burns, S.
Tomczyk, K.
Simpson, G.
Jacobs, K.B.
Chanock, S.J.
Hunter, D.J.
Tomlinson, I.P.
Swerdlow, A.
Ashworth, A.
Ross, G.
dos Santos Silva, I.
Lathrop, M.
Houlston, R.S.
Peto, J.
(2011). Novel breast cancer susceptibility locus at 9q31 2: results of a genome-wide association study. J natl cancer inst,
Vol.103
(5),
pp. 425-435.
show abstract
BACKGROUND: Genome-wide association studies have identified several common genetic variants associated with breast cancer risk. It is likely, however, that a substantial proportion of such loci have not yet been discovered. METHODS: We compared 296,114 tagging single-nucleotide polymorphisms in 1694 breast cancer case subjects (92% with two primary cancers or at least two affected first-degree relatives) and 2365 control subjects, with validation in three independent series totaling 11,880 case subjects and 12,487 control subjects. Odds ratios (ORs) and associated 95% confidence intervals (CIs) in each stage and all stages combined were calculated using unconditional logistic regression. Heterogeneity was evaluated with Cochran Q and I(2) statistics. All statistical tests were two-sided. RESULTS: We identified a novel risk locus for breast cancer at 9q31.2 (rs865686: OR = 0.89, 95% CI = 0.85 to 0.92, P = 1.75 × 10(-10)). This single-nucleotide polymorphism maps to a gene desert, the nearest genes being Kruppel-like factor 4 (KLF4, 636 kb centromeric), RAD23 homolog B (RAD23B, 794 kb centromeric), and actin-like 7A (ACTL7A, 736 kb telomeric). We also identified two variants (rs3734805 and rs9383938) mapping to 6q25.1 estrogen receptor 1 (ESR1), which were associated with breast cancer in subjects of northern European ancestry (rs3734805: OR = 1.19, 95% CI = 1.11 to 1.27, P = 1.35 × 10(-7); rs9383938: OR = 1.18, 95% CI = 1.11 to 1.26, P = 1.41 × 10(-7)). A variant mapping to 10q26.13, approximately 300 kb telomeric to the established risk locus within the second intron of FGFR2, was also associated with breast cancer risk, although not at genome-wide statistical significance (rs10510102: OR = 1.12, 95% CI = 1.07 to 1.17, P = 1.58 × 10(-6)). CONCLUSIONS: These findings provide further evidence on the role of genetic variation in the etiology of breast cancer. Fine mapping will be needed to identify causal variants and to determine their functional effects..
Zhao, D.-.
Chandler, I.
Chen, Z.-.
Pan, H.-.
Popat, S.
Shao, Y.-.
Houlston, R.S.
(2011). Mismatch repair, minichromosome maintenance complex component 2, cyclin A, and transforming growth factor β receptor type II as prognostic factors for colorectal cancer: results of a 10-year prospective study using tissue microarray analysis. Chin med j (engl),
Vol.124
(4),
pp. 483-490.
show abstract
BACKGROUND: The expression of genes encoding a number of pathogenetic pathways involved in colorectal cancer could potentially act as prognostic markers. Large prospective studies are required to establish their relevance to disease prognosis. METHODS: We investigated the relevance of 19 markers in 790 patients enrolled in a large randomised trial of 5-fluorouracil using immunohistochemistry and chromogenic in situ hybridisation. The relationship between overall 10-year survival and marker status was assessed. RESULTS: Minichromosome maintenance complex component 2 (MCM2) and cyclin A were significantly associated with overall survival. Elevated MCM2 expression was associated with a better prognosis (HR = 0.63, 95%CI: 0.46 - 0.86). Cyclin A expression above the median predicted an improved patient prognosis (HR = 0.71, 95%CI: 0.53 - 0.95). For mismatch repair deficiency and transforming growth factor β receptor type II (TGFBRII) overexpression there was a borderline association with a poorer prognosis (HR = 0.69, 95%CI: 0.46 - 1.04 and HR = 2.11, 95%CI: 1.02 - 4.40, respectively). No apparent associations were found for other markers. CONCLUSION: This study identified cell proliferation and cyclin A expression as prognostic indicators of patient outcome in colorectal cancer..
Hemminki, K.
Foersti, A.
Houlston, R.
Bermejo, J.L.
(2011). Searching for the Missing Heritability of Complex Diseases. Human mutation,
Vol.32
(2),
pp. 259-262.
Hosking, F.J.
Leslie, S.
Dilthey, A.
Moutsianas, L.
Wang, Y.
Dobbins, S.E.
Papaemmanuil, E.
Sheridan, E.
Kinsey, S.E.
Lightfoot, T.
Roman, E.
Irving, J.A.
Allan, J.M.
Taylor, M.
Greaves, M.
McVean, G.
Houlston, R.S.
(2011). MHC variation and risk of childhood B-cell precursor acute lymphoblastic leukemia. Blood,
Vol.117
(5),
pp. 1633-1640.
show abstract
A role for specific human leukocyte antigen (HLA) variants in the etiology of childhood acute lymphoblastic leukemia (ALL) has been extensively studied over the last 30 years, but no unambiguous association has been identified. To comprehensively study the relationship between genetic variation within the 4.5 Mb major histocompatibility complex genomic region and precursor B-cell (BCP) ALL risk, we analyzed 1075 observed and 8176 imputed single nucleotide polymorphisms and their related haplotypes in 824 BCP-ALL cases and 4737 controls. Using these genotypes we also imputed both common and rare alleles at class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DRB1, HLA-DQA1, and HLA-DQB1) HLA loci. Overall, we found no statistically significant association between variants and BCP-ALL risk. We conclude that major histocompatibility complex-defined variation in immune-mediated response is unlikely to be a major risk factor for BCP-ALL..
Yu, H.
Zhao, H.
Wang, L.-.
Han, Y.
Chen, W.V.
Amos, C.I.
Rafnar, T.
Sulem, P.
Stefansson, K.
Landi, M.T.
Caporaso, N.
Albanes, D.
Thun, M.
McKay, J.D.
Brennan, P.
Wang, Y.
Houlston, R.S.
Spitz, M.R.
Wei, Q.
(2011). An analysis of single nucleotide polymorphisms of 125 DNA repair genes in the Texas genome-wide association study of lung cancer with a replication for the XRCC4 SNPs. Dna repair (amst),
Vol.10
(4),
pp. 398-407.
show abstract
DNA repair genes are important for maintaining genomic stability and limiting carcinogenesis. We analyzed all single nucleotide polymorphisms (SNPs) of 125 DNA repair genes covered by the Illumina HumanHap300 (v1.1) BeadChips in a previously conducted genome-wide association study (GWAS) of 1154 lung cancer cases and 1137 controls and replicated the top-hits of XRCC4 SNPs in an independent set of 597 cases and 611 controls in Texas populations. We found that six of 20 XRCC4 SNPs were associated with a decreased risk of lung cancer with a P-value of 0.01 or lower in the discovery dataset, of which the most significant SNP was rs10040363 (P for allelic test=4.89 x 10⁻⁴). Moreover, the data in this region allowed us to impute a potentially functional SNP rs2075685 (imputed P for allelic test=1.3 x 10⁻³). A luciferase reporter assay demonstrated that the rs2075685G>T change in the XRCC4 promoter increased expression of the gene. In the replication study of rs10040363, rs1478486, rs9293329, and rs2075685, however, only rs10040363 achieved a borderline association with a decreased risk of lung cancer in a dominant model (adjusted OR=0.80, 95% CI=0.62-1.03 and P=0.079). In the final combined analysis of both the Texas GWAS discovery and replication datasets, the strength of the association was increased for rs10040363 (adjusted OR=0.77, 95% CI=0.66-0.89, P(dominant)=5 x 10⁻⁴ and P for trend=5 x 10⁻⁴) and rs1478486 (adjusted OR=0.82, 95% CI=0.71-0.94, P(dominant)=6 x 10⁻³ and P for trend=3.5 x 10⁻³). Finally, we conducted a meta-analysis of these XRCC4 SNPs with available data from published GWA studies of lung cancer with a total of 12,312 cases and 47,921 controls, in which none of these XRCC4 SNPs was associated with lung cancer risk. It appeared that rs2075685, although associated with increased expression of a reporter gene and lung cancer risk in the Texas populations, did not have an effect on lung cancer risk in other populations. This study underscores the importance of replication using published data in larger populations..
Wei, S.
Niu, J.
Zhao, H.
Liu, Z.
Wang, L.-.
Han, Y.
Chen, W.V.
Amos, C.I.
Rafnar, T.
Sulem, P.
Stefansson, K.
Landi, M.T.
Caporaso, N.E.
Albanes, D.
Thun, M.J.
McKay, J.D.
Brennan, P.
Wang, Y.
Houlston, R.S.
Spitz, M.R.
Wei, Q.
(2011). Association of a novel functional promoter variant (rs2075533 C>T) in the apoptosis gene TNFSF8 with risk of lung cancer--a finding from Texas lung cancer genome-wide association study. Carcinogenesis,
Vol.32
(4),
pp. 507-515.
show abstract
Published genome-wide association studies (GWASs) have identified few variants in the known biological pathways involved in lung cancer etiology. To mine the possibly hidden causal single nucleotide polymorphisms (SNPs), we explored all SNPs in the extrinsic apoptosis pathway from our published GWAS dataset for 1154 lung cancer cases and 1137 cancer-free controls. In an initial association analysis of 611 tagSNPs in 41 apoptosis-related genes, we identified only 10 tagSNPs associated with lung cancer risk with a P value<10(-2), including four tagSNPs in DAPK1 and three tagSNPs in TNFSF8. Unlike DAPK1 SNPs, TNFSF8 rs2181033 tagged other four predicted functional but untyped SNPs (rs776576, rs776577, rs31813148 and rs2075533) in the promoter region. Therefore, we further tested binding affinity of these four SNPs by performing the electrophoretic mobility shift assay. We found that only rs2075533T allele modified levels of nuclear proteins bound to DNA, leading to significantly decreased expression of luciferase reporter constructs by 5- to -10-fold in H1299, HeLa and HCT116 cell lines compared with the C allele. We also performed a replication study of the untyped rs2075533 in an independent Texas population but did not confirm the protective effect. We further performed a mini meta-analysis for SNPs of TNFSF8 obtained from other four published lung cancer GWASs with 12 214 cases and 47 721 controls, and we found that only rs3181366 (r2=0.69 with the untyped rs2075533) was associated to lung cancer risk (P=0.008). Our findings suggest a possible role of novel TNFSF8 variants in susceptibility to lung cancer..
Slade, I.
Bacchelli, C.
Davies, H.
Murray, A.
Abbaszadeh, F.
Hanks, S.
Barfoot, R.
Burke, A.
Chisholm, J.
Hewitt, M.
Jenkinson, H.
King, D.
Morland, B.
Pizer, B.
Prescott, K.
Saggar, A.
Side, L.
Traunecker, H.
Vaidya, S.
Ward, P.
Futreal, P.A.
Vujanic, G.
Nicholson, A.G.
Sebire, N.
Turnbull, C.
Priest, J.R.
Pritchard-Jones, K.
Houlston, R.
Stiller, C.
Stratton, M.R.
Douglas, J.
Rahman, N.
(2011). DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J med genet,
Vol.48
(4),
pp. 273-278.
show abstract
BACKGROUND: Constitutional DICER1 mutations were recently reported to cause familial pleuropulmonary blastoma (PPB). AIM: To investigate the contribution and phenotypic spectrum of constitutional and somatic DICER1 mutations to cancer. METHODS AND RESULTS: The authors sequenced DICER1 in constitutional DNA from 823 unrelated patients with a variety of tumours and in 781 cancer cell lines. Constitutional DICER1 mutations were identified in 19 families including 11/14 with PPB, 2/3 with cystic nephroma, 4/7 with ovarian Sertoli-Leydig-type tumours, 1/243 with Wilms tumour (this patient also had a Sertoli-Leydig tumour), 1/1 with intraocular medulloepithelioma (this patient also had PPB), 1/86 with medulloblastoma/infratentorial primitive neuroectodermal tumour, and 1/172 with germ cell tumour. The inheritance was investigated in 17 families. DICER1 mutations were identified in 25 relatives: 17 were unaffected, one mother had ovarian Sertoli-Leydig tumour, one half-sibling had cystic nephroma, and six relatives had non-toxic thyroid cysts/goitre. Analysis of eight tumours from DICER1 mutation-positive patients showed universal retention of the wild-type allele. DICER1 truncating mutations were identified in 4/781 cancer cell lines; all were in microsatellite unstable lines and therefore unlikely to be driver mutations. CONCLUSION: Constitutional DICER1 haploinsufficiency predisposes to a broad range of tumours, making a substantial contribution to PPB, cystic nephroma and ovarian Sertoli-Leydig tumours, but a smaller contribution to other tumours. Most mutation carriers are unaffected, indicating that tumour risk is modest. The authors define the clinical contexts in which DICER1 mutation testing should be considered, the associated tumour risks, and the implications for at-risk individuals. They have termed this condition 'DICER1 syndrome'. ACCESSION NUMBERS: The cDNA Genbank accession number for the DICER1 sequence reported in this paper is NM_030621.2..
Rio Frio, T.
Bahubeshi, A.
Kanellopoulou, C.
Hamel, N.
Niedziela, M.
Sabbaghian, N.
Pouchet, C.
Gilbert, L.
O'Brien, P.K.
Serfas, K.
Broderick, P.
Houlston, R.S.
Lesueur, F.
Bonora, E.
Muljo, S.
Schimke, R.N.
Bouron-Dal Soglio, D.
Arseneau, J.
Schultz, K.A.
Priest, J.R.
Nguyen, V.-.
Harach, H.R.
Livingston, D.M.
Foulkes, W.D.
Tischkowitz, M.
(2011). DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors. Jama,
Vol.305
(1),
pp. 68-77.
show abstract
CONTEXT: Nontoxic multinodular goiter (MNG) is frequently observed in the general population, but little is known about the underlying genetic susceptibility to this disease. Familial cases of MNG have been reported, and published reports describe 5 families that also contain at least 1 individual with a Sertoli-Leydig cell tumor of the ovary (SLCT). Germline mutations in DICER1, a gene that codes for an RNase III endoribonuclease, have been identified in families affected by pleuropulmonary blastoma (PPB), some of whom include cases of MNG and gonadal tumors such as SLCTs. OBJECTIVE: To determine whether familial MNG with or without SLCT in the absence of PPB was associated with mutations in DICER1. DESIGN, SETTING, AND PATIENTS: From September 2009 to September 2010, we screened 53 individuals from 2 MNG and 3 MNG/SLCT families at McGill University for mutations in DICER1. We investigated blood lymphocytes and MNG and SLCT tissue from family members for loss of the wild-type DICER1 allele (loss of heterozygosity), DICER1 expression, and microRNA (miRNA) dysregulation. MAIN OUTCOME MEASURE: Detection of germline DICER1 gene mutations in familial MNG with and without SLCT. RESULTS: We identified and characterized germline DICER1 mutations in 37 individuals from 5 families. Two mutations were predicted to be protein truncating, 2 resulted in in-frame deletions, and 1 was a missense mutation. Molecular analysis of the 3 SLCTs showed no loss of heterozygosity of DICER1, and immunohistochemical analysis in 2 samples showed strong expression of DICER1 in Sertoli cells but weak staining of Leydig cells. miRNA profiling of RNA from lymphoblastoid cell lines from both affected and unaffected members of the familial MNG cases revealed miRNA perturbations in DICER1 mutation carriers. CONCLUSIONS: DICER1 mutations are associated with both familial MNG and MNG with SLCT, independent of PPB. These germline DICER1 mutations are associated with dysregulation of miRNA expression patterns..
Tomlinson, I.P.
Carvajal-Carmona, L.G.
Dobbins, S.E.
Tenesa, A.
Jones, A.M.
Howarth, K.
Palles, C.
Broderick, P.
Jaeger, E.E.
Farrington, S.
Lewis, A.
Prendergast, J.G.
Pittman, A.M.
Theodoratou, E.
Olver, B.
Walker, M.
Penegar, S.
Barclay, E.
Whiffin, N.
Martin, L.
Ballereau, S.
Lloyd, A.
Gorman, M.
Lubbe, S.
COGENT Consortium,
CORGI Collaborators,
EPICOLON Consortium,
Howie, B.
Marchini, J.
Ruiz-Ponte, C.
Fernandez-Rozadilla, C.
Castells, A.
Carracedo, A.
Castellvi-Bel, S.
Duggan, D.
Conti, D.
Cazier, J.-.
Campbell, H.
Sieber, O.
Lipton, L.
Gibbs, P.
Martin, N.G.
Montgomery, G.W.
Young, J.
Baird, P.N.
Gallinger, S.
Newcomb, P.
Hopper, J.
Jenkins, M.A.
Aaltonen, L.A.
Kerr, D.J.
Cheadle, J.
Pharoah, P.
Casey, G.
Houlston, R.S.
Dunlop, M.G.
(2011). Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer. Plos genet,
Vol.7
(6),
p. e1002105.
show abstract
Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10(-10)) and BMP2 (rs4813802, P = 4.65×10(-11)). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10(-8)) and rs11632715 (P = 2.30×10(-10)). As low-penetrance predisposition variants become harder to identify-owing to small effect sizes and/or low risk allele frequencies-approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases..
Abulí, A.
Fernández-Rozadilla, C.
Giráldez, M.D.
Muñoz, J.
Gonzalo, V.
Bessa, X.
Bujanda, L.
Reñé, J.M.
Lanas, A.
García, A.M.
Saló, J.
Argüello, L.
Vilella, A.
Carreño, R.
Jover, R.
Xicola, R.M.
Llor, X.
Carvajal-Carmona, L.
Tomlinson, I.P.
Kerr, D.J.
Houlston, R.S.
Piqué, J.M.
Carracedo, A.
Castells, A.
Andreu, M.
Ruiz-Ponte, C.
Castellví-Bel, S.
Gastrointestinal Oncology Group of the Spanish Gastroenterological Association,
(2011). A two-phase case-control study for colorectal cancer genetic susceptibility: candidate genes from chromosomal regions 9q22 and 3q22. Br j cancer,
Vol.105
(6),
pp. 870-875.
show abstract
BACKGROUND: Colorectal cancer (CRC) is the second cause of cancer-related death in the Western world. Much of the CRC genetic risk remains unidentified and may be attributable to a large number of common, low-penetrance genetic variants. Genetic linkage studies in CRC families have reported additional association with regions 9q22-31, 3q21-24, 7q31, 11q, 14q and 22q. There are several plausible candidate genes for CRC susceptibility within the aforementioned linkage regions including PTCH1, XPA and TGFBR1 in 9q22-31, and EPHB1 and MRAS in 3q21-q24. METHODS: CRC cases and matched controls were from EPICOLON, a prospective, multicentre, nationwide Spanish initiative, composed of two independent phases. Phase 1 corresponded to 515 CRC cases and 515 controls, whereas phase 2 consisted of 901 CRC cases and 909 controls. Genotyping was performed for 172 single-nucleotide polymorphisms (SNPs) in 84 genes located within regions 9q22-31 and 3q21-q24. RESULTS: None of the 172 SNPs analysed in our study could be formally associated with CRC risk. However, rs1444601 (TOPBP1) and rs13088006 (CDV3) in region 3q22 showed interesting results and may have an effect on CRC risk. CONCLUSIONS: TOPBP1 and CDV3 genetic variants on region 3q22 may modulate CRC risk. Further validation and meta-analysis should be undertaken in larger CRC cohorts..
Crowther-Swanepoel, D.
Di Bernardo, M.C.
Jamroziak, K.
Karabon, L.
Frydecka, I.
Deaglio, S.
D'Arena, G.
Rossi, D.
Gaidano, G.
Olver, B.
Lloyd, A.
Broderick, P.
Laurenti, L.
Szemraj-Rogucka, Z.
Robak, T.
Catovsky, D.
Houlston, R.S.
(2011). Common genetic variation at 15q25 2 impacts on chronic lymphocytic leukaemia risk. Br j haematol,
Vol.154
(2),
pp. 229-233.
show abstract
A genome-wide association study of chronic lymphocytic leukaemia (CLL) suggested that common variants at 15q25.2 (rs783540) and 18q21.1 (rs1036935) influence CLL. To validate these associations and explore their relationship with CLL risk we genotyped case-control datasets from Poland, UK and Italy totalling 1428 cases and 1920 controls. Combined data from these and previously genotyped series (2503 cases and 5789 controls) provided evidence for an association between 15q25.2 and 18q21.1 loci and CLL risk (P(combined) = 1·10 × 10(-7) and 1·30 × 10(-5) respectively). These data provide further evidence for the involvement of common genetic variants in CLL risk and insight into the biological basis of disease development..
Wang, Y.
Broderick, P.
Matakidou, A.
Vijayakrishnan, J.
Eisen, T.
Houlston, R.S.
(2011). Variation in TP63 is associated with lung adenocarcinoma in the UK population. Cancer epidemiol biomarkers prev,
Vol.20
(7),
pp. 1453-1462.
show abstract
BACKGROUND: Variation at TP63 has recently been shown to be associated with lung adenocarcinoma in the Asian population. METHODS: To investigate how this finding translates to the European population we compared the genotypes of SNPs annotating the TP63 locus at 3q28 in 4,462 lung cancer patients, including 911 with adenocarcinoma, and 8,235 controls from the United Kingdom. RESULTS: A statistically significant association between adenocarcinoma risk and SNP genotype was shown: rs10937405, OR = 1.21, P = 1.82 × 10(-4); rs17429138, OR = 1.23, P = 7.49 × 10(-5); and rs4396880, OR = 1.21, P = 2.03 × 10(-4). Haplotype analysis was consistent with a single TP63 risk locus defined by SNPs rs10937405, rs17429138, and rs4396880. While no association between SNPs and small cell lung cancer was shown, the rs10937405 and rs439680 associations were significant for squamous cancer (respective P-values, 0.0022 and 0.02). CONCLUSIONS: These findings show TP63 variation is a risk factor for the development of lung adenocarcinoma in the UK population. Furthermore, they provide additional insight into the subtype-specificity of the 3q28 lung cancer association. IMPACT: Our data confirm the association of 3q28 with lung adenocarcinoma and that this association is not confined to the Asian population. Elucidating the functional basis of this association will be contingent on future fine mapping of the TP63 loci..
Sherborne, A.L.
Hemminki, K.
Kumar, R.
Bartram, C.R.
Stanulla, M.
Schrappe, M.
Petridou, E.
Semsei, A.F.
Szalai, C.
Sinnett, D.
Krajinovic, M.
Healy, J.
Lanciotti, M.
Dufour, C.
Indaco, S.
El-Ghouroury, E.A.
Sawangpanich, R.
Hongeng, S.
Pakakasama, S.
Gonzalez-Neira, A.
Ugarte, E.L.
Leal, V.P.
Espinoza, J.P.
Kamel, A.M.
Ebid, G.T.
Radwan, E.R.
Yalin, S.
Yalin, E.
Berkoz, M.
Simpson, J.
Roman, E.
Lightfoot, T.
Hosking, F.J.
Vijayakrishnan, J.
Greaves, M.
Houlston, R.S.
(2011). Rationale for an international consortium to study inherited genetic susceptibility to childhood acute lymphoblastic leukemia. Haematologica,
Vol.96
(7),
pp. 1049-1054.
show abstract
Acute lymphoblastic leukemia is the major pediatric cancer in developed countries. To date most association studies of acute lymphoblastic leukemia have been based on the candidate gene approach and have evaluated a restricted number of polymorphisms. Such studies have served to highlight difficulties in conducting statistically and methodologically rigorous investigations into acute lymphoblastic leukemia risk. Recent genome-wide association studies of childhood acute lymphoblastic leukemia have provided robust evidence that common variation at four genetic loci confers a modest increase in risk. The accumulated experience to date and relative lack of success of initial efforts to identify novel acute lymphoblastic leukemia predisposition loci emphasize the need for alternative study designs and methods. The International Childhood Acute Lymphoblastic Leukaemia Genetics Consortium includes 12 research groups in Europe, Asia, the Middle East and the Americas engaged in studying the genetics of acute lymphoblastic leukemia. The initial goal of this consortium is to identify and characterize low-penetrance susceptibility variants for acute lymphoblastic leukemia through association-based analyses. Efforts to develop genome-wide association studies of acute lymphoblastic leukemia, in terms of both sample size and single nucleotide polymorphism coverage, and to increase the number of single nucleotide polymorphisms taken forward to large-scale replication should lead to the identification of additional novel risk variants for acute lymphoblastic leukemia. Ethnic differences in the risk of acute lymphoblastic leukemia are well recognized and thus in assessing the interplay between inherited and non-genetic risk factors, analyses using different population cohorts with different incidence rates are likely to be highly informative. Given that the frequency of many acute lymphoblastic leukemia subgroups is small, identifying differential effects will realistically only be possible through multi-center pooled analyses. Here, we review the rationale for identifying genetic risk variants for acute lymphoblastic leukemia and our proposed strategy for establishing the International Childhood Acute Lymphoblastic Leukaemia Genetics Consortium..
Whiffin, N.
Broderick, P.
Lubbe, S.J.
Pittman, A.M.
Penegar, S.
Chandler, I.
Houlston, R.S.
(2011). MLH1-93G > A is a risk factor for MSI colorectal cancer. Carcinogenesis,
Vol.32
(8),
pp. 1157-1161.
show abstract
The -93G > A (rs1800734) polymorphism within the core promoter region of the MutL homolog 1 (MLH1) gene has recently been proposed as a low penetrance variant for colorectal cancer (CRC). We evaluated the significance of rs1800734 on CRC risk by genotyping 10 409 CRC cases and 6965 controls. The per allele odds ratio (OR) for all CRC-associated MLH1-93G > A was 1.06 (P = 0.037). Using a subset of 3132 cases with known microsatellite instability (MSI) status, the risk was shown to be confined to microsatellite instability-high (MSI-H) CRC; OR = 1.39 (P = 1.45 × 10(-4)). A meta-analysis of our study and four smaller published studies (totalling 801 cases, 10 890 controls) provided for increased evidence of relationship between MLH1-93G > A and MSI-H CRC risk (P = 3.43 × 10(-12)). The impact of MLH1-93G > A on CRC risk was shown to be independent of the 14 low penetrance loci for CRC identified by recent genome-wide association studies. These data provide further evidence that MLH1-93G > A is a low-penetrance variant for CRC and support the proposition that MLH1-93G > A acts as marker for a somatic event defining a specific CRC subtype..
Amirian, E.S.
Scheurer, M.E.
Liu, Y.
D'Amelio, A.M.
Houlston, R.S.
Etzel, C.J.
Shete, S.
Swerdlow, A.J.
Schoemaker, M.J.
McKinney, P.A.
Fleming, S.J.
Muir, K.R.
Lophatananon, A.
Bondy, M.L.
(2011). A novel approach to exploring potential interactions among single-nucleotide polymorphisms of inflammation genes in gliomagenesis: an exploratory case-only study. Cancer epidemiol biomarkers prev,
Vol.20
(8),
pp. 1683-1689.
show abstract
BACKGROUND: Despite extensive research on the topic, glioma etiology remains largely unknown. Exploration of potential interactions between single-nucleotide polymorphisms (SNP) of immune genes is a promising new area of glioma research. The case-only study design is a powerful and efficient design for exploring possible multiplicative interactions between factors that are independent of one another. The purpose of our study was to use this exploratory design to identify potential pair wise SNP-SNP interactions from genes involved in several different immune-related pathways for investigation in future studies. METHODS: The study population consisted of two case groups: 1,224 histologic confirmed, non-Hispanic white glioma cases from the United States and a validation population of 634 glioma cases from the United Kingdom. Polytomous logistic regression, in which one SNP was coded as the outcome and the other SNP was included as the exposure, was utilized to calculate the ORs of the likelihood of cases simultaneously having the variant alleles of two different SNPs. Potential interactions were examined only between SNPs located in different genes or chromosomes. RESULTS: Using this data mining strategy, we found 396 significant SNP-SNP interactions among polymorphisms of immune-related genes that were present in both the U.S. and U.K. study populations. CONCLUSION: This exploratory study was conducted for the purpose of hypothesis generation, and thus has provided several new hypotheses that can be tested using traditional case-control study designs to obtain estimates of risk. IMPACT: This is the first study, to our knowledge, to take this novel approach to identifying SNP-SNP interactions relevant to glioma etiology..
Orr, N.
Cooke, R.
Jones, M.
Fletcher, O.
Dudbridge, F.
Chilcott-Burns, S.
Tomczyk, K.
Broderick, P.
Houlston, R.
Ashworth, A.
Swerdlow, A.
(2011). Genetic variants at chromosomes 2q35, 5p12, 6q25 1, 10q26 13, and 16q12 1 influence the risk of breast cancer in men. Plos genet,
Vol.7
(9),
p. e1002290.
show abstract
Male breast cancer accounts for approximately 1% of all breast cancer. To date, risk factors for male breast cancer are poorly defined, but certain risk factors and genetic features appear common to both male and female breast cancer. Genome-wide association studies (GWAS) have recently identified common single nucleotide polymorphisms (SNPs) that influence female breast cancer risk; 12 of these have been independently replicated. To examine if these variants contribute to male breast cancer risk, we genotyped 433 male breast cancer cases and 1,569 controls. Five SNPs showed a statistically significant association with male breast cancer: rs13387042 (2q35) (odds ratio (OR) = 1.30, p = 7.98×10⁻⁴), rs10941679 (5p12) (OR = 1.26, p = 0.007), rs9383938 (6q25.1) (OR = 1.39, p = 0.004), rs2981579 (FGFR2) (OR = 1.18, p = 0.03), and rs3803662 (TOX3) (OR = 1.48, p = 4.04×10⁻⁶). Comparing the ORs for male breast cancer with the published ORs for female breast cancer, three SNPs--rs13387042 (2q35), rs3803662 (TOX3), and rs6504950 (COX11)--showed significant differences in ORs (p<0.05) between sexes. Breast cancer is a heterogeneous disease; the relative risks associated with loci identified to date show subtype and, based on these data, gender specificity. Additional studies of well-defined patient subgroups could provide further insight into the biological basis of breast cancer development..
Wade, R.
Di Bernardo, M.C.
Richards, S.
Rossi, D.
Crowther-Swanepoel, D.
Gaidano, G.
Oscier, D.G.
Catovsky, D.
Houlston, R.S.
(2011). Association between single nucleotide polymorphism-genotype and outcome of patients with chronic lymphocytic leukemia in a randomized chemotherapy trial. Haematologica,
Vol.96
(10),
pp. 1496-1503.
show abstract
BACKGROUND: There is variability in the outcome of patients with chronic lymphocytic leukemia with apparently the same stage of disease. Identifying genetic variants that influence patients' outcome and response to treatment may provide important insights into the biology of the disease. DESIGN AND METHODS: We investigated the possibility that genetic variation influences outcome by conducting a genome-wide analysis of 346,831 single nucleotide polymorphisms in 356 patients entered into a phase III trial comparing the efficacy of fludarabine, chlorambucil, and fludarabine with cyclophosphamide as first-line treatment. Genotypes were linked to individual patients' outcome data and response to chemotherapy. The association between genotype and progression-free survival was assessed by Cox regression analysis adjusting for treatment and clinicopathology. RESULTS: The strongest associations were shown for rs1949733 (ACOX3; P=8.22x10-7), rs1342899 (P=7.72×10(-7)) and rs11158493 (PPP2R5E; P=8.50×10(-7)). In addition, the 52 single nucleotide polymorphisms associated at P<10(-4) included rs438034 (CENPF; P=4.86×10(-6)), previously correlated with cancer progression, and rs2255235 (B2M; P=3.10×10(-5)) and rs2064501 (IL22RA2; P=4.81×10(-5)) which map to B-cell genes. CONCLUSIONS: Our findings provide evidence that genetic variation is a determinant of progression-free survival of patients with chronic lymphocytic leukemia. Specific associations warrant further analyses..
Huang, X.
Kushekhar, K.
Nolte, I.
Kooistra, W.
Visser, L.
Bouwman, I.
Kouprie, N.
Veenstra, R.
van Imhoff, G.
Olver, B.
Houlston, R.S.
Poppema, S.
Diepstra, A.
Hepkema, B.
van den Berg, A.
(2011). Multiple HLA class I and II associations in classical Hodgkin lymphoma and EBV status defined subgroups. Blood,
Vol.118
(19),
pp. 5211-5217.
show abstract
The pathogenesis of classical Hodgkin lymphoma (cHL) involves environmental and genetic factors. To explore the role of the human leukocyte antigen (HLA) genes, we performed a case-control genotyping study in 338 Dutch cHL patients and more than 5000 controls using a PCR-based sequence-specific oligonucleotide probe hybridization approach. HLA-A68 and HLA-DR11 (5) were significantly increased in the cHL patient population compared with the controls. Three class II associations were observed in the EBV(-) cHL population with an increase of HLA-DR15 (2) and a decrease of HLA-DR4 and HLA-DR7. Allele frequencies of HLA-A1, HLA-B37, and HLA-DR10 were significantly increased in the EBV(+) cHL population; these alleles are in strong linkage disequilibrium and form a common haplotype in whites. The allele frequency of HLA-A2 was significantly decreased in the EBV(+) cHL population. Sequence-specific oligonucleotide probe analysis revealed significant differences between EBV(+) and EBV(-) cHL patients for 19 probes that discriminate between HLA-A*01 and HLA-A*02. In conclusion, the HLA-A1 and HLA-A2 antigens and not specific single nucleotide variants shared by multiple alleles are responsible for the association with EBV(+) cHL. Furthermore, several new protective and predisposing HLA class I and II associations for the EBV(+), the EBV(-), and the entire cHL population were identified..
Pastorczak, A.
Górniak, P.
Sherborne, A.
Hosking, F.
Trelińska, J.
Lejman, M.
Szczepański, T.
Borowiec, M.
Fendler, W.
Kowalczyk, J.
Houlston, R.S.
Młynarski, W.
(2011). Role of 657del5 NBN mutation and 7p12 2 (IKZF1), 9p21 (CDKN2A), 10q21 2 (ARID5B) and 14q11 2 (CEBPE) variation and risk of childhood ALL in the Polish population. Leuk res,
Vol.35
(11),
pp. 1534-1536.
show abstract
Recent studies have shown that SNPs mapping to 7p12.2 (IKZF1), 9p21 (CDKN2A), 10q21.2 (ARID5B), and 14q11.2 (CEBPE) and carrier status for recessively inherited Nijmegen Breakage syndrome (NBS) influence childhood acute lymphoblastic leukemia (ALL) risk. To examine these relationship, we analysed 398 ALL cases and 731 controls from Poland. Statistically significant association between genotype at 7p12.2 (IKZF1), 10q21.2 (ARID5B) and the NBS associated locus, 8q21.3 (NBN) and ALL risk was found; odds ratios (ORs), 1.34 (P=0.002), 1.33 (P=0.003), and 1325.21 (P=0.0028), respectively. These data provide further insights into the biological basis of ALL highlighting the existence of both common and rare disease susceptibility variants..
Berntsson, S.G.
Wibom, C.
Sjostrom, S.
Henriksson, R.
Brannstrom, T.
Broholm, H.
Johansson, C.
Fleming, S.J.
McKinney, P.A.
Bethke, L.
Houlston, R.
Smits, A.
Andersson, U.
Melin, B.S.
(2011). Analysis of DNA repair gene polymorphisms and survival in low-grade and anaplastic gliomas. Journal of neuro-oncology,
Vol.105
(3),
pp. 531-538.
Niittymäki, I.
Tuupanen, S.
Li, Y.
Järvinen, H.
Mecklin, J.-.
Tomlinson, I.P.
Houlston, R.S.
Karhu, A.
Aaltonen, L.A.
(2011). Systematic search for enhancer elements and somatic allelic imbalance at seven low-penetrance colorectal cancer predisposition loci. Bmc med genet,
Vol.12,
p. 23.
show abstract
BACKGROUND: Common single-nucleotide polymorphisms (SNPs) in ten chromosomal loci have been shown to predispose to colorectal cancer (CRC) in genome-wide association studies. A plausible biological mechanism of CRC susceptibility associated with genetic variation has so far only been proposed for three loci, each pointing to variants that affect gene expression through distant regulatory elements. In this study, we aimed to gain insight into the molecular basis of seven low-penetrance CRC loci tagged by rs4779584 at 15q13, rs10795668 at 10p14, rs3802842 at 11q23, rs4444235 at 14q22, rs9929218 at 16q22, rs10411210 at 19q13, and rs961253 at 20p12. METHODS: Possible somatic gain of the risk allele or loss of the protective allele was studied by analyzing allelic imbalance in tumour and corresponding normal tissue samples of heterozygous patients. Functional variants were searched from in silico predicted enhancer elements locating inside the CRC-associating linkage-disequilibrium regions. RESULTS: No allelic imbalance targeting the SNPs was observed at any of the seven loci. Altogether, 12 SNPs that were predicted to disrupt potential transcription factor binding sequences were genotyped in the same population-based case-control series as the seven tagging SNPs originally. None showed association with CRC. CONCLUSIONS: The results of the allelic imbalance analysis suggest that the seven CRC risk variants are not somatically selected for in the neoplastic progression. The bioinformatic approach was unable to pinpoint cancer-causing variants at any of the seven loci. While it is possible that many of the predisposition loci for CRC are involved in control of gene expression by targeting transcription factor binding sites, also other possibilities, such as regulatory RNAs, should be considered..
Hosking, F.J.
Feldman, D.
Bruchim, R.
Olver, B.
Lloyd, A.
Vijayakrishnan, J.
Flint-Richter, P.
Broderick, P.
Houlston, R.S.
Sadetzki, S.
(2011). Search for inherited susceptibility to radiation-associated meningioma by genomewide SNP linkage disequilibrium mapping. Br j cancer,
Vol.104
(6),
pp. 1049-1054.
show abstract
BACKGROUND: Exposure to ionising radiation is a well-established risk factor for multiple types of tumours, including malignant brain tumours. In the 1950s, radiotherapy was used to treat Tinea Capitis (TC) in thousands of children, mostly of North-African and Middle Eastern origin, during the mass migration to Israel. The over-representation of radiation-associated meningioma (RAM) and other cancers in specific families provide support for inherited genetic susceptibility to radiation-induced cancer. METHODS: To test this hypothesis, we genotyped 15 families segregating RAM using high-density single-nucleotide polymorphism (SNP) arrays. Using the family-based association test (FBAT) programme, we tested each polymorphism and haplotype for an association with RAM. RESULTS: The strongest haplotype associations were attained at 18q21.1 (P=7.5 × 10(-5)), 18q21.31 (P=2.8 × 10(-5)) and 10q21.3 (P=1.6 × 10(-4)). Although associations were not formally statistically significant after adjustment for multiple testing, the 18q21.1 and 10q21.3 associations provide support for a variation in PIAS2, KATNAL2, TCEB3C, TCEB3CL and CTNNA3 genes as risk factors for RAM. CONCLUSION: These findings suggest that any underlying genetic susceptibility to RAM is likely to be mediated through the co-inheritance of multiple risk alleles rather than a single major gene locus determining radiosensitivity..
Sanson, M.
Hosking, F.J.
Shete, S.
Zelenika, D.
Dobbins, S.E.
Ma, Y.
Enciso-Mora, V.
Idbaih, A.
Delattre, J.-.
Hoang-Xuan, K.
Marie, Y.
Boisselier, B.
Carpentier, C.
Wang, X.-.
Di Stefano, A.L.
Labussière, M.
Gousias, K.
Schramm, J.
Boland, A.
Lechner, D.
Gut, I.
Armstrong, G.
Liu, Y.
Yu, R.
Lau, C.
Di Bernardo, M.C.
Robertson, L.B.
Muir, K.
Hepworth, S.
Swerdlow, A.
Schoemaker, M.J.
Wichmann, H.-.
Müller, M.
Schreiber, S.
Franke, A.
Moebus, S.
Eisele, L.
Försti, A.
Hemminki, K.
Lathrop, M.
Bondy, M.
Houlston, R.S.
Simon, M.
(2011). Chromosome 7p11 2 (EGFR) variation influences glioma risk. Hum mol genet,
Vol.20
(14),
pp. 2897-2904.
show abstract
While gliomas are the most common primary brain tumors, their etiology is largely unknown. To identify novel risk loci for glioma, we conducted genome-wide association (GWA) analysis of two case-control series from France and Germany (2269 cases and 2500 controls). Pooling these data with previously reported UK and US GWA studies provided data on 4147 glioma cases and 7435 controls genotyped for 424 460 common tagging single-nucleotide polymorphisms. Using these data, we demonstrate two statistically independent associations between glioma and rs11979158 and rs2252586, at 7p11.2 which encompasses the EGFR gene (population-corrected statistics, P(c) = 7.72 × 10(-8) and 2.09 × 10(-8), respectively). Both associations were independent of tumor subtype, and were independent of EGFR amplification, p16INK4a deletion and IDH1 mutation status in tumors; compatible with driver effects of the variants on glioma development. These findings show that variation in 7p11.2 is a determinant of inherited glioma risk..
Yu, H.
Zhao, H.
Wang, L.-.
Han, Y.
V., C.W.
Amos, C.I.
Rafnar, T.
Sulem, P.
Stefansson, K.
Landi, M.T.
Caporaso, N.
Albanes, D.
Thun, M.
McKay, J.D.
Brennan, P.
Wang, Y.
Houlston, R.S.
Spitz, M.R.
Wei, Q.
(2011). Abstract 889: An analysis of single nucleotide polymorphisms of 125 DNA repair genes in the Texas genome-wide association study of lung cancer with a replication for theXRCC4SNPs. Epidemiology,
.
Shete, S.
Lau, C.C.
Houlston, R.S.
Claus, E.B.
Barnholtz-Sloan, J.
Lai, R.
Il'yasova, D.
Schildkraut, J.
Sadetzki, S.
Johansen, C.
Bernstein, J.L.
Olson, S.H.
Jenkins, R.B.
Yang, P.
Vick, N.A.
Wrensch, M.
Davis, F.G.
McCarthy, B.J.
Leung, E.H.
Davis, C.
Cheng, R.
Hosking, F.J.
Armstrong, G.N.
Liu, Y.
Yu, R.K.
Henriksson, R.
Gliogene Consortium,
Melin, B.S.
Bondy, M.L.
(2011). Genome-wide high-density SNP linkage search for glioma susceptibility loci: results from the Gliogene Consortium. Cancer res,
Vol.71
(24),
pp. 7568-7575.
show abstract
Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have shown that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium single-nucleotide polymorphism, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P = 0.0005) at 17q12-21.32 and the Z-score of 4.20 (P = 0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P = 0.008) and the Z-score of 1.47 (P = 0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P = 0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma..
Carvajal-Carmona, L.G.
Cazier, J.-.
Jones, A.M.
Howarth, K.
Broderick, P.
Pittman, A.
Dobbins, S.
Tenesa, A.
Farrington, S.
Prendergast, J.
Theodoratou, E.
Barnetson, R.
Conti, D.
Newcomb, P.
Hopper, J.L.
Jenkins, M.A.
Gallinger, S.
Duggan, D.J.
Campbell, H.
Kerr, D.
Casey, G.
Houlston, R.
Dunlop, M.
Tomlinson, I.
(2011). Fine-mapping of colorectal cancer susceptibility loci at 8q23 3, 16q22 1 and 19q13 11: refinement of association signals and use of in silico analysis to suggest functional variation and unexpected candidate target genes. Human molecular genetics,
Vol.20
(14),
pp. 2879-2888.
Ho, J.W.
Choi, S.-.
Lee, Y.-.
Hui, T.C.
Cherny, S.S.
Garcia-Barceló, M.-.
Carvajal-Carmona, L.
Liu, R.
To, S.-.
Yau, T.-.
Chung, C.C.
Yau, C.C.
Hui, S.M.
Lau, P.Y.
Yuen, C.-.
Wong, Y.-.
Ho, S.
Fung, S.S.
Tomlinson, I.P.
Houlston, R.S.
Cheng, K.K.
Sham, P.C.
(2011). Replication study of SNP associations for colorectal cancer in Hong Kong Chinese. Br j cancer,
Vol.104
(2),
pp. 369-375.
show abstract
BACKGROUND: Recent genome-wide association studies of colorectal cancer (CRC) have identified common single-nucleotide polymorphisms (SNPs) mapping to 10 independent loci that confer modest increased risk. These studies have been conducted in European populations and it is unclear whether these observations generalise to populations with different ethnicities and rates of CRC. METHODS: An association study was performed on 892 CRC cases and 890 controls recruited from the Hong Kong Chinese population, genotyping 32 SNPs, which were either associated with CRC in previous studies or are in close proximity to previously reported risk SNPs. RESULTS: Twelve of the SNPs showed evidence of an association. The strongest associations were provided by rs10795668 on 10p14, rs4779584 on 15q14 and rs12953717 on 18q21.2. There was significant linear association between CRC risk and the number of independent risk variants possessed by an individual (P=2.29 × 10(-5)). CONCLUSION: These results indicate that some previously reported SNP associations also impact on CRC risk in the Chinese population. Possible reasons for failure of replication for some loci include inadequate study power, differences in allele frequency, linkage disequilibrium structure or effect size between populations. Our results suggest that many associations for CRC are likely to generalise across populations..
Moutsianas, L.
Enciso-Mora, V.
Ma, Y.P.
Leslie, S.
Dilthey, A.
Broderick, P.
Sherborne, A.
Cooke, R.
Ashworth, A.
Swerdlow, A.J.
McVean, G.
Houlston, R.S.
(2011). Multiple Hodgkin lymphoma-associated loci within the HLA region at chromosome 6p21 3. Blood,
Vol.118
(3),
pp. 670-674.
show abstract
Since an association between the human leukocyte antigen (HLA) region and Hodgkin lymphoma (HL) was first reported in 1967, many studies have reported associations between HL risk and both single nucleotide polymorphism (SNP) and classic HLA allele variation in the major histocompatibility complex. However, population stratification and the extent and complexity of linkage disequilibrium within the major histocompatibility complex have hindered efforts to fine-map causal signals. Using SNP data to impute alleles at classic HLA loci, we have conducted an integrated analysis of HL risk within the HLA region in 582 early-onset HL cases and 4736 controls. We confirm that the strongest signal of association comes from an SNP located in the class II region, rs6903608 (odds ratio [OR] = 1.79, P = 6.63 × 10(-19)), which is unlikely to be driven by association to HLA-DRB, DQA, or DQB alleles. In addition, we identify independent signals at rs2281389 (OR = 1.73, P = 6.31 × 10(-13)), a SNP that maps closely to HLA-DPB1, and the class II HLA allele DQA1*02:01 (OR = 0.56, P = 1.51 × 10(-7)). These data suggest that multiple independent loci within the HLA class II region contribute to the risk of developing early-onset HL..
Saarinen, S.
Aavikko, M.
Aittomäki, K.
Launonen, V.
Lehtonen, R.
Franssila, K.
Lehtonen, H.J.
Kaasinen, E.
Broderick, P.
Tarkkanen, J.
Bain, B.J.
Bauduer, F.
Ünal, A.
Swerdlow, A.J.
Cooke, R.
Mäkinen, M.J.
Houlston, R.
Vahteristo, P.
Aaltonen, L.A.
(2011). Exome sequencing reveals germline NPAT mutation as a candidate risk factor for Hodgkin lymphoma. Blood,
Vol.118
(3),
pp. 493-498.
show abstract
A strong clustering of Hodgkin lymphoma in certain families has been long acknowledged. However, the genetic factors in the background of familial Hodgkin lymphoma are largely unknown. We have studied a family of 4 cousins with a rare subtype of the disease, nodular lymphocyte predominant Hodgkin lymphoma. We applied exome sequencing together with genome-wide linkage analysis to this family and identified a truncating germline mutation in nuclear protein, ataxia-telangiectasia locus (NPAT) gene, which segregated in the family. We also studied a large number of samples from other patients with Hodgkin lymphoma, and a germline variation leading to the deletion of serine 724 was found in several cases suggesting an elevated risk for the disease (odds ratio = 4.11; P = .018). NPAT is thus far the first gene implicated in nodular lymphocyte predominant Hodgkin lymphoma predisposition..
Wang, Y.
Broderick, P.
Matakidou, A.
Eisen, T.
Houlston, R.S.
(2011). Chromosome 15q25 (CHRNA3-CHRNA5) variation impacts indirectly on lung cancer risk. Plos one,
Vol.6
(4),
p. e19085.
show abstract
Genetic variants at the 15q25 CHRNA5-CHRNA3 locus have been shown to influence lung cancer risk however there is controversy as to whether variants have a direct carcinogenic effect on lung cancer risk or impact indirectly through smoking behavior. We have performed a detailed analysis of the 15q25 risk variants rs12914385 and rs8042374 with smoking behavior and lung cancer risk in 4,343 lung cancer cases and 1,479 controls from the Genetic Lung Cancer Predisposition Study (GELCAPS). A strong association between rs12914385 and rs8042374, and lung cancer risk was shown, odds ratios (OR) were 1.44, (95% confidence interval (CI): 1.29-1.62, P = 3.69×10(-10)) and 1.35 (95% CI: 1.18-1.55, P = 9.99×10(-6)) respectively. Each copy of risk alleles at rs12914385 and rs8042374 was associated with increased cigarette consumption of 1.0 and 0.9 cigarettes per day (CPD) (P = 5.18×10(-5) and P = 5.65×10(-3)). These genetically determined modest differences in smoking behavior can be shown to be sufficient to account for the 15q25 association with lung cancer risk. To further verify the indirect effect of 15q25 on the risk, we restricted our analysis of lung cancer risk to never-smokers and conducted a meta-analysis of previously published studies of lung cancer risk in never-smokers. Never-smoker studies published in English were ascertained from PubMed stipulating--lung cancer, risk, genome-wide association, candidate genes. Our study and five previously published studies provided data on 2,405 never-smoker lung cancer cases and 7,622 controls. In the pooled analysis no association has been found between the 15q25 variation and lung cancer risk (OR = 1.09, 95% CI: 0.94-1.28). This study affirms the 15q25 association with smoking and is consistent with an indirect link between genotype and lung cancer risk..
Dobbins, S.E.
Broderick, P.
Melin, B.
Feychting, M.
Johansen, C.
Andersson, U.
Brännström, T.
Schramm, J.
Olver, B.
Lloyd, A.
Ma, Y.P.
Hosking, F.J.
Lönn, S.
Ahlbom, A.
Henriksson, R.
Schoemaker, M.J.
Hepworth, S.J.
Hoffmann, P.
Mühleisen, T.W.
Nöthen, M.M.
Moebus, S.
Eisele, L.
Kosteljanetz, M.
Muir, K.
Swerdlow, A.
Simon, M.
Houlston, R.S.
(2011). Common variation at 10p12 31 near MLLT10 influences meningioma risk. Nat genet,
Vol.43
(9),
pp. 825-827.
show abstract
To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 × 10(-14)). This finding advances our understanding of the genetic basis of meningioma development..
Hosking, F.J.
Dobbins, S.E.
Houlston, R.S.
(2011). Genome-wide association studies for detecting cancer susceptibility. Br med bull,
Vol.97,
pp. 27-46.
show abstract
Genome-wide association (GWA) studies search for genetic variants, across the entire genome, which display differences in frequencies between cases and controls. Studies in PubMed using the keywords 'genomewide association' and 'cancer' are reported together with selected literature. Since 2007, GWA studies have successfully yielded risk loci for most common cancers. Findings have provided insights into the biological basis of cancer susceptibility implicating previously unsuspected genes in tumourogenesis. The variants identified typically account for only a small proportion of the familial risk of cancer and thus their application for individual risk prediction is poor. Furthermore, the genotyped variants are unlikely to be directly causal and identifying the causal basis is a major challenge. Methodological developments are desirable to fully utilize existing data sets and to enable more complex models of inherited predisposition to be investigated. Annotation of low frequency variation coupled with next-generation sequencing is making the search for rare disease-causing variants a realistic prospect..
Huang, Z.
Wang, J.
Wu, C.-.
Houlston, R.S.
Bondy, M.L.
Shete, S.
(2011). False-negative-rate based approach selecting top single-nucleotide polymorphisms in the first stage of a two-stage genome-wide association study. Statistics and its interface,
Vol.4
(3),
pp. 359-371.
Broderick, P.
Chubb, D.
Johnson, D.C.
Weinhold, N.
Försti, A.
Lloyd, A.
Olver, B.
Ma, Y.
Dobbins, S.E.
Walker, B.A.
Davies, F.E.
Gregory, W.A.
Childs, J.A.
Ross, F.M.
Jackson, G.H.
Neben, K.
Jauch, A.
Hoffmann, P.
Mühleisen, T.W.
Nöthen, M.M.
Moebus, S.
Tomlinson, I.P.
Goldschmidt, H.
Hemminki, K.
Morgan, G.J.
Houlston, R.S.
(2011). Common variation at 2p23 3 and 7p15 3 influences multiple myeloma risk. Nature genetics,
Vol.Accepted for publication.
Crowther-Swanepoel, D.
Broderick, P.
Ma, Y.
Robertson, L.
Pittman, A.M.
Price, A.
Twiss, P.
Vijayakrishnan, J.
Qureshi, M.
Dyer, M.J.
Matutes, E.
Dearden, C.
Catovsky, D.
Houlston, R.S.
(2010). Fine-scale mapping of the 6p25 3 chronic lymphocytic leukaemia susceptibility locus. Hum mol genet,
Vol.19
(9),
pp. 1840-1845.
show abstract
A recent genome-wide association study of chronic lymphocytic leukaemia (CLL) has identified a susceptibility locus on 6p25.3 associated with a modest but highly significant increase in CLL risk. Using a set of single nucleotide polymorphism (SNP) markers, we generated a fine-scale map and narrowed the association signal to a 18 kb DNA segment within the 3'-untranslated region (UTR) of the IRF4 (interferon regulatory factor 4) gene. Resequencing this segment in European subjects identified 55 common polymorphisms, including 13 highly correlated candidate causal variants. In a large case-control study, it was shown that all but four variants could be excluded with 95% confidence. These four SNPs map to a 3 kb region of the 3'-UTR of IRF4, consistent with the causal basis of the association being mediated through differential IRF4 expression..
Schoemaker, M.J.
Robertson, L.
Wigertz, A.
Jones, M.E.
Hosking, F.J.
Feychting, M.
Lönn, S.
McKinney, P.A.
Hepworth, S.J.
Muir, K.R.
Auvinen, A.
Salminen, T.
Kiuru, A.
Johansen, C.
Houlston, R.S.
Swerdlow, A.J.
(2010). Interaction between 5 genetic variants and allergy in glioma risk. Am j epidemiol,
Vol.171
(11),
pp. 1165-1173.
show abstract
The etiology of glioma is barely known. Epidemiologic studies have provided evidence for an inverse relation between glioma risk and allergic disease. Genome-wide association data have identified common genetic variants at 5p15.33 (rs2736100, TERT), 8q24.21 (rs4295627, CCDC26), 9p21.3 (rs4977756, CDKN2A-CDKN2B), 11q23.3 (rs498872, PHLDB1), and 20q13.33 (rs6010620, RTEL1) as determinants of glioma risk. The authors investigated whether there is interaction between the effects of allergy and these 5 variants on glioma risk. Data from 5 case-control studies carried out in Denmark, Finland, Sweden, and the United Kingdom (2000-2004) were used, totaling 1,029 cases and 1,668 controls. Risk was inversely associated with asthma, hay fever, eczema, and "any allergy," significantly for each factor except asthma, and was significantly positively associated with number of risk alleles for each of the 5 single nucleotide polymorphisms. There was interaction between asthma and rs498872 (greater protective effect of asthma with increasing number of risk alleles; per-allele interaction odds ratio (OR) = 0.65, P = 0.041), between "any allergy" and rs4977756 (smaller protective effect; interaction OR = 1.27, P = 0.047), and between "any allergy" and rs6010620 (greater protective effect; interaction OR = 0.70, P = 0.017). Case-only analyses provided further support for atopy interactions for rs4977756 and rs498872. This study provides evidence for possible gene-environment interactions in glioma development..
Simon, M.
Hosking, F.J.
Marie, Y.
Gousias, K.
Boisselier, B.
Carpentier, C.
Schramm, J.
Mokhtari, K.
Hoang-Xuan, K.
Idbaih, A.
Delattre, J.-.
Lathrop, M.
Robertson, L.B.
Houlston, R.S.
Sanson, M.
(2010). Genetic risk profiles identify different molecular etiologies for glioma. Clin cancer res,
Vol.16
(21),
pp. 5252-5259.
show abstract
PURPOSE: Genome-wide association studies have recently identified single-nucleotide polymorphisms (SNP) in five loci at 5p15.33 (rs2736100, TERT), 8q24.21 (rs4295627, CCDC26), 9p21.3 (rs4977756, CDKN2A/CDKN2B), 20q13.33 (rs6010620, RTEL1), and 11q23.3 (rs498872, PHLDB1) to be associated with glioma risk. Because gliomas are heterogeneous in histology, molecular alterations, and clinical behavior, we have investigated these polymorphisms for potential correlations with tumor histology and patient survival. EXPERIMENTAL DESIGN: We studied the relationship between SNPs and glioma subtype in two large patient cohorts from France and Germany, totaling 1,577 patients, as well as the relationship between SNP genotype and overall survival. RESULTS: In both cohorts, the frequencies of rs2736100 and rs6010620 risk genotypes were highly correlated with high-grade disease (P < 0.001), whereas rs4295627 and rs498872 risk genotypes were inversely related to tumor grade (P < 0.001). These data show that genetic variations at these loci have subtype-specific effects on the risk of developing glioma. In contrast, the rs4977756 genotype was not correlated with tumor grade, consistent with the causal variant having a generic influence on glioma development. None of the five SNPs was associated with prognosis independent of tumor grade. CONCLUSIONS: Our findings provide novel insight into etiologic pathways in the different glioma subtypes..
Broderick, P.
Cunningham, D.
Vijayakrishnan, J.
Cooke, R.
Ashworth, A.
Swerdlow, A.
Houlston, R.
(2010). IRF4 polymorphism rs872071 and risk of Hodgkin lymphoma. British journal of haematology,
Vol.148
(3),
pp. 413-3.
Bolton, K.L.
Tyrer, J.
Song, H.
Ramus, S.J.
Notaridou, M.
Jones, C.
Sher, T.
Gentry-Maharaj, A.
Wozniak, E.
Tsai, Y.-.
Weidhaas, J.
Paik, D.
Van den Berg, D.J.
Stram, D.O.
Pearce, C.L.
Wu, A.H.
Brewster, W.
Anton-Culver, H.
Ziogas, A.
Narod, S.A.
Levine, D.A.
Kaye, S.B.
Brown, R.
Paul, J.
Flanagan, J.
Sieh, W.
McGuire, V.
Whittemore, A.S.
Campbell, I.
Gore, M.E.
Lissowska, J.
Yang, H.P.
Medrek, K.
Gronwald, J.
Lubinski, J.
Jakubowska, A.
Le, N.D.
Cook, L.S.
Kelemen, L.E.
Brook-Wilson, A.
Massuger, L.F.
Kiemeney, L.A.
Aben, K.K.
van Altena, A.M.
Houlston, R.
Tomlinson, I.
Palmieri, R.T.
Moorman, P.G.
Schildkraut, J.
Iversen, E.S.
Phelan, C.
Vierkant, R.A.
Cunningham, J.M.
Goode, E.L.
Fridley, B.L.
Kruger-Kjaer, S.
Blaeker, J.
Hogdall, E.
Hogdall, C.
Gross, J.
Karlan, B.Y.
Ness, R.B.
Edwards, R.P.
Odunsi, K.
Moyisch, K.B.
Baker, J.A.
Modugno, F.
Heikkinenen, T.
Butzow, R.
Nevanlinna, H.
Leminen, A.
Bogdanova, N.
Antonenkova, N.
Doerk, T.
Hillemanns, P.
Duerst, M.
Runnebaum, I.
Thompson, P.J.
Carney, M.E.
Goodman, M.T.
Lurie, G.
Wang-Gohrke, S.
Hein, R.
Chang-Claude, J.
Rossing, M.A.
Cushing-Haugen, K.L.
Doherty, J.
Chen, C.
Rafnar, T.
Besenbacher, S.
Sulem, P.
Stefansson, K.
Birrer, M.J.
Terry, K.L.
Hernandez, D.
Cramer, D.W.
Vergote, I.
Amant, F.
Lambrechts, D.
Despierre, E.
Fasching, P.A.
Beckmann, M.W.
Thiel, F.C.
Ekici, A.B.
Chen, X.
Johnatty, S.E.
Webb, P.M.
Beesley, J.
Chanock, S.
Garcia-Closas, M.
Sellers, T.
Easton, D.F.
Berchuck, A.
Chenevix-Trench, G.
Pharoah, P.D.
Gayther, S.A.
(2010). Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nature genetics,
Vol.42
(10),
pp. 880-7.
Wang, Y.
Broderick, P.
Matakidou, A.
Eisen, T.
Houlston, R.S.
(2010). Role of 5p15 33 (TERT-CLPTM1L), 6p21 33 and 15q25 1 (CHRNA5-CHRNA3) variation and lung cancer risk in never-smokers. Carcinogenesis,
Vol.31
(2),
pp. 234-238.
show abstract
Genome-wide association studies have provided evidence that common variation at 5p15.33 (TERT-CLPTM1L), 6p21.33 and 15q25.1 (CHRNA5-CHRNA3) influences lung cancer risk. To examine if variation at any of these loci influences the risk of lung cancer in never-smokers, we compared 5p15.33-TERT (rs2736100), 5p15.33-CLPTM1L (rs4975616), 6p21.33-BAT3 (rs3117582), 15q25.1-CHRNA3 (rs8042374) and 15q25.1-CHRNA3 (rs12914385) genotypes in a series of 239 never-smoker lung cancer cases and 553 never-smoker controls. A statistically significant association between lung cancer risk and 5p15.33 genotypes was found: rs2736100 (odds ratio = 0.78, 95% confidence interval: 0.63-0.97; P = 0.02), rs4975616 (odds ratio = 0.69, 95% confidence interval: 0.55-0.85; P = 7.95 x 10(-4)), primarily for adenocarcinoma. There was no evidence of association between 6p21.33 or 15q25.1 variation and risk of lung cancer. This analysis provides evidence that TERT-CLPTM1L variants may influence the risk of lung cancer outside the context of tobacco smoking..
Crowther-Swanepoel, D.
Broderick, P.
Di Bernardo, M.C.
Dobbins, S.E.
Torres, M.
Mansouri, M.
Ruiz-Ponte, C.
Enjuanes, A.
Rosenquist, R.
Carracedo, A.
Jurlander, J.
Campo, E.
Juliusson, G.
Montserrat, E.
Smedby, K.E.
Dyer, M.J.
Matutes, E.
Dearden, C.
Sunter, N.J.
Hall, A.G.
Mainou-Fowler, T.
Jackson, G.H.
Summerfield, G.
Harris, R.J.
Pettitt, A.R.
Allsup, D.J.
Bailey, J.R.
Pratt, G.
Pepper, C.
Fegan, C.
Parker, A.
Oscier, D.
Allan, J.M.
Catovsky, D.
Houlston, R.S.
(2010). Common variants at 2q37 3, 8q24 21, 15q21 3 and 16q24 1 influence chronic lymphocytic leukemia risk. Nat genet,
Vol.42
(2),
pp. 132-136.
show abstract
To identify new risk variants for chronic lymphocytic leukemia (CLL), we conducted a genome-wide association study of 299,983 tagging SNPs, with validation in four additional series totaling 2,503 cases and 5,789 controls. We identified four new risk loci for CLL at 2q37.3 (rs757978, FARP2; odds ratio (OR) = 1.39; P = 2.11 x 10(-9)), 8q24.21 (rs2456449; OR = 1.26; P = 7.84 x 10(-10)), 15q21.3 (rs7169431; OR = 1.36; P = 4.74 x 10(-7)) and 16q24.1 (rs305061; OR = 1.22; P = 3.60 x 10(-7)). We also found evidence for risk loci at 15q25.2 (rs783540, CPEB1; OR = 1.18; P = 3.67 x 10(-6)) and 18q21.1 (rs1036935; OR = 1.22; P = 2.28 x 10(-6)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy..
Liu, Y.
Shete, S.
Hosking, F.J.
Robertson, L.B.
Bondy, M.L.
Houlston, R.S.
(2010). New insights into susceptibility to glioma. Arch neurol,
Vol.67
(3),
pp. 275-278.
show abstract
The study of inherited susceptibility to cancer has been one of the most informative areas of research in the past decade. Most of the cancer genetics studies have been focused on the common tumors such as breast and colorectal cancers. As the allelic architecture of these tumors is unraveled, research attention is turning to other rare cancers such as glioma, which are also likely to have a major genetic component as the basis of their development. In this brief review we discuss emerging data on glioma whole genome-association searches to identify risk loci. Two glioma genome-wide association studies have so far been reported. Our group identified 5 risk loci for glioma susceptibility (TERT rs2736100, CCDC26 rs4295627, CDKN2A/CDKN2B rs4977756, RTEL1 rs6010620, and PHLDB1 rs498872). Wrensch and colleagues provided further evidence to 2 risk loci (CDKN2B rs1412829 and RTEL1 rs6010620) for GBM and anaplastic astrocytoma. Although these data provide the strongest evidence to date for the role of common low-risk variants in the etiology of glioma, the single-nucleotide polymorphisms identified alone are unlikely to be candidates for causality. Identifying the causal variant at each specific locus and its biological impact now poses a significant challenge, contingent on a combination of fine mapping and functional analyses. Finally, we hope that a greater understanding of the biological basis of the disease will lead to the development of novel therapeutic interventions..
Hosking, F.J.
Papaemmanuil, E.
Sheridan, E.
Kinsey, S.E.
Lightfoot, T.
Roman, E.
Irving, J.A.
Allan, J.M.
Taylor, M.
Tomlinson, I.P.
Greaves, M.
Houlston, R.S.
(2010). Genome-wide homozygosity signatures and childhood acute lymphoblastic leukemia risk. Blood,
Vol.115
(22),
pp. 4472-4477.
show abstract
Recent studies have reported that regions of homozygosity (ROH) in the genome are detectable in outbred populations and can be associated with an increased risk of malignancy. To examine whether homozygosity is associated with an increased risk of developing childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), we analyzed 824 ALL cases and 2398 controls genotyped for 292 200 tagging SNPs. Across the genome, cumulative distribution of ROH was not significantly different between cases and controls. Four common ROH at 10p11.2-10q11.21, 1p31.1, 19p13.2-3, and 20q11.1-23 were, however, associated with ALL risk at P less than .01 (including 1 ROH to which the erythropoietin receptor [EPOR] gene maps, P = .005) but were nonsignificant after adjusting for multiple testing. Our findings make it unlikely that levels of measured homozygosity, caused by autozygosity, uniparental isodisomy, or hemizygosity, play a major role in defining BCP-ALL risk in predominantly outbred populations..
Prasad, R.B.
Hosking, F.J.
Vijayakrishnan, J.
Papaemmanuil, E.
Koehler, R.
Greaves, M.
Sheridan, E.
Gast, A.
Kinsey, S.E.
Lightfoot, T.
Roman, E.
Taylor, M.
Pritchard-Jones, K.
Stanulla, M.
Schrappe, M.
Bartram, C.R.
Houlston, R.S.
Kumar, R.
Hemminki, K.
(2010). Verification of the susceptibility loci on 7p12 2, 10q21 2, and 14q11 2 in precursor B-cell acute lymphoblastic leukemia of childhood. Blood,
Vol.115
(9),
pp. 1765-1767.
show abstract
Recent genome-wide association data have implicated genetic variation at 7p12.2 (IKZF1), 10q21.2 (ARIDB5), and 14q11.2 (CEBPE) in the etiology of B-cell childhood acute lymphoblastic leukemia (ALL). To verify and further examine the relationship between these variants and ALL risk, we genotyped 1384 cases of precursor B-cell childhood ALL and 1877 controls from Germany and the United Kingdom. The combined data provided statistically significant support for an association between genotype at each of these loci and ALL risk; odds ratios (OR), 1.69 (P = 7.51 x10(-22)), 1.80 (P = 5.90 x 10(-28)), and 1.27 (P = 4.90 x 10(-6)), respectively. Furthermore, the risk of ALL increases with an increasing numbers of variant alleles for the 3 loci (OR(per-allele) = 1.53, 95% confidence interval, 1.44-1.62; P(trend) = 3.49 x 10(-42)), consistent with a polygenic model of disease susceptibility. These data provide unambiguous evidence for the role of these variants in defining ALL risk underscoring approximately 64% of cases..
Allan, J.M.
Sunter, N.J.
Bailey, J.R.
Pettitt, A.R.
Harris, R.J.
Pepper, C.
Fegan, C.
Hall, A.G.
Deignan, L.
Bacon, C.M.
Pointon, J.C.
Houlston, R.S.
Broderick, P.
Mainou-Fowler, T.
Jackson, G.H.
Summerfield, G.
Evans, P.A.
Strefford, J.C.
Parker, A.
Oscier, D.
Pratt, G.
Allsup, D.J.
(2010). Variant IRF4/MUM1 associates with CD38 status and treatment-free survival in chronic lymphocytic leukaemia. Leukemia,
Vol.24
(4),
pp. 877-881.
White, S.M.
Morgan, A.
Da Costa, A.
Lacombe, D.
Knight, S.J.
Houlston, R.
Whiteford, M.L.
Newbury-Ecob, R.A.
Hurst, J.A.
(2010). The Phenotype of Floating-Harbor Syndrome in 10 Patients. American journal of medical genetics part a,
Vol.152A
(4),
pp. 821-829.
Fletcher, O.
Houlston, R.S.
(2010). Architecture of inherited susceptibility to common cancer. Nat rev cancer,
Vol.10
(5),
pp. 353-361.
show abstract
This Timeline article looks back at 40 years of research into the inherited genetic basis of cancer and the insights these studies have yielded. Early epidemiological research provided evidence for the 'two-hit' model of cancer predisposition. During the 1980s and 1990s linkage and positional cloning analyses led to the identification of high-penetrance cancer susceptibility genes. The past decade has seen a shift from models of predisposition based on single-gene causative mutations to multigenic models. These models suggest that a high proportion of cancers may arise in a genetically susceptible minority as a consequence of the combined effects of common low-penetrance alleles and rare disease-causing variants that confer moderate cancer risks..
Houlston, R.S.
(2010). Low-penetrance susceptibility to hematological malignancy. Curr opin genet dev,
Vol.20
(3),
pp. 245-250.
show abstract
There is increasing evidence for inherited genetic susceptibility to cancer, and much of this is thought to be caused by the co-inheritance of multiple low risk alleles. Recent developments have allowed the search for this class of susceptibility allele to be conducted on a genome-wide basis. Here we discuss the impact genome-wide association studies are having on our understanding of two of the major hematological malignancies, chronic lymphocytic leukemia and acute lymphoblastic leukemia..
Sherborne, A.L.
Hosking, F.J.
Prasad, R.B.
Kumar, R.
Koehler, R.
Vijayakrishnan, J.
Papaemmanuil, E.
Bartram, C.R.
Stanulla, M.
Schrappe, M.
Gast, A.
Dobbins, S.E.
Ma, Y.
Sheridan, E.
Taylor, M.
Kinsey, S.E.
Lightfoot, T.
Roman, E.
Irving, J.A.
Allan, J.M.
Moorman, A.V.
Harrison, C.J.
Tomlinson, I.P.
Richards, S.
Zimmermann, M.
Szalai, C.
Semsei, A.F.
Erdelyi, D.J.
Krajinovic, M.
Sinnett, D.
Healy, J.
Gonzalez Neira, A.
Kawamata, N.
Ogawa, S.
Koeffler, H.P.
Hemminki, K.
Greaves, M.
Houlston, R.S.
(2010). Variation in CDKN2A at 9p21 3 influences childhood acute lymphoblastic leukemia risk. Nat genet,
Vol.42
(6),
pp. 492-494.
show abstract
Using data from a genome-wide association study of 907 individuals with childhood acute lymphoblastic leukemia (cases) and 2,398 controls and with validation in samples totaling 2,386 cases and 2,419 controls, we have shown that common variation at 9p21.3 (rs3731217, intron 1 of CDKN2A) influences acute lymphoblastic leukemia risk (odds ratio = 0.71, P = 3.01 x 10(-11)), irrespective of cell lineage..
Niittymäki, I.
Kaasinen, E.
Tuupanen, S.
Karhu, A.
Järvinen, H.
Mecklin, J.-.
Tomlinson, I.P.
Di Bernardo, M.C.
Houlston, R.S.
Aaltonen, L.A.
(2010). Low-penetrance susceptibility variants in familial colorectal cancer. Cancer epidemiol biomarkers prev,
Vol.19
(6),
pp. 1478-1483.
show abstract
BACKGROUND: Genomewide association studies have identified 10 low-penetrance loci that confer modestly increased risk for colorectal cancer (CRC). Although they underlie a significant proportion of CRC in the general population, their impact on the familial risk for CRC has yet to be formally enumerated. The aim of this study was to examine the combined contribution of the 10 variants, rs6983267, rs4779584, rs4939827, rs16892766, rs10795668, rs3802842, rs4444235, rs9929218, rs10411210, and rs961253, on familial CRC. METHODS: The population-based series of CRC samples included in this study consisted of 97 familial cases and 691 sporadic cases. Genotypes in the 10 loci and clinical data, including family history of cancer verified from the Finnish Cancer Registry, were available. The overall number of risk alleles (0-20) was determined, and its association with familial CRC was analyzed. Excess familial risk was estimated using cancer incidence data from the first-degree relatives of the cases. RESULTS: A linear association between the number of risk alleles and familial CRC was observed (P = 0.006). With each risk-allele addition, the odds of having an affected first-degree relative increased by 1.16 (95% confidence interval, 1.04-1.30). The 10 low-penetrance loci collectively explain approximately 9% of the variance in familial risk for CRC. CONCLUSIONS: This study provides evidence to support the previous indirect estimations that these low-penetrance variants account for a relatively small proportion of the familial aggregation of CRC. IMPACT: Our results emphasize the need to characterize the remaining molecular basis of familial CRC, which should eventually yield in individualized targeting of preventive interventions..
Turnbull, C.
Ahmed, S.
Morrison, J.
Pernet, D.
Renwick, A.
Maranian, M.
Seal, S.
Ghoussaini, M.
Hines, S.
Healey, C.S.
Hughes, D.
Warren-Perry, M.
Tapper, W.
Eccles, D.
Evans, D.G.
Breast Cancer Susceptibility Collaboration (UK),
Hooning, M.
Schutte, M.
van den Ouweland, A.
Houlston, R.
Ross, G.
Langford, C.
Pharoah, P.D.
Stratton, M.R.
Dunning, A.M.
Rahman, N.
Easton, D.F.
(2010). Genome-wide association study identifies five new breast cancer susceptibility loci. Nat genet,
Vol.42
(6),
pp. 504-507.
show abstract
Breast cancer is the most common cancer in women in developed countries. To identify common breast cancer susceptibility alleles, we conducted a genome-wide association study in which 582,886 SNPs were genotyped in 3,659 cases with a family history of the disease and 4,897 controls. Promising associations were evaluated in a second stage, comprising 12,576 cases and 12,223 controls. We identified five new susceptibility loci, on chromosomes 9, 10 and 11 (P = 4.6 x 10(-7) to P = 3.2 x 10(-15)). We also identified SNPs in the 6q25.1 (rs3757318, P = 2.9 x 10(-6)), 8q24 (rs1562430, P = 5.8 x 10(-7)) and LSP1 (rs909116, P = 7.3 x 10(-7)) regions that showed more significant association with risk than those reported previously. Previously identified breast cancer susceptibility loci were also found to show larger effect sizes in this study of familial breast cancer cases than in previous population-based studies, consistent with polygenic susceptibility to the disease..
Liu, Y.
Shete, S.
Hosking, F.
Robertson, L.
Houlston, R.
Bondy, M.
(2010). Genetic advances in glioma: susceptibility genes and networks. Current opinion in genetics & development,
Vol.20
(3),
pp. 239-244.
Middeldorp, A.
Jagmohan-Changur, S.C.
van der Klift, H.M.
van Puijenbroek, M.
Houwing-Duistermaat, J.J.
Webb, E.
Houlston, R.
Tops, C.
Vasen, H.F.
Devilee, P.
Morreau, H.
van Wezel, T.
Wijnen, J.
(2010). Comprehensive Genetic Analysis of Seven Large Families with Mismatch Repair Proficient Colorectal Cancer. Genes chromosomes & cancer,
Vol.49
(6),
pp. 539-548.
Vahteristo, P.
Koski, T.A.
Naatsaari, L.
Kiuru, M.
Karhu, A.
Herva, R.
Sallinen, S.-.
Vierimaa, O.
Bjorck, E.
Richard, S.
Gardie, B.
Bessis, D.
Van Glabeke, E.
Blanco, I.
Houlston, R.
Senter, L.
Hietala, M.
Aittomaki, K.
Aaltonen, L.A.
Launonen, V.
Lehtonen, R.
(2010). No evidence for a genetic modifier for renal cell cancer risk in HLRCC syndrome. Familial cancer,
Vol.9
(2),
pp. 245-251.
Bancroft, E.K.
Locke, I.
Ardern-Jones, A.
D'Mello, L.
McReynolds, K.
Lennard, F.
Barbachano, Y.
Barwell, J.
Walker, L.
Mitchell, G.
Dorkins, H.
Cummings, C.
Paterson, J.
Kote-Jarai, Z.
Mitra, A.
Jhavar, S.
Thomas, S.
Houlston, R.
Shanley, S.
Eeles, R.A.
(2010). The carrier clinic: an evaluation of a novel clinic dedicated to the follow-up of BRCA1 and BRCA2 carriers--implications for oncogenetics practice. J med genet,
Vol.47
(7),
pp. 486-491.
show abstract
BACKGROUND: A novel oncogenetic clinic was established in 2002 at the Royal Marsden NHS Foundation Trust offering advice and specialist follow-up for families with a germline mutation in BRCA1 or BRCA2. The remit of this multidisciplinary clinic, staffed by individuals in both oncology and genetics, is to provide individualised screening recommendations, support in decision making, risk reducing strategies, cascade testing, and an extensive research portfolio. METHODS: A retrospective analysis was performed to evaluate uptake of genetic testing, risk reducing surgery and cancer prevalence in 346 BRCA1/BRCA2 families seen between January 1996 and December 2006. RESULTS: 661 individuals attended the clinic and 406 mutation carriers were identified; 85.8% mutation carriers have chosen to attend for annual follow-up. 70% of mutation carriers elected for risk reducing bilateral salpingo-oophorectomy (RRBSO). 32% of unaffected women chose risk reducing bilateral mastectomy. 32% of women with breast cancer chose contralateral risk reducing mastectomy at time of diagnosis. Some women took over 8 years to decide to have surgery. 91% of individuals approached agreed to participate in research programmes. INTERPRETATION: A novel specialist clinic for BRCA1/2 mutation carriers has been successfully established. The number of mutation positive families is increasing. This, and the high demand for RRBSO in women over 40, is inevitably going to place an increasing demand on existing health resources. Our clinic model has subsequently been adopted in other centres and this will greatly facilitate translational studies and provide a healthcare structure for management and follow-up of such people who are at a high cancer risk..
Theodoratou, E.
Campbell, H.
Tenesa, A.
Houlston, R.
Webb, E.
Lubbe, S.
Broderick, P.
Gallinger, S.
Croitoru, E.M.
Jenkins, M.A.
Win, A.K.
Cleary, S.P.
Koessler, T.
Pharoah, P.D.
Kuery, S.
Bezieau, S.
Buecher, B.
Ellis, N.A.
Peterlongo, P.
Offit, K.
Aaltonen, L.A.
Enholm, S.
Lindblom, A.
Zhou, X.-.
Tomlinson, I.P.
Moreno, V.
Blanco, I.
Capella, G.
Barnetson, R.
Porteous, M.E.
Dunlop, M.G.
Farrington, S.M.
(2010). A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. British journal of cancer,
Vol.103
(12),
pp. 1875-1884.
Enciso-Mora, V.
Hosking, F.J.
Houlston, R.S.
(2010). Risk of breast and prostate cancer is not associated with increased homozygosity in outbred populations. Eur j hum genet,
Vol.18
(8),
pp. 909-914.
show abstract
Regions of restricted genetic heterogeneity due to identity by descent (autozygosity) are known to confer susceptibility to a number of diseases. Regions of germline homozygosity (ROHs) of 1-2 Mb, the result of autozygosity, are detectable at high frequency in outbred populations. Recent studies have reported that ROHs, possibly through exposing recessive disease-causing alleles or alternative mechanisms, are associated with an increased cancer risk. To examine whether homozygosity is associated with breast or prostate cancer risk, we analysed 500K single-nucleotide polymorphism data from two genome-wide association studies conducted by the Cancer Genetics Markers of Susceptibility initiatives (http://cgems.cancer.gov/). Six common ROHs were associated with breast cancer risk and four with prostate cancer (P<0.01). Intriguingly, one of the breast cancer ROHs maps to 6q22.31-6q22.3, a region that has been previously shown to confer breast cancer risk. Although none of the ROHs remained significantly associated with cancer risk after adjustment for multiple testing, a number of ROHs merit further interrogation. However, our findings provide no strong evidence that levels of measured homozygosity, whatever their aetiology (autozygosity, uniparental isodisomy or hemizygosity), confer an increased risk of developing breast or prostate cancer in predominantly outbred populations..
Vijayakrishnan, J.
Houlston, R.S.
(2010). Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: a systematic review and meta-analysis. Haematologica,
Vol.95
(8),
pp. 1405-1414.
show abstract
To evaluate the contribution of candidate gene association studies to the understanding of genetic susceptibility to childhood acute lymphoblastic leukemia we conducted a systematic review and meta-analysis of published studies (January 1996-July 2009). Studies had to meet the following criteria: be case-control design, be studied by two or more studies, not be focused on HLA antigen genetic markers and be published in English. We identified 47 studies of polymorphic variation in 16 genes and acute lymphoblastic leukemia risk. To clarify the impact of individual polymorphisms on risk, pooled analyses were performed. Of the 25 polymorphic variants studied, significant associations (P<0.05) were seen in pooled analyses for eight variants: GSTM1 (OR =1.16; 95%CI: 1.04-1.30), MTRR A66G (OR=0.73, 95%CI:0.59-0.91), SHMT1 C1420T (OR=0.79, 95%CI: 0.65-0.98), RFC1 G80A (OR=1.37, 95%CI: 1.11-1.69), CYP1A1*2A (OR=1.36, 95%CI:1.11-1.66), CYP2E1*5B (OR=1.99, 95%CI:1.32-3.00) NQO1 C609T (OR=1.24, 95%CI:1.02-1.50) and XRCC1 G28152A (OR=1.78, 95%CI:1.32-2.42). These findings should, however, be interpreted with caution as the estimated false-positive report probabilities (FPRP) for each association were not noteworthy (i.e. FPRP>0.2). While candidate gene analyses are complementary to genome-wide association studies, future analyses should be based on sample sizes commensurate with the detection of small effects and attention needs to be paid to study design..
Crowther-Swanepoel, D.
Mansouri, M.
Enjuanes, A.
Vega, A.
Smedby, K.E.
Ruiz-Ponte, C.
Jurlander, J.
Juliusson, G.
Montserrat, E.
Catovsky, D.
Campo, E.
Carracedo, A.
Rosenquist, R.
Houlston, R.S.
(2010). Verification that common variation at 2q37 1, 6p25 3, 11q24 1, 15q23, and 19q13 32 influences chronic lymphocytic leukaemia risk. Br j haematol,
Vol.150
(4),
pp. 473-479.
show abstract
A recent genome wide association study of chronic lymphocytic leukaemia (CLL) provided evidence that common variation at 2q13 (rs17483466), 2q37.1 (rs13397985), 6p25.3 (rs872071), 11q24.1 (rs735665), 15q23 (rs7176508) and 19q13.32 (rs11083846) affects CLL risk. To verify and further explore the relationship between these variants and CLL risk we genotyped case-control datasets from Spain and Sweden (824 cases, 850 controls). Combined data provided statistically significant support for an association between genotypes at rs13397985, rs872071, rs735665, rs7176508 and rs11083846 and CLL risk. CLL risk increased with increasing numbers of risk alleles (P(trend) = 1.40 x 10(-15)), consistent with a polygenic model of disease susceptibility. These data validate the relationship between common variation and risk of CLL..
Landi, M.T.
Chatterjee, N.
Caporaso, N.E.
Rotunno, M.
Albanes, D.
Thun, M.
Wheeler, W.
Rosenberger, A.
Bickeböller, H.
Risch, A.
Wang, Y.
Gaborieau, V.
Thorgeirsson, T.
Gudbjartsson, D.
Sulem, P.
Spitz, M.R.
Wichmann, H.E.
Rafnar, T.
Stefansson, K.
Houlston, R.S.
Brennan, P.
(2010). GPC5 rs235202