Sud, A.
Parry, E.M.
Wu, C.J.
(2024). The molecular map of CLL and Richter's syndrome. Semin hematol,
.
show abstract
Clonal expansion of B-cells, from the early stages of monoclonal B-cell lymphocytosis through to chronic lymphocytic leukemia (CLL), and then in some cases to Richter's syndrome (RS) provides a comprehensive model of cancer evolution, notable for the marked morphological transformation and distinct clinical phenotypes. High-throughput sequencing of large cohorts of patients and single-cell studies have generated a molecular map of CLL and more recently, of RS, yielding fundamental insights into these diseases and of clonal evolution. A selection of CLL driver genes have been functionally interrogated to yield novel insights into the biology of CLL. Such findings have the potential to impact patient care through risk stratification, treatment selection and drug discovery. However, this molecular map remains incomplete, with extant questions concerning the origin of the B-cell clone, the role of the TME, inter- and intra-compartmental heterogeneity and of therapeutic resistance mechanisms. Through the application of multi-modal single-cell technologies across tissues, disease states and clinical contexts, these questions can now be addressed with the answers holding great promise of generating translatable knowledge to improve patient care..
Went, M.
Sud, A.
Mills, C.
Hyde, A.
Culliford, R.
Law, P.
Vijayakrishnan, J.
Gockel, I.
Maj, C.
Schumacher, J.
Palles, C.
Kaiser, M.
Houlston, R.
(2024). Phenome-wide Mendelian randomisation analysis of 378,142 cases reveals risk factors for eight common cancers. Nat commun,
Vol.15
(1),
p. 2637.
show abstract
For many cancers there are only a few well-established risk factors. Here, we use summary data from genome-wide association studies (GWAS) in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to identify potentially causal relationships for over 3,000 traits. Our outcome datasets comprise 378,142 cases across breast, prostate, colorectal, lung, endometrial, oesophageal, renal, and ovarian cancers, as well as 485,715 controls. We complement this analysis by systematically mining the literature space for supporting evidence. In addition to providing supporting evidence for well-established risk factors (smoking, alcohol, obesity, lack of physical activity), we also find sex steroid hormones, plasma lipids, and telomere length as determinants of cancer risk. A number of the molecular factors we identify may prove to be potential biomarkers. Our analysis, which highlights aetiological similarities and differences in common cancers, should aid public health prevention strategies to reduce cancer burden. We provide a R/Shiny app to visualise findings..
Hemminki, K.
Hemminki, J.
Försti, A.
Sud, A.
(2023). Survival in hematological malignancies in the Nordic countries through a half century with correlation to treatment. Leukemia,
Vol.37
(4),
pp. 854-863.
show abstract
full text
Studies of survival in hematological malignancies (HMs) have generally shown an improvement over time, although most of these studies are limited by a short follow-up period. Using the NORDCAN database with data from Denmark, Finland, Norway and Sweden, we follow periodic increases in relative survival in seven HMs through half a century up to 2015-2019. Five-year survival improved in all seven HMs, reaching 90% for Hodgkin lymphoma (HL), myeloproliferative neoplasias and chronic lymphocytic leukemia (CLL), 60% for multiple myeloma (MM) and chronic myeloid leukemias (CMLs), 50% for the myelodysplastic syndromes and 30% for acute myeloid leukemia (AML). Improvements in survival over 50 years ranged from 20% to more than 50% units across the different HMs. The likely reasons for such progress include earlier diagnoses, improved risk stratification and advances in treatment. We observed differing temporal trends in improvements in survival. The gradual increases observed in HL, CLL and AML highlight the impact of optimization of existing therapies and improvements in diagnostics and risk stratification, whereas the rapid increases observed in the CMLs and MM highlight the impact of novel therapies. Recent therapeutic advances may further improve survival in HMs where survival remains low such as in AML..
Huntley, C.
Torr, B.
Sud, A.
Rowlands, C.F.
Way, R.
Snape, K.
Hanson, H.
Swanton, C.
Broggio, J.
Lucassen, A.
McCartney, M.
Houlston, R.S.
Hingorani, A.D.
Jones, M.E.
Turnbull, C.
(2023). Utility of polygenic risk scores in UK cancer screening: a modelling analysis. Lancet oncol,
Vol.24
(6),
pp. 658-668.
show abstract
full text
BACKGROUND: It is proposed that, through restriction to individuals delineated as high risk, polygenic risk scores (PRSs) might enable more efficient targeting of existing cancer screening programmes and enable extension into new age ranges and disease types. To address this proposition, we present an overview of the performance of PRS tools (ie, models and sets of single nucleotide polymorphisms) alongside harms and benefits of PRS-stratified cancer screening for eight example cancers (breast, prostate, colorectal, pancreas, ovary, kidney, lung, and testicular cancer). METHODS: For this modelling analysis, we used age-stratified cancer incidences for the UK population from the National Cancer Registration Dataset (2016-18) and published estimates of the area under the receiver operating characteristic curve for current, future, and optimised PRS for each of the eight cancer types. For each of five PRS-defined high-risk quantiles (ie, the top 50%, 20%, 10%, 5%, and 1%) and according to each of the three PRS tools (ie, current, future, and optimised) for the eight cancers, we calculated the relative proportion of cancers arising, the odds ratios of a cancer arising compared with the UK population average, and the lifetime cancer risk. We examined maximal attainable rates of cancer detection by age stratum from combining PRS-based stratification with cancer screening tools and modelled the maximal impact on cancer-specific survival of hypothetical new UK programmes of PRS-stratified screening. FINDINGS: The PRS-defined high-risk quintile (20%) of the population was estimated to capture 37% of breast cancer cases, 46% of prostate cancer cases, 34% of colorectal cancer cases, 29% of pancreatic cancer cases, 26% of ovarian cancer cases, 22% of renal cancer cases, 26% of lung cancer cases, and 47% of testicular cancer cases. Extending UK screening programmes to a PRS-defined high-risk quintile including people aged 40-49 years for breast cancer, 50-59 years for colorectal cancer, and 60-69 years for prostate cancer has the potential to avert, respectively, a maximum of 102, 188, and 158 deaths annually. Unstratified screening of the full population aged 48-49 years for breast cancer, 58-59 years for colorectal cancer, and 68-69 years for prostate cancer would use equivalent resources and avert, respectively, an estimated maximum of 80, 155, and 95 deaths annually. These maximal modelled numbers will be substantially attenuated by incomplete population uptake of PRS profiling and cancer screening, interval cancers, non-European ancestry, and other factors. INTERPRETATION: Under favourable assumptions, our modelling suggests modest potential efficiency gain in cancer case detection and deaths averted for hypothetical new PRS-stratified screening programmes for breast, prostate, and colorectal cancer. Restriction of screening to high-risk quantiles means many or most incident cancers will arise in those assigned as being low-risk. To quantify real-world clinical impact, costs, and harms, UK-specific cluster-randomised trials are required. FUNDING: The Wellcome Trust..
El-Sharkawi, D.
Sud, A.
Prodger, C.
Khwaja, J.
Shotton, R.
Hanley, B.
Peacock, V.
Peng, Y.Y.
Arasaretnam, A.
Sharma, S.
Aldridge, F.
Sharma, B.
Wotherspoon, A.
Cheung, B.
De Lord, C.
Johnston, R.
Kassam, S.
Pettengel, R.
Linton, K.
Greaves, P.
Cook, L.
Naresh, K.N.
Cwynarski, K.
Eyre, T.A.
Chau, I.
Cunningham, D.
Iyengar, S.
(2023). A retrospective study of MYC rearranged diffuse large B-cell lymphoma in the context of the new WHO and ICC classifications. Blood cancer j,
Vol.13
(1),
p. 54.
full text
Sud, A.
Horton, R.H.
Hingorani, A.D.
Tzoulaki, I.
Turnbull, C.
Houlston, R.S.
Lucassen, A.
(2023). Realistic expectations are key to realising the benefits of polygenic scores. Bmj,
Vol.380,
p. e073149.
show abstract
full text
We must not let enthusiasm around polygenic scores allow us to forget other factors that are bigger, more modifiable, and relevant for everyone, argue Amit Sud, Rachel Horton, and colleagues.
HaemSTAR Collaborators,
(2022). Diagnostic uncertainty presented barriers to the timely management of acute thrombotic thrombocytopenic purpura in the United Kingdom between 2014 and 2019. J thromb haemost,
Vol.20
(6),
pp. 1428-1436.
show abstract
full text
BACKGROUND: Acute thrombotic thrombocytopenic purpura (TTP) is a life-threatening emergency and plasma exchange (PEX) is the initial treatment shown to reduce acute mortality. OBJECTIVES: To compare current practice in the United Kingdom (UK) against the standards set out in the 2012 British Society of Haematology guideline, and to better understand the issues affecting prompt initiation of PEX. PATIENTS/METHODS: The trainee research network HaemSTAR conducted a retrospective nationwide review of adults presenting to UK hospitals with a first episode of acute TTP. RESULTS: Data on 148 patients treated at 80 UK hospitals between 2014 and 2019 demonstrated that 64.8% of patients received PEX within 24 h. Diagnostic uncertainty was the most commonly cited reason for delayed treatment. Conversely, a shorter time to PEX occurred in patients who had red cell fragments or severe thrombocytopenia identified on their first complete blood count. Availability of on-site PEX was associated with a greater proportion of patients receiving PEX within 8 h compared to patients transferred, but by 24 h there was no difference between the two groups and two-thirds of all patients had received their first PEX. The mortality rate for patients that received PEX was 9.2%, with 27.8% of deaths linked to delayed treatment initiation. CONCLUSIONS: This is the first multi-center evaluation of treatment delays in acute TTP and it will inform targeted pathways to improve prompt access to life-saving intervention..
Vickers, A.J.
Sud, A.
Bernstein, J.
Houlston, R.
(2022). Polygenic risk scores to stratify cancer screening should predict mortality not incidence. Npj precis oncol,
Vol.6
(1),
p. 32.
show abstract
full text
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..
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.
(2021). 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,
Vol.70
(6),
pp. 1053-1060.
show abstract
full text
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..
Bird, S.
Panopoulou, A.
Shea, R.L.
Tsui, M.
Saso, R.
Sud, A.
West, S.
Smith, K.
Barwood, J.
Kaczmarek, E.
Panlaqui, C.
Kaiser, M.
Stern, S.
Pawlyn, C.
Boyd, K.
(2021). Response to first vaccination against SARS-CoV-2 in patients with multiple myeloma. Lancet haematol,
Vol.8
(6),
pp. e389-e392.
full text
Sud, A.
Law, P.J.
Houlston, R.S.
(2021). The clinical utility of polygenic risk scores for chronic lymphocytic leukemia. Leukemia,
Vol.35
(12),
pp. 3608-3610.
full text
Hemminki, K.
Försti, A.
Houlston, R.
Sud, A.
(2021). Epidemiology, genetics and treatment of multiple myeloma and precursor diseases. Int j cancer,
Vol.149
(12),
pp. 1980-1996.
show abstract
full text
Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion of plasma cells. The incidence of MM worldwide is increasing with greater than 140 000 people being diagnosed with MM per year. Whereas 5-year survival after a diagnosis of MM has improved from 28% in 1975 to 56% in 2012, the disease remains essentially incurable. In this review, we summarize our current understanding of MM including its epidemiology, genetics and biology. We will also provide an overview of MM management that has led to improvements in survival, including recent changes to diagnosis and therapies. Areas of unmet need include the management of patients with high-risk MM, those with reduced performance status and those refractory to standard therapies. Ongoing research into the biology and early detection of MM as well as the development of novel therapies, such as immunotherapies, has the potential to influence MM practice in the future..
Sud, A.
Turnbull, C.
Houlston, R.
(2021). Will polygenic risk scores for cancer ever be clinically useful?. Npj precis oncol,
Vol.5
(1),
p. 40.
full text
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. Ann oncol,
Vol.31
(8),
pp. 1065-1074.
show abstract
full text
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..
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. Lancet oncol,
Vol.21
(8),
pp. 1035-1044.
show abstract
full text
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..
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. Int j cancer,
Vol.146
(4),
pp. 970-976.
show abstract
full text
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..
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. Br j haematol,
Vol.185
(2),
pp. 232-239.
show abstract
full text
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..
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. Ann hum genet,
Vol.83
(4),
pp. 231-238.
show abstract
full text
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
full text
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..
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. Nat commun,
Vol.10
(1),
p. 2154.
show abstract
full text
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 oncol,
.
show abstract
full text
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..
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..
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. Hum genomics,
Vol.13
(1),
p. 37.
show abstract
full text
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. Sci rep,
Vol.9
(1),
p. 309.
show abstract
full text
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 [ORSD] = 1.27, 95% confidence interval [CI] = 1.03-1.56, P = 0.028) and body fat percentage (ORSD = 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..
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 j,
Vol.9
(4),
p. 40.
full text
Schmidt, A.F.
Holmes, M.V.
Preiss, D.
Swerdlow, D.I.
Denaxas, S.
Fatemifar, G.
Faraway, R.
Finan, C.
Valentine, D.
Fairhurst-Hunter, Z.
Hartwig, F.P.
Horta, B.L.
Hypponen, E.
Power, C.
Moldovan, M.
van Iperen, E.
Hovingh, K.
Demuth, I.
Norman, K.
Steinhagen-Thiessen, E.
Demuth, J.
Bertram, L.
Lill, C.M.
Coassin, S.
Willeit, J.
Kiechl, S.
Willeit, K.
Mason, D.
Wright, J.
Morris, R.
Wanamethee, G.
Whincup, P.
Ben-Shlomo, Y.
McLachlan, S.
Price, J.F.
Kivimaki, M.
Welch, C.
Sanchez-Galvez, A.
Marques-Vidal, P.
Nicolaides, A.
Panayiotou, A.G.
Onland-Moret, N.C.
van der Schouw, Y.T.
Matullo, G.
Fiorito, G.
Guarrera, S.
Sacerdote, C.
Wareham, N.J.
Langenberg, C.
Scott, R.A.
Luan, J.
Bobak, M.
Malyutina, S.
Pająk, A.
Kubinova, R.
Tamosiunas, A.
Pikhart, H.
Grarup, N.
Pedersen, O.
Hansen, T.
Linneberg, A.
Jess, T.
Cooper, J.
Humphries, S.E.
Brilliant, M.
Kitchner, T.
Hakonarson, H.
Carrell, D.S.
McCarty, C.A.
Lester, K.H.
Larson, E.B.
Crosslin, D.R.
de Andrade, M.
Roden, D.M.
Denny, J.C.
Carty, C.
Hancock, S.
Attia, J.
Holliday, E.
Scott, R.
Schofield, P.
O'Donnell, M.
Yusuf, S.
Chong, M.
Pare, G.
van der Harst, P.
Said, M.A.
Eppinga, R.N.
Verweij, N.
Snieder, H.
Lifelines Cohort authors,
Christen, T.
Mook-Kanamori, D.O.
ICBP Consortium,
Gustafsson, S.
Lind, L.
Ingelsson, E.
Pazoki, R.
Franco, O.
Hofman, A.
Uitterlinden, A.
Dehghan, A.
Teumer, A.
Baumeister, S.
Dörr, M.
Lerch, M.M.
Völker, U.
Völzke, H.
Ward, J.
Pell, J.P.
Meade, T.
Christophersen, I.E.
Maitland-van der Zee, A.H.
Baranova, E.V.
Young, R.
Ford, I.
Campbell, A.
Padmanabhan, S.
Bots, M.L.
Grobbee, D.E.
Froguel, P.
Thuillier, D.
Roussel, R.
Bonnefond, A.
Cariou, B.
Smart, M.
Bao, Y.
Kumari, M.
Mahajan, A.
Hopewell, J.C.
Seshadri, S.
METASTROKE Consortium of the ISGC,
Dale, C.
Costa, R.P.
Ridker, P.M.
Chasman, D.I.
Reiner, A.P.
Ritchie, M.D.
Lange, L.A.
Cornish, A.J.
Dobbins, S.E.
Hemminki, K.
Kinnersley, B.
Sanson, M.
Labreche, K.
Simon, M.
Bondy, M.
Law, P.
Speedy, H.
Allan, J.
Li, N.
Went, M.
Weinhold, N.
Morgan, G.
Sonneveld, P.
Nilsson, B.
Goldschmidt, H.
Sud, A.
Engert, A.
Hansson, M.
Hemingway, H.
Asselbergs, F.W.
Patel, R.S.
Keating, B.J.
Sattar, N.
Houlston, R.
Casas, J.P.
Hingorani, A.D.
(2019). Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9. Bmc cardiovasc disord,
Vol.19
(1),
p. 240.
show abstract
full text
BACKGROUND: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate..
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. Br j cancer,
Vol.118
(7),
pp. 1020-1027.
show abstract
full text
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. Sci rep,
Vol.8
(1),
p. 2339.
show abstract
full text
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..
Chattopadhyay, S.
Yu, H.
Sud, A.
Sundquist, J.
Försti, A.
Hemminki, A.
Hemminki, K.
(2018). Multiple myeloma: family history and mortality in second primary cancers. Blood cancer j,
Vol.8
(8),
p. 75.
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. Lancet haematol,
Vol.5
(8),
pp. e368-e377.
show abstract
full text
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.
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
full text
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..
Turnbull, C.
Sud, A.
Houlston, R.S.
(2018). Cancer genetics, precision prevention and a call to action. Nat genet,
Vol.50
(9),
pp. 1212-1218.
show abstract
full text
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..
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 clin cancer inform,
Vol.2,
pp. 1-11.
show abstract
full text
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..
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. Nat commun,
Vol.9
(1),
p. 3707.
show abstract
full text
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..
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 med,
Vol.16
(1),
p. 42.
show abstract
full text
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..
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. Int j cancer,
Vol.143
(10),
pp. 2449-2457.
show abstract
full text
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..
Lawrie, A.
Han, S.
Sud, A.
Hosking, F.
Cezard, T.
Turner, D.
Clark, C.
Murray, G.I.
Culligan, D.J.
Houlston, R.S.
Vickers, M.A.
(2018). Combined linkage and association analysis of classical Hodgkin lymphoma. Oncotarget,
Vol.9
(29),
pp. 20377-20385.
show abstract
full text
The heritability of classical Hodgkin lymphoma (cHL) has yet to be fully deciphered. We report a family with five members diagnosed with nodular sclerosis cHL. Genetic analysis of the family provided evidence of linkage at chromosomes 2q35-37, 3p14-22 and 21q22, with logarithm of odds score >2. We excluded the possibility of common genetic variation influencing cHL risk at regions of linkage, by analysing GWAS data from 2,201 cHL cases and 12,460 controls. Whole exome sequencing of affected family members identified the shared missense mutations p.(Arg76Gln) in FAM107A and p.(Thr220Ala) in SLC26A6 at 3p21 as being predicted to impact on protein function. FAM107A expression was shown to be low or absent in lymphoblastoid cell lines and SLC26A6 expression lower in lymphoblastoid cell lines derived from p.(Thr220Ala) mutation carriers. Expression of FAM107A and SLC26A6 was low or absent in Hodgkin Reed-Sternberg (HRS) cell lines and in HRS cells in Hodgkin lymphoma tissue. No sequence variants were detected in KLHDC8B, a gene previously suggested as a cause of familial cHL linked to 3p21. Our findings provide evidence for candidate gene susceptibility to familial cHL..
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 j,
Vol.9
(1),
p. 1.
show abstract
full text
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 (Rg = 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..
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.
full text
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. Nat commun,
Vol.8
(1),
p. 1892.
show abstract
full text
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..
Sud, A.
Hemminki, K.
Houlston, R.S.
(2017). Candidate gene association studies and risk of Hodgkin lymphoma: a systematic review and meta-analysis. Hematol oncol,
Vol.35
(1),
pp. 34-50.
show abstract
full text
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..
Sud, A.
Hemminki, K.
Houlston, R.S.
(2017). Second cancer risk following Hodgkin lymphoma. Oncotarget,
Vol.8
(45),
pp. 78261-78262.
full text
Sud, A.
Dearden, C.
(2017). T-cell Prolymphocytic Leukemia. Hematol oncol clin north am,
Vol.31
(2),
pp. 273-283.
show abstract
full text
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-cell malignancy. T-PLL can be distinguished from other lymphoid diseases by the evaluation and integration of clinical features, morphology, immunophenotyping, cytogenetics, and molecular features. The current therapeutic approach relies on immunotherapy followed by a hematopoietic stem cell transplant in selected cases. Clinical outcomes are generally poor, although insights from genomic and molecular studies may increase our understanding of this disease, with the promise of additional effective therapeutic options..
Sud, A.
(2017). Survivors at risk: Hodgkin lymphoma survivors at high risk of second cancers. International journal of hematologic oncology,
Vol.6
(1),
pp. 5-8.
full text
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
full text
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..
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. J clin oncol,
Vol.35
(14),
pp. 1584-1590.
show abstract
full text
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..
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. Eur j cancer,
Vol.84,
pp. 228-238.
show abstract
full text
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..
Sud, A.
Kinnersley, B.
Houlston, R.S.
(2017). Genome-wide association studies of cancer: current insights and future perspectives. Nat rev cancer,
Vol.17
(11),
pp. 692-704.
show abstract
full text
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..
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 rep,
Vol.20
(11),
pp. 2556-2564.
show abstract
full text
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..
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. Int j cancer,
Vol.140
(12),
pp. 2701-2708.
show abstract
full text
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..
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 j,
Vol.7
(6),
pp. e573-e573.
full text
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. Sci rep,
Vol.7,
p. 41071.
show abstract
full text
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..
Sud, A.
Morilla, R.
Ethell, M.
Taussig, D.
Liapis, K.
(2015). Green-grey crystals in acute myeloid leukaemia. Br j haematol,
Vol.168
(5),
p. 618.
Sud, A.
Cooke, R.
Swerdlow, A.J.
Houlston, R.S.
(2015). Genome-wide homozygosity signature and risk of Hodgkin lymphoma. Sci rep,
Vol.5,
p. 14315.
show abstract
full text
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..
Hanson, D.
Murray, P.G.
Coulson, T.
Sud, A.
Omokanye, A.
Stratta, E.
Sakhinia, F.
Bonshek, C.
Wilson, L.C.
Wakeling, E.
Temtamy, S.A.
Aglan, M.
Rosser, E.M.
Mansour, S.
Carcavilla, A.
Nampoothiri, S.
Khan, W.I.
Banerjee, I.
Chandler, K.E.
Black, G.C.
Clayton, P.E.
(2012). Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling. J mol endocrinol,
Vol.49
(3),
pp. 267-275.
show abstract
3-M syndrome is a primordial growth disorder caused by mutations in CUL7, OBSL1 or CCDC8. 3-M patients typically have a modest response to GH treatment, but the mechanism is unknown. Our aim was to screen 13 clinically identified 3-M families for mutations, define the status of the GH-IGF axis in 3-M children and using fibroblast cell lines assess signalling responses to GH or IGF1. Eleven CUL7, three OBSL1 and one CCDC8 mutations in nine, three and one families respectively were identified, those with CUL7 mutations being significantly shorter than those with OBSL1 or CCDC8 mutations. The majority of 3-M patients tested had normal peak serum GH and normal/low IGF1. While the generation of IGF binding proteins by 3-M cells was dysregulated, activation of STAT5b and MAPK in response to GH was normal in CUL7(-/-) cells but reduced in OBSL1(-/-) and CCDC8(-/-) cells compared with controls. Activation of AKT to IGF1 was reduced in CUL7(-/-) and OBSL1(-/-) cells at 5 min post-stimulation but normal in CCDC8(-/-) cells. The prevalence of 3-M mutations was 69% CUL7, 23% OBSL1 and 8% CCDC8. The GH-IGF axis evaluation could reflect a degree of GH resistance and/or IGF1 resistance. This is consistent with the signalling data in which the CUL7(-/-) cells showed impaired IGF1 signalling, CCDC8(-/-) cells showed impaired GH signalling and the OBSL1(-/-) cells showed impairment in both pathways. Dysregulation of the GH-IGF-IGF binding protein axis is a feature of 3-M syndrome..
Hanson, D.
Murray, P.G.
Sud, A.
Temtamy, S.A.
Aglan, M.
Superti-Furga, A.
Holder, S.E.
Urquhart, J.
Hilton, E.
Manson, F.D.
Scambler, P.
Black, G.C.
Clayton, P.E.
(2009). The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1. Am j hum genet,
Vol.84
(6),
pp. 801-806.
show abstract
3-M syndrome is an autosomal-recessive primordial growth disorder characterized by significant intrauterine and postnatal growth restriction. Mutations in the CUL7 gene are known to cause 3-M syndrome. In 3-M syndrome patients that do not carry CUL7 mutations, we performed high-density genome-wide SNP mapping to identify a second locus at 2q35-q36.1. Further haplotype analysis revealed a 1.29 Mb interval in which the underlying gene is located and we subsequently discovered seven distinct null mutations from 10 families within the gene OBSL1. OBSL1 is a putative cytoskeletal adaptor protein that localizes to the nuclear envelope. We were also able to demonstrate that loss of OBSL1 leads to downregulation of CUL7, implying a role for OBSL1 in the maintenance of CUL7 protein levels and suggesting that both proteins are involved within the same molecular pathway..
Sud, A.
Survival trends in hematological malignancies in the nordic countries through 50 years. Blood cancer journal,
.
full text