Siddiqui, M.S.
Lai, Z.M.
Spain, L.
Greener, V.
Turajlic, S.
Larkin, J.
Morganstein, D.L.
(2021). Predicting development of ipilimumab-induced hypophysitis: utility of T4 and TSH index but not TSH. Journal of endocrinological investigation,
Vol.44
(1),
pp. 195-203.
show abstract
Abstract
Purpose
Ipilimumab, a monoclonal antibody inhibiting CLTA-4, is an established treatment in metastatic melanoma, either alone or in combination with nivolumab, and results in immune mediated adverse events, including endocrinopathy. Hypophysitis is one of the most common endocrine abnormalities. An early recognition of hypophysitis may prevent life threatening consequences of hypopituitarism; therefore, biomarkers to predict which patients will develop hypophysitis would have clinical utility. Recent studies suggested that a decline in TSH may serve as an early marker of IH. This study was aimed at assessing the utility of thyroid function tests in predicting development of hypophysitis.
Methods
A retrospective cohort study was performed for all patients (n = 308) treated with ipilimumab either as a monotherapy or in combination with nivolumab for advanced melanoma at the Royal Marsden Hospital from 2010 to 2016. Thyroid function tests, other pituitary function tests and Pituitary MRIs were used to identify those with hypophysitis.
Results and conclusions
Ipilimumab-induced hypophysitis (IH) was diagnosed in 25 patients (8.15%). A decline in TSH was observed in hypophysitis cohort during the first three cycles but it did not reach statistical significance (P = 0.053). A significant fall in FT4 (P < 0.001), TSH index (P < 0.001) and standardised TSH index (P < 0.001) prior to cycles 3 and 4 in hypophysitis cohort was observed. TSH is not useful in predicting development of IH. FT4, TSH index and standardised TSH index may be valuable but a high index of clinical suspicion remains paramount in early detection of hypophysitis.
.
Gudd, C.L.
Au, L.
Triantafyllou, E.
Shum, B.
Liu, T.
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Kumar, N.
Mukherjee, S.
Dhar, A.
Woollard, K.J.
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Pinato, D.J.
Thursz, M.R.
Goldin, R.D.
Gore, M.E.
Larkin, J.
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(2021). Activation and transcriptional profile of monocytes and CD8+ T cells are altered in checkpoint inhibitor-related hepatitis. Journal of hepatology,
.
Litchfield, K.
Reading, J.L.
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Thakkar, K.
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Lee, S.-.
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Turajlic, S.
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McGranahan, N.
Swanton, C.
(2021). Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell,
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pp. 596-614.e14.
Edwards, C.L.
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Agraso Busto, S.
Harland, C.
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Larkin, J.
Heelan, K.
Fearfield, L.
(2021). Cutaneous toxicities in patients with melanoma receiving checkpoint inhibitor therapy: a retrospective review The experience of a single large specialist institution. Clinical and experimental dermatology,
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Turajlic, S.
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O’Reilly, A.
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Husson, O.
(2020). An immunotherapy survivor population: health-related quality of life and toxicity in patients with metastatic melanoma treated with immune checkpoint inhibitors. Supportive care in cancer,
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(2020). Representative Sequencing: Unbiased Sampling of Solid Tumor Tissue. Cell reports,
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Lindsay, J.O.
Gore, M.
(2020). British Society of Gastroenterology endorsed guidance for the management of immune checkpoint inhibitor-induced enterocolitis. The lancet gastroenterology & hepatology,
Vol.5
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Larkin, J.
(2020). Oligoprogression After Checkpoint Inhibition in Metastatic Melanoma Treated With Locoregional Therapy: A Single-center Retrospective Analysis. Journal of immunotherapy,
Vol.43
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Rini, B.
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Merghoub, T.
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Svane, I.M.
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Swanton, C.
(2020). Escape from nonsense-mediated decay associates with anti-tumor immunogenicity. Nature communications,
Vol.11
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Spain, L.
Tippu, Z.
Larkin, J.M.
Carr, A.
Turajlic, S.
(2020). How we treat neurological toxicity from immune checkpoint inhibitors. Esmo open,
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Spain, L.
Au, L.
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Yousaf, N.
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Vol.5
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Shepherd, S.T.
Litchfield, K.
Turajlic, S.
(2019). Searching for the needle in the haystack: deconvoluting the evolutionary dynamics of residual disease in human glioblastoma. Annals of oncology,
Vol.30
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pp. 355-357.
Turajlic, S.
(2019). Standing on the shoulders of giants. Nature medicine,
Vol.25
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pp. 357-357.
Turajlic, S.
Sottoriva, A.
Graham, T.
Swanton, C.
(2019). Resolving genetic heterogeneity in cancer. Nat rev genet,
Vol.20
(7),
pp. 404-416.
show abstract
To a large extent, cancer conforms to evolutionary rules defined by the rates at which clones mutate, adapt and grow. Next-generation sequencing has provided a snapshot of the genetic landscape of most cancer types, and cancer genomics approaches are driving new insights into cancer evolutionary patterns in time and space. In contrast to species evolution, cancer is a particular case owing to the vast size of tumour cell populations, chromosomal instability and its potential for phenotypic plasticity. Nevertheless, an evolutionary framework is a powerful aid to understand cancer progression and therapy failure. Indeed, such a framework could be applied to predict individual tumour behaviour and support treatment strategies..
Amaria, R.N.
Menzies, A.M.
Burton, E.M.
Scolyer, R.A.
Tetzlaff, M.T.
Antdbacka, R.
Ariyan, C.
Bassett, R.
Carter, B.
Daud, A.
Faries, M.
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Hamid, O.
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Rizos, H.
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Spillane, A.J.
van Akkooi, A.C.
Wargo, J.A.
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Long, G.V.
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Fisher, D.E.
Fusi, A.
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(2019). Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium. The lancet oncology,
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Turajlic, S.
Swanton, C.
Boshoff, C.
(2018). Kidney cancer: The next decade. Journal of experimental medicine,
Vol.215
(10),
pp. 2477-2479.
show abstract
Chris Boshoff, Senior Vice President of Immuno-Oncology, Translational and Early Development at Pfizer, and colleagues Samra Turajlic and Charles Swanton from the Francis Crick Institute and University College London give us their personal point of view on new insights and future therapeutic approaches for renal cancer..
Flynn, M.
Pickering, L.
Larkin, J.
Turajlic, S.
(2018). Immune-checkpoint inhibitors in melanoma and kidney cancer: from sequencing to rational selection. Therapeutic advances in medical oncology,
Vol.10,
pp. 175883591877742-175883591877742.
show abstract
Immune-checkpoint inhibitors (ICPIs), including antibodies against cytotoxic T-lymphocyte associated antigen 4 and programmed cell death protein 1, have been shown to induce durable complete responses in a proportion of patients in the first-line and refractory setting in advanced melanoma and renal cell carcinoma. In fact, there are several lines of both targeted agents and ICPI that are now feasible treatment options. However, survival in the metastatic setting continues to be poor and there remains a need for improved therapeutic approaches. In order to enhance patient selection for the most appropriate next line of therapy, better predictive biomarkers of responsiveness will need to be developed in tandem with technologies to identify mechanisms of ICPI resistance. Adaptive, biomarker-driven trials will drive this evolution. The combination of ICPI with specific chemotherapies, targeted therapies and other immuno-oncology (IO) drugs in order to circumvent ICPI resistance and enhance efficacy is discussed. Recent data support the role for both targeted therapies and ICPI in the adjuvant setting of melanoma and targeted therapies in the adjuvant setting for renal cell carcinoma, which may influence the consideration of treatment on subsequent relapse. Approaches to select the optimal treatment sequences for these patients will need to be refined. .
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(2018). Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies. Cancer cell,
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pp. 649-663.e4.
Turajlic, S.
Xu, H.
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Rowan, A.
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Chambers, T.
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Lall, S.
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(10),
pp. 565-566.
Turajlic, S.
Larkin, J.
Swanton, C.
(2015). SnapShot: Renal Cell Carcinoma. Cell,
Vol.163
(6),
pp. 1556-1556.e1.
Turajlic, S.
Furney, S.J.
Stamp, G.
Rana, S.
Ricken, G.
Oduko, Y.
Saturno, G.
Springer, C.
Hayes, A.
Gore, M.
Larkin, J.
Marais, R.
(2014). Whole-genome sequencing reveals complex mechanisms of intrinsic resistance to BRAF inhibition. Annals of oncology,
Vol.25
(5),
pp. 959-967.
Furney, S.J.
Turajlic, S.
Stamp, G.
Thomas, J.M.
Hayes, A.
Strauss, D.
Gavrielides, M.
Xing, W.
Gore, M.
Larkin, J.
Marais, R.
(2014). The mutational burden of acral melanoma revealed by whole-genome sequencing and comparative analysis. Pigment cell & melanoma research,
Vol.27
(5),
pp. 835-838.
Sanchez-Laorden, B.
Viros, A.
Girotti, M.R.
Pedersen, M.
Saturno, G.
Zambon, A.
Niculescu-Duvaz, D.
Turajlic, S.
Hayes, A.
Gore, M.
Larkin, J.
Lorigan, P.
Cook, M.
Springer, C.
Marais, R.
(2014). BRAF Inhibitors Induce Metastasis in RAS Mutant or Inhibitor-Resistant Melanoma Cells by Reactivating MEK and ERK Signaling. Science signaling,
Vol.7
(318),
pp. ra30-ra30.
Girotti, M.R.
Pedersen, M.
Sanchez-Laorden, B.
Viros, A.
Turajlic, S.
Niculescu-Duvaz, D.
Zambon, A.
Sinclair, J.
Hayes, A.
Gore, M.
Lorigan, P.
Springer, C.
Larkin, J.
Jorgensen, C.
Marais, R.
(2013). Inhibiting EGF Receptor or SRC Family Kinase Signaling Overcomes BRAF Inhibitor Resistance in Melanoma. Cancer discovery,
Vol.3
(2),
pp. 158-167.
Khattak, M.
Fisher, R.
Turajlic, S.
Larkin, J.
(2013). Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm. Therapeutic advances in medical oncology,
Vol.5
(2),
pp. 105-118.
Furney, S.J.
Turajlic, S.
Stamp, G.
Nohadani, M.
Carlisle, A.
Thomas, J.M.
Hayes, A.
Strauss, D.
Gore, M.
van den Oord, J.
Larkin, J.
Marais, R.
(2013). Genome sequencing of mucosal melanomas reveals that they are driven by distinct mechanisms from cutaneous melanoma. The journal of pathology,
Vol.230
(3),
pp. 261-269.
Turajlic, S.
Ali, Z.
Yousaf, N.
Larkin, J.
(2013). Phase I/II RAF kinase inhibitors in cancer therapy. Expert opinion on investigational drugs,
Vol.22
(6),
pp. 739-749.
Furney, S.J.
Pedersen, M.
Gentien, D.
Dumont, A.G.
Rapinat, A.
Desjardins, L.
Turajlic, S.
Piperno-Neumann, S.
de la Grange, P.
Roman-Roman, S.
Stern, M.-.
Marais, R.
(2013). SF3B1 Mutations Are Associated with Alternative Splicing in Uveal Melanoma. Cancer discovery,
Vol.3
(10),
pp. 1122-1129.
Turajlic, S.
Furney, S.J.
Lambros, M.B.
Mitsopoulos, C.
Kozarewa, I.
Geyer, F.C.
MacKay, A.
Hakas, J.
Zvelebil, M.
Lord, C.J.
Ashworth, A.
Thomas, M.
Stamp, G.
Larkin, J.
Reis-Filho, J.S.
Marais, R.
(2012). Whole genome sequencing of matched primary and metastatic acral melanomas. Genome research,
Vol.22
(2),
pp. 196-207.
Natrajan, R.
Mackay, A.
Lambros, M.B.
Weigelt, B.
Wilkerson, P.M.
Manie, E.
Grigoriadis, A.
A'Hern, R.
van der Groep, P.
Kozarewa, I.
Popova, T.
Mariani, O.
Turajlic, S.
Furney, S.J.
Marais, R.
Rodruigues, D.-.
Flora, A.C.
Wai, P.
Pawar, V.
McDade, S.
Carroll, J.
Stoppa-Lyonnet, D.
Green, A.R.
Ellis, I.O.
Swanton, C.
van Diest, P.
Delattre, O.
Lord, C.J.
Foulkes, W.D.
Vincent-Salomon, A.
Ashworth, A.
Stern, M.H.
Reis-Filho, J.S.
(2012). A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers. The journal of pathology,
Vol.227
(1),
pp. 29-41.
Furney, S.J.
Turajlic, S.
Fenwick, K.
Lambros, M.B.
MacKay, A.
Ricken, G.
Mitsopoulos, C.
Kozarewa, I.
Hakas, J.
Zvelebil, M.
Lord, C.J.
Ashworth, A.
Reis-Filho, J.S.
Herlyn, M.
Murata, H.
Marais, R.
(2012). Genomic characterisation of acral melanoma cell lines. Pigment cell & melanoma research,
Vol.25
(4),
pp. 488-492.
Larkin, J.M.
Turajlic, S.
Nathan, P.D.
Lorigan, P.
Stamp, G.
Gonzalez de Castro, D.
Martin, N.
Griffiths, J.
Edmonds, K.
Sarker, S.
James, M.G.
A'Hern, R.
Coombes, G.
Snowdon, C.
Bliss, J.M.
Gore, M.E.
Marais, R.
(2011). A phase II trial of nilotinib in the treatment of patients with KIT mutated advanced acral and mucosal melanoma (NICAM). J clin oncol,
Vol.29
(15_suppl),
p. TPS229.
show abstract
TPS229 Background: Recent studies have indicated that KIT mutations occur in approximately 20% of acral and mucosal melanomas (Curtin, al. 2006; Beadling, et al. 2008). Several case reports have shown that KIT mutated melanomas can respond to treatment with KIT inhibitors (Hodi et al. 2008; Lutzky et al. 2008; Quintas-Cardama et al. 2008; Handolias et al. 2010; Itoh, et al. 2010; Satzger et al. 2010; Terheyden et al. 2010; Woodman and Davies 2010) suggesting that such tumours critically depend on upregulated KIT signalling. Nilotinib, which potently inhibits the tyrosine kinase activity of BCR-ABL and KIT, has been evaluated in patients with advanced KIT mutated GIST and has shown clinical efficacy at well tolerated doses (Demetri et al. 2009; Montemurro et al. 2009; Schlemmer et al. 2010). METHODS: NICAM is a single arm 2-stage open label phase II study of nilotinib in KIT mutated advanced mucosal or acral melanoma. Patients with KIT mutations known to confer resistance to nilotinib are excluded. The primary objective in this feasibility study is to evaluate the efficacy of nilotinib in KIT mutated advanced mucosal and acral melanoma with a primary endpoint of progression free survival at 6 months. Secondary endpoints include response rate at 12 weeks; overall survival; toxicity of treatment; correlation between the response to nilotinib and KIT genotype, KIT gene copy number and KIT expression. In addition, the following will be explored: 1. Suppression of phosphorylation of KIT and downstream pathways on day 15 tumour biopsies; 2. Possible mechanisms of resistance by analysis of biopsies obtained at disease progression; 3. The use of circulating tumour DNA for non-invasive KIT mutational testing; 4. Genetic lesions that potentially cooperate with oncogenic KIT in melanoma (using Next Generation Sequencing). All patients are treated until disease progression or unacceptable toxicity. If 2 or more of the first 9 patients are progression free at 6 months, patient entry will continue into the second stage until a total of 24 patients have been recruited. To date, 45 patients have been registered and screened for KIT mutation and 5 patients have entered the study..
Perez, A.
Turajlic, S.
Szyszko, T.
O'Doherty, M.
Calonje, E.
Harries, M.
Acland, K.
(2010). Generalized melanosis and melanuria in a patient with metastatic melanoma. Clinical and experimental dermatology,
Vol.35
(3),
pp. e37-e39.
Ferronika, P.
Hof, J.
Kats-Ugurlu, G.
Sijmons, R.H.
Terpstra, M.M.
de Lange, K.
Leliveld-Kors, A.
Westers, H.
Kok, K.
Comprehensive Profiling of Primary and Metastatic ccRCC Reveals a High Homology of the Metastases to a Subregion of the Primary Tumour. Cancers,
Vol.11
(6),
pp. 812-812.
show abstract
While intratumour genetic heterogeneity of primary clear cell renal cell carcinoma (ccRCC) is well characterized, the genomic profiles of metastatic ccRCCs are seldom studied. We profiled the genomes and transcriptomes of a primary tumour and matched metastases to better understand the evolutionary processes that lead to metastasis. In one ccRCC patient, four regions of the primary tumour, one region of the thrombus in the inferior vena cava, and four lung metastases (including one taken after pegylated (PEG)-interferon therapy) were analysed separately. Each sample was analysed for copy number alterations and somatic mutations by whole exome sequencing. We also evaluated gene expression profiles for this patient and 15 primary tumour and 15 metastasis samples from four additional patients. Copy number profiles of the index patient showed two distinct subgroups: one consisted of three primary tumours with relatively minor copy number changes, the other of a primary tumour, the thrombus, and the lung metastases, all with a similar copy number pattern and tetraploid-like characteristics. Somatic mutation profiles indicated parallel clonal evolution with similar numbers of private mutations in each primary tumour and metastatic sample. Expression profiling of the five patients revealed significantly changed expression levels of 57 genes between primary tumours and metastases, with enrichment in the extracellular matrix cluster. The copy number profiles suggest a punctuated evolution from a subregion of the primary tumour. This process, which differentiated the metastases from the primary tumours, most likely occurred rapidly, possibly even before metastasis formation. The evolutionary patterns we deduced from the genomic alterations were also reflected in the gene expression profiles..
Litchfield, K.
Reading, J.L.
Puttick, C.
Abbosh, C.
Bentham, R.
Watkins, T.B.
Rosenthal, R.
Biswas, D.
Lim, E.
AL-Bakir, M.
Turati, V.
Guerra-Assunção, J.A.
Conde, L.
Furness, A.J.
Saini, S.K.
Hadrup, S.R.
Herrero, J.
Rowan, A.
Enver, T.
Hellmann, M.D.
Larkin, J.
Turajlic, S.
Quezada, S.
McGranahan, N.
Swanton, C.
Meta-analysis of tumor and T cell intrinsic mechanisms of sensitization to checkpoint inhibition. ,
.
show abstract
Abstract
Checkpoint inhibitors (CPIs) augment adaptive immunity. Systematic pan-tumor analyses may reveal the relative importance of tumour cell intrinsic and microenvironmental features underpinning CPI sensitization. Here we collated whole-exome and transcriptomic data for >1000 CPI-treated patients across eight tumor-types, utilizing standardized bioinformatics-workflows and clinical outcome-criteria to validate multivariate predictors of CPI-sensitization. Clonal-TMB was the strongest predictor of CPI response, followed by TMB and CXCL9 expression. Subclonal-TMB, somatic copy alteration burden and HLA-evolutionary divergence failed to attain significance. Discovery analysis identified two additional determinants of CPI-response supported by prior functional evidence: 9q34.3 (TRAF2) loss and CCND1 amplification, both independently validated in >1600 CPI-treated patients. We find evidence for collateral sensitivity, likely mediated through selection for CDKN2A-loss, with 9q34.3 loss as a passenger event leading to CPI-sensitization. Finally, scRNA sequencing of clonal neoantigen-reactive CD8-TILs, combined with bulk RNAseq analysis of CPI responding tumors, identified CCR5 and CXCL13 as T cell-intrinsic mediators of CPI-sensitisation..
Carbone, F.
Huang, J.K.
Perelli, L.
Poggetto, E.D.
Gutschner, T.
Tomihara, H.
Soeung, M.
Lam, T.N.
Xia, R.
Zhu, C.
Song, X.
Zhang, J.
Sircar, K.
Malouf, G.G.
Sgambato, A.
Karam, J.A.
Gao, J.
Jonasch, E.
Viale, A.
Draetta, G.F.
Futreal, A.
Bakouny, Z.
Van Allen, E.M.
Choueiri, T.
Msaouel, P.
Litchfield, K.
Turajlic, S.
Heffernan, T.P.
Chen, Y.B.
DiNatale, R.G.
Hakimi, A.A.
Bristow, C.A.
Tannir, N.M.
Carugo, A.
Genovese, G.
9p21 Loss Defines the Evolutionary Patterns of Aggressive Renal Cell Carcinomas. ,
.
show abstract
AbstractDedifferentiation and acquisition of chromosomal instability in renal cell carcinoma portends dismal prognosis and aggressive clinical behavior. However, the absence of reliable experimental models dramatically impacts the understanding of mechanisms underlying malignant progression. Here we established an in vivo genetic platform to rapidly generate somatic mosaic genetically engineerd immune-competent mouse models of renal tumors, recapitulating the genomic and phenotypic features of these malignancies. Leveraging somatic chromosomal engineering, we demonstrated that ablation of the murine locus syntenic to human 9p21 drives the rapid expansion of aggressive mesenchymal clones with prominent metastatic behavior, characterized by early emergence of chromosomal instability, whole-genome duplication, and conserved patterns of aneuploidy. This model of punctuated equilibrium provides a remarkable example of cross-species convergent evolution.SignificanceTo better understand the role of 9p21 in malignant progression, we generated a somatic mosaic GEMM of renal cancer, capturing the histological, genomic and evolutionary features of human disease. With this technology we demonstrated a critica role of 9p21 loss in metastatic evolution of RCC and provide a unique tool for testing new therapeutic treatments..
Hodzic, E.
Shrestha, R.
Malikic, S.
Collins, C.C.
Litchfield, K.
Turajlic, S.
Sahinalp, S.C.
Identification of Conserved Evolutionary Trajectories in Tumors. ,
.
show abstract
AbstractMotivationAs multi-region, time-series, and single cell sequencing data become more widely available, it is becoming clear that certain tumors share evolutionary characteristics with others. In the last few years, several computational methods have been developed with the goal of inferring the subclonal composition and evolutionary history of tumors from tumor biopsy sequencing data. However, the phylogenetic trees that they report differ significantly between tumors (even those with similar characteristics).ResultsIn this paper, we present a novel combinatorial optimization method, CONETT, for detection of recurrent tumor evolution trajectories. Our method constructs a consensus tree of conserved evolutionary trajectories based on the information about temporal order of alteration events in a set of tumors. We apply our method to previously published datasets of 100 clear-cell renal cell carcinoma and 99 non-small-cell lung cancer patients and identify both conserved trajectories that were reported in the original studies, as well as new trajectories.AvailabilityCONETT is implemented in C++ and available at https://github.com/ehodzic/CONETT..
Fendler, A.
Au, L.
Boos, L.A.
Byrne, F.
Shepherd, S.T.
Shum, B.
Gerard, C.L.
Ward, B.
Xie, W.
Cerrone, M.
Cornish, G.H.
Pule, M.
Mekkaoui, L.
Ng, K.W.
Stone, R.
Gomes, C.
Flynn, H.R.
Agua-Doce, A.
Hobson, P.
Caidan, S.
Howell, M.
Goldstone, R.
Gavrielides, M.
Nye, E.
Snijders, B.
Macrae, J.
Nicod, J.
Hayday, A.
Gronthoud, F.
Messiou, C.
Cunningham, D.
Chau, I.
Starling, N.
Turner, N.
Rusby, J.
Welsh, L.
van As, N.
Jones, R.
Droney, J.
Banerjee, S.
Tatham, K.
Jhanji, S.
O’Brien, M.
Curtis, O.
Harrington, K.
Bhide, S.
Slattery, T.
Khan, Y.
Tippu, Z.
Leslie, I.
Gennatas, S.
Okines, A.
Reid, A.
Young, K.
Furness, A.
Pickering, L.
Ghandi, S.
Gamblin, S.
Swanton, C.
Nicholson, E.
Kumar, S.
Yousaf, N.
Wilkinson, K.
Swerdlow, A.
Harvey, R.
Kassiotis, G.
Wilkinson, R.
Larkin, J.
Turajlic, S.
Adaptive immunity to SARS-CoV-2 in cancer patients: The CAPTURE study. ,
.
show abstract
SUMMARYThere is a pressing need to characterise the nature, extent and duration of immune response to SARS-CoV-2 in cancer patients and inform risk-reduction strategies and preserve cancer outcomes. CAPTURE is a prospective, longitudinal cohort study of cancer patients and healthcare workers (HCWs) integrating longitudinal immune profiling and clinical annotation. We evaluated 529 blood samples and 1051 oronasopharyngeal swabs from 144 cancer patients and 73 HCWs and correlated with >200 clinical variables. In patients with solid cancers and HCWs, S1-reactive and neutralising antibodies to SARS-CoV-2 were detectable five months post-infection. SARS-CoV-2-specific T-cell responses were detected, and CD4+ T-cell responses correlated with S1 antibody levels. Patients with haematological malignancies had impaired but partially compensated immune responses. Overall, cancer stage, disease status, and therapies did not correlate with immune responses. These findings have implications for understanding individual risks and potential effectiveness of SARS-CoV-2 vaccination in the cancer population..
Zhao, Y.
Fu, X.
Lopez, J.
Rowan, A.
Au, L.
Fendler, A.
Hazell, S.
Xu, H.
Horswell, S.
Shephard, S.
Spain, L.
Byrne, F.
Stamp, G.
O'Brien, T.
Nicol, D.
Augustine, M.
Chandra, A.
Rudman, S.
Toncheva, A.
Pickering, L.
Larkin, J.
Sahai, E.
Bates, P.
Swanton, C.
Turajlic, S.
Litchfield, K.
Selection of metastasis competent subclones in the tumour interior: TRACERx renal. ,
.
show abstract
Abstract
While the genetic evolutionary features of solid tumour growth are becoming increasingly described, the spatial and physical nature of subclonal growth remains unclear. Here we utilise 102 macroscopic whole tumour images from clear cell renal cell carcinoma (ccRCC) patients, with matched genetic and phenotypic data from 756 biopsies. Utilising a digital image processing pipeline the boundaries between tumour and normal tissue were marked by a renal pathologist, and positions of boundary line and biopsy regions were extracted to X- and Y-coordinates. The coordinates were then integrated with genomic data to map exact spatial subclone locations, revealing how genetically distinct subclones grow and evolve spatially. A phenotype of advanced and more aggressive subclonal growth was present in the tumour centre, characterised by an elevated burden of somatic copy number alterations, higher necrosis, proliferation rate and Fuhrman grade. Moreover, metastasising subclones were found to preferentially originate from the tumour centre. Collectively these observations suggest a model of accelerated evolution in the tumour interior, with harsh hypoxic environmental conditions leading to heightened cellular turnover and greater opportunity for driver SCNAs to arise and expand due to selective advantage. Tumour subclone growth was found to be predominantly spatially contiguous in nature, with subclone dispersal a rare event found in two cases, which notably was associated with metastasis. In terms of genetic events, the largest subclones spatially were dominated by driver somatic copy number alterations, suggesting a large selective advantage can be conferred to subclones upon acquisition of these alterations. In conclusion, spatial dynamics is strongly associated with genomic alterations and plays an important role in tumour evolution..
Fu, X.
Zhao, Y.
Lopez, J.
Rowan, A.
Au, L.
Fendler, A.
Hazell, S.
Xu, H.
Horswell, S.
Shepherd, S.
Spain, L.
Byrne, F.
Stamp, G.
O'Brien, T.
Nicol, D.
Augustine, M.
Chandra, A.
Rudman, S.
Toncheva, A.
Furness, A.
Pickering, L.
Orton, M.
Doran, S.
Koh, D.-.
Messiou, C.
Dafydd, D.A.
Kumar, S.
Larkin, J.
Swanton, C.
Sahai, E.
Litchfield, K.
Turajlic, S.
Bates, P.
Spatial patterns of tumour growth impact clonal diversification: computational modelling and evidence in the TRACERx Renal study. ,
.
show abstract
Abstract
Intra-tumour genetic heterogeneity (ITH) fuels cancer evolution. The role of clonal diversity and genetic complexity in the progression of clear-cell renal cell carcinomas (ccRCCs) has been characterised, but the ability to predict clinically relevant evolutionary trajectories remains limited. Here, towards enhancing this ability, we investigated spatial features of clonal diversification through a combined computational modelling and experimental analysis in the TRACERx Renal study. We observe through modelling that spatial patterns of tumour growth impact the extent and trajectory of subclonal diversification. Moreover, subpopulations with high clonal diversity, and parallel evolution events, are frequently observed near the tumour margin. In-silico time-course studies further showed that budding structures on the tumour surface could indicate future steps of subclonal evolution. Such structures were evident radiologically in 15 early-stage ccRCCs, raising the possibility that spatially resolved sampling of these regions, when combined with sequencing, may enable identification of evolutionary potential in early-stage tumours..
Buck, M.D.
Poirier, E.Z.
Cardoso, A.
Frederico, B.
Canton, J.
Barrell, S.
Beale, R.
Byrne, R.
Caidan, S.
Crawford, M.
Cubitt, L.
Gandhi, S.
Goldstone, R.
Grant, P.R.
Gulati, K.
Hindmarsh, S.
Howell, M.
Hubank, M.
Instrell, R.
Jiang, M.
Kassiotis, G.
Lu, W.-.
MacRae, J.I.
Martini, I.
Miller, D.
Moore, D.
Nastouli, E.
Nicod, J.
Nightingale, L.
Olsen, J.
Oomatia, A.
O'Reilly, N.
Rideg, A.
Song, O.-.
Strange, A.
Swanton, C.
Turajlic, S.
Wu, M.
Reis e Sousa, C.
SARS-CoV-2 detection by a clinical diagnostic RT-LAMP assay. Wellcome open research,
Vol.6,
pp. 9-9.
show abstract
The ongoing pandemic of SARS-CoV-2 calls for rapid and cost-effective methods to accurately identify infected individuals. The vast majority of patient samples is assessed for viral RNA presence by RT-qPCR. Our biomedical research institute, in collaboration between partner hospitals and an accredited clinical diagnostic laboratory, established a diagnostic testing pipeline that has reported on more than 252,000 RT-qPCR results since its commencement at the beginning of April 2020. However, due to ongoing demand and competition for critical resources, alternative testing strategies were sought. In this work, we present a clinically-validated procedure for high-throughput SARS-CoV-2 detection by RT-LAMP in 25 minutes that is robust, reliable, repeatable, sensitive, specific, and inexpensive..