Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes

Dentro, S. C. et al. (2021) Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes. Cell, 184(8), 2239-2254.e39. (doi: 10.1016/j.cell.2021.03.009) (PMID:33831375) (PMCID:PMC8054914)

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Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.

Item Type:Articles
Additional Information:This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202), and the Wellcome Trust (FC001202). This project was enabled through the Crick Scientific Computing STP and through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (MR/L016311/1). M.T. and J.D. are postdoctoral fellows supported by the European Union Horizon 2020 Research and Innovation Program (Marie Skłodowska-Curie grant agreements 747852-SIOMICS and 703594-DECODE). J.D. is a postdoctoral fellow of the Research Foundation – Flanders (FWO). I.V.G. is supported by a Wellcome Trust PhD fellowship (WT097678) and the Ann and Sol Schreiber Mentored Investigator Award of the Ovarian Cancer Research Alliance. S.M. is funded by a Vanier Canada graduate scholarship. S.C.S. is supported by the NSERC Discovery Frontiers Project “The Cancer Genome Collaboratory” and by NIH GM108308. D.J.A. is supported by Cancer Research UK. F.M., G.M., and K. Yuan acknowledge support from the University of Cambridge, Cancer Research UK, and Hutchison Whampoa Limited. G.M., K. Yuan, and F.M. are funded by CRUK core grants C14303/A17197 and A19274. K. Yuan is further supported by EPSRC EP/R018634/1. S.S. and Y.J. are supported by NIH R01 CA132897. H.Z. is supported by grant NIMH086633 and an endowed Bao-Shan Jing Professorship in Diagnostic Imaging. P.T.S. is supported by U24CA210957 and 1U24CA143799. N.M. is a Sir Henry Dale Fellow, funded jointly by the Wellcome Trust and the Royal Society (211179/Z/18/Z) and also receives funding from Cancer Research UK, Rosetrees and the NIHR BRC at University College London Hospitals, and the CRUK University College London Experimental Cancer Medicine Centre. T.B.K.W. and C.S. are supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169). C.S. is Royal Society Napier Research Professor (RP150154). T.B.K.W. receives support from a Royal Society Research Professorships Enhancement Award (RP/EA/180007). W.W. is supported by the National Cancer Institute (1R01 CA183793 and P30 CA016672). D.C.W. is funded by the Li Ka Shing Foundation. P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation’s support toward establishment of The Francis Crick Institute.
Glasgow Author(s) Enlighten ID:Yuan, Dr Ke
Authors: Dentro, S. C., Leshchiner, I., Haase, K., Tarabichi, M., Wintersinger, J., Deshwar, A. G., Yu, K., Rubanova, Y., Macintyre, G., Demeulemeester, J., Vázquez-García, I., Kleinheinz, K., Livitz, D. G., Malikic, S., Donmez, N., Sengupta, S., Anur, P., Jolly, C., Cmero, M., Rosebrock, D., Schumacher, S. E., Fan, Y., Fittall, M., Drews, R. M., Yao, X., Watkins, T. B. K., Lee, J., Schlesner, M., Zhu, H., Adams, D. J., McGranahan, N., Swanton, C., Getz, G., Boutros, P. C., Imielinski, M., Beroukhim, R., Sahinalp, S. C., Ji, Y., Peifer, M., Martincorena, I., Markowetz, F., Mustonen, V., Yuan, K., Gerstung, M., Spellman, P. T., Wang, W., Morris, Q. D., Wedge, D. C., and Van Loo, P.
College/School:College of Science and Engineering > School of Computing Science
Journal Name:Cell
ISSN (Online):1097-4172
Published Online:07 April 2021
Copyright Holders:Copyright © 2021 The Author(s)
First Published:First published in Cell 184(8):2239-2254.e39
Publisher Policy:Reproduced under a Creative Commons Licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
300982Exploiting Closed-Loop Aspects in Computationally and Data Intensive AnalyticsRoderick Murray-SmithEngineering and Physical Sciences Research Council (EPSRC)EP/R018634/1Computing Science