Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes
AuthorsDentro, S. C.
Deshwar, A. G.
Livitz, D. G.
Schumacher, S. E.
Drews, R. M.
Watkins, T. B. K.
Adams, D. J.
Boutros, P. C.
Sahinalp, S. C.
Spellman, P. T.
Morris, Q. D.
Wedge, David C
Van Loo, P.
AffiliationCancer Genomics Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK; Big Data Institute, University of Oxford, Oxford OX3 7L
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AbstractIntra-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.
CitationDentro SC, Leshchiner I, Haase K, Tarabichi M, Wintersinger J, Deshwar AG, et al. Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes. Cell. 2021 Apr;184(8):2239-2254.e39.
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