1. Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes.
- Author
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Dentro SC, Leshchiner I, Haase K, Tarabichi M, Wintersinger J, Deshwar AG, Yu K, Rubanova Y, Macintyre G, Demeulemeester J, Vázquez-García I, Kleinheinz K, Livitz DG, Malikic S, Donmez N, Sengupta S, Anur P, Jolly C, Cmero M, Rosebrock D, Schumacher SE, Fan Y, Fittall M, Drews RM, Yao X, Watkins TBK, Lee J, Schlesner M, Zhu H, Adams DJ, McGranahan N, Swanton C, Getz G, Boutros PC, Imielinski M, Beroukhim R, Sahinalp SC, Ji Y, Peifer M, Martincorena I, Markowetz F, Mustonen V, Yuan K, Gerstung M, Spellman PT, Wang W, Morris QD, Wedge DC, and Van Loo P
- Subjects
- DNA Copy Number Variations, DNA, Neoplasm chemistry, DNA, Neoplasm metabolism, Databases, Genetic, Drug Resistance, Neoplasm genetics, Humans, Neoplasms pathology, Polymorphism, Single Nucleotide, Whole Genome Sequencing, Genetic Heterogeneity, Neoplasms genetics
- Abstract
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., Competing Interests: Declaration of interests G.M. and F.M. are cofounders and shareholders of Tailor Bio. R.B. owns equity in Ampressa Therapeutics. G.G. receives research funds from IBM and Pharmacyclics and is an inventor on patent applications related to MuTect, ABSOLUTE, MutSig, MSMuTect, and POLYSOLVER. I.L. is a consultant for PACT Pharma. B.J.R. is a consultant at and has ownership interest (including stock and patents) in Medley Genomics. N.M. has stock options in and has consulted for Achilles Therapeutics. C.S. acknowledges grant support from Pfizer, AstraZeneca, Bristol Myers Squibb, Roche-Ventana, Boehringer-Ingelheim, Archer Dx, and Ono Pharmaceutical; is an AstraZeneca Advisory Board Member and Chief Investigator for the MeRmaiD-1 clinical trial; has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol Myers Squibb, Celgene, AstraZeneca, Illumina, Amgen, Genentech, Roche-Ventana, GRAIL, Medicxi, Bicycle Therapeutics, and the Sarah Cannon Research Institute; has stock options in Apogen Biotechnologies, Epic Bioscience, and GRAIL; and has stock options and is co-founder of Achilles Therapeutics., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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