RT Journal Article
SR Electronic
T1 Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 312041
DO 10.1101/312041
A1 Dentro, Stefan C.
A1 Leshchiner, Ignaty
A1 Haase, Kerstin
A1 Tarabichi, Maxime
A1 Wintersinger, Jeff
A1 Deshwar, Amit G.
A1 Yu, Kaixian
A1 Rubanova, Yulia
A1 Macintyre, Geoff
A1 Demeulemeester, Jonas
A1 Vázquez-García, Ignacio
A1 Kleinheinz, Kortine
A1 Livitz, Dimitri G.
A1 Malikic, Salem
A1 Donmez, Nilgun
A1 Sengupta, Subhajit
A1 Anur, Pavana
A1 Jolly, Clemency
A1 Cmero, Marek
A1 Rosebrock, Daniel
A1 Schumacher, Steven
A1 Fan, Yu
A1 Fittall, Matthew
A1 Drews, Ruben M.
A1 Yao, Xiaotong
A1 Lee, Juhee
A1 Schlesner, Matthias
A1 Zhu, Hongtu
A1 Adams, David J.
A1 Getz, Gad
A1 Boutros, Paul C.
A1 Imielinski, Marcin
A1 Beroukhim, Rameen
A1 Sahinalp, S. Cenk
A1 Ji, Yuan
A1 Peifer, Martin
A1 Martincorena, Inigo
A1 Markowetz, Florian
A1 Mustonen, Ville
A1 Yuan, Ke
A1 Gerstung, Moritz
A1 Spellman, Paul T.
A1 Wang, Wenyi
A1 Morris, Quaid D.
A1 Wedge, David C.
A1 Van Loo, Peter
A1 ,
A1 ,
YR 2020
UL http://biorxiv.org/content/early/2020/04/22/312041.abstract
AB 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 question, 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 an unprecedented pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.Competing Interest StatementR.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. All other authors declare no competing interests.