Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes
Stefan C. Dentro(The Francis Crick Institute), Ignaty Leshchiner(Broad Institute), Kerstin Haase(The Francis Crick Institute), Maxime Tarabichi(The Francis Crick Institute), Jeff Wintersinger(University of Toronto), Amit G. Deshwar(University of Toronto), Kaixian Yu(The University of Texas MD Anderson Cancer Center), Yulia Rubanova(University of Toronto), Geoff Macintyre(University of Cambridge), Jonas Demeulemeester(The Francis Crick Institute), Ignacio Vázquez-Garćıa(Memorial Sloan Kettering Cancer Center), Kortine Kleinheinz(German Cancer Research Center), Dimitri Livitz(Broad Institute), Salem Malikić(National Cancer Institute), Nilgun Donmez(Simon Fraser University), Subhajit Sengupta(NorthShore University HealthSystem), Pavana Anur(Oregon Health & Science University), Clemency Jolly(The Francis Crick Institute), Marek Cmero(The University of Melbourne), Daniel Rosebrock(Broad Institute), Steven E. Schumacher(Broad Institute), Yu Fan(The University of Texas MD Anderson Cancer Center), Matthew W. Fittall(The Francis Crick Institute), Ruben M. Drews(University of Cambridge), Xiaotong Yao(Cornell University), Thomas B.K. Watkins(The Francis Crick Institute), Ju‐Hee Lee(University of California, Santa Cruz), Matthias Schlesner(German Cancer Research Center), Hongtu Zhu(The University of Texas MD Anderson Cancer Center), David J. Adams(Wellcome Sanger Institute), Nicholas McGranahan(Cancer Research UK), Charles Swanton(The Francis Crick Institute), Gad Getz(Broad Institute), Paul C. Boutros(Ontario Institute for Cancer Research), Marcin Imieliński(Cornell University), Rameen Beroukhim(Broad Institute), S. Cenk Şahinalp(National Cancer Institute), Yuan Ji(NorthShore University HealthSystem), Martin Peifer(University of Cologne), Iñigo Martincorena(Wellcome Sanger Institute), Florian Markowetz(University of Cambridge), Ville Mustonen(University of Helsinki), Ke Yuan(University of Cambridge), Moritz Gerstung(European Bioinformatics Institute), Paul T. Spellman(Oregon Health & Science University), Wenyi Wang(The University of Texas MD Anderson Cancer Center), Quaid Morris(Ontario Institute for Cancer Research), David C. Wedge(Open Data Institute), Peter Van Loo(The Francis Crick Institute), Stefan C. Dentro(The Francis Crick Institute), Ignaty Leshchiner(Broad Institute), Moritz Gerstung(European Bioinformatics Institute), Clemency Jolly(The Francis Crick Institute), Kerstin Haase(The Francis Crick Institute), Maxime Tarabichi(The Francis Crick Institute), Jeff Wintersinger(University of Toronto), Amit G. Deshwar(University of Toronto), Kaixian Yu(The University of Texas MD Anderson Cancer Center), Santiago González, Yulia Rubanova(University of Toronto), Geoff Macintyre(University of Cambridge), Jonas Demeulemeester(The Francis Crick Institute), David J. Adams(Wellcome Sanger Institute), Pavana Anur(Oregon Health & Science University), Rameen Beroukhim(Broad Institute), Paul C. Boutros(Ontario Institute for Cancer Research), David D.L. Bowtell(Simon Fraser University), Peter J. Campbell, Shaolong Cao, Elizabeth L. Christie(The University of Melbourne), Marek Cmero(The University of Melbourne), Yupeng Cun, Kevin J. Dawson, Nilgun Donmez(Simon Fraser University), Ruben M. Drews(University of Cambridge), Roland Eils(Cornell University), Yu Fan(The University of Texas MD Anderson Cancer Center), Matthew W. Fittall(The Francis Crick Institute), Dale W. Garsed, Gad Getz(Broad Institute), Gavin Ha, Marcin Imieliński(Cornell University), Lara Jerman(Massachusetts General Hospital), Yuan Ji(NorthShore University HealthSystem), Kortine Kleinheinz(German Cancer Research Center), Juhee Lee(University of California, Santa Cruz), Henry Lee-Six, Dimitri Livitz(Broad Institute), Salem Malikić(National Cancer Institute), Florian Markowetz(University of Cambridge), Iñigo Martincorena(Wellcome Sanger Institute), Thomas J. Mitchell(Dana-Farber Cancer Institute), Ville Mustonen(University of Helsinki), Layla Oesper(University of Cologne), Martin Peifer(University of Cologne), Myron Peto, Benjamin J. Raphael(University of Helsinki), Daniel Rosebrock(Broad Institute), S. Cenk Şahinalp(National Cancer Institute), Adriana Salcedo, Matthias Schlesner(German Cancer Research Center), Steven E. Schumacher(Broad Institute), Subhajit Sengupta(NorthShore University HealthSystem), Ruian Shi, Seung Jun Shin(University of Glasgow), Lincoln Stein, Oliver Spiro, Ignacio Vázquez-Garćıa(Memorial Sloan Kettering Cancer Center), Shankar Vembu, David A. Wheeler(Open Data Institute), Tsun-Po Yang, Xiaotong Yao(Cornell University), Ke Yuan(University of Cambridge), Hongtu Zhu(The University of Texas MD Anderson Cancer Center), Wenyi Wang(The University of Texas MD Anderson Cancer Center), Quaid Morris(Ontario Institute for Cancer Research), Paul T. Spellman(Oregon Health & Science University), David C. Wedge(Open Data Institute), Peter Van Loo(The Francis Crick Institute)
Cited by 551Open Access
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.
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