Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes
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Stefan C Dentro Ignaty Leshchiner Kerstin Haase Maxime Tarabichi Jeff Wintersinger Amit G Deshwar Kaixian Yu Yulia Rubanova Geoff Macintyre Jonas Demeulemeester Ignacio Vázquez-García Kortine Kleinheinz Dimitri G Livitz Salem Malikic Nilgun Donmez Subhajit Sengupta Pavana Anur Clemency Jolly Marek Cmero Daniel Rosebrock Steven E Schumacher Yu Fan Matthew Fittall Ruben M Drews Xiaotong Yao Tom Watkins Juhee Lee Matthias Schlesner Hongtu Zhu David J Adams Nicholas McGranahan Charles Swanton Gad Getz Paul C Boutros Marcin Imielinski Rameen Beroukhim S Cenk Sahinalp Yuan Ji Martin Peifer Inigo Martincorena Florian Markowetz Ville Mustonen Ke Yuan Moritz Gerstung Paul T Spellman Wenyi Wang Quaid D Morris David C Wedge Peter Van Loo Stefan C Dentro Ignaty Leshchiner Moritz Gerstung Clemency Jolly Kerstin Haase Maxime Tarabichi Jeff Wintersinger Amit G Deshwar Kaixian Yu Santiago Gonzalez Yulia Rubanova Geoff Macintyre Jonas Demeulemeester David J Adams Pavana Anur Rameen Beroukhim Paul C Boutros David D Bowtell Peter J Campbell Shaolong Cao Elizabeth L Christie Marek Cmero Yupeng Cun Kevin J Dawson Nilgun Donmez Ruben M Drews Roland Eils Yu Fan Matthew Fittall Dale W Garsed Gad Getz Gavin Ha Marcin Imielinski Lara Jerman Yuan Ji Kortine Kleinheinz Juhee Lee Henry Lee-Six Dimitri G Livitz Salem Malikic Florian Markowetz Inigo Martincorena Thomas J Mitchell Ville Mustonen Layla Oesper Martin Peifer Myron Peto Benjamin J Raphael Daniel Rosebrock S Cenk Sahinalp Adriana Salcedo Matthias Schlesner Steven E Schumacher Subhajit Sengupta Ruian Shi Seung Jun Shin Lincoln D Stein Oliver Spiro Ignacio Vázquez-García Shankar Vembu David A Wheeler Tsun-Po Yang Xiaotong Yao Ke Yuan Hongtu Zhu Wenyi Wang Quaid D Morris Paul T Spellman David C Wedge Peter Van Loo PCAWG Evolution and Heterogeneity Working Group PCAWG Consortium Toggle all authors (121)
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.
Journal details
Journal Cell
Volume 184
Issue number 8
Pages 2239-2254.e39
Available online
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Publisher website (DOI) 10.1016/j.cell.2021.03.009
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Europe PubMed Central 33831375
Pubmed 33831375
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