作者
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 Livitz,Salem Malikić,Nilgun Donmez,Subhajit Sengupta,Pavana Anur,Clemency Jolly,Marek Cmero,Daniel Rosebrock,Steven E. Schumacher,Yu Fan,Matthew Fittall,Ruben M. Drews,Xiaotong Yao,Thomas B.K. Watkins,Ju Hee Lee,Matthias Schlesner,Hongtu Zhu,David J. Adams,Nicholas McGranahan,Charles Swanton,Gad Getz,Paul C. Boutros,Marcin Imieliński,Rameen Beroukhim,S. Cenk Şahinalp,Yuan Ji,Martin Peifer,Iñigo Martincorena,Florian Markowetz,Ville Mustonen,Ke Yuan,Moritz Gerstung,Paul T. Spellman,Wenyi Wang,Quaid Morris,David C. Wedge,Peter Van Loo,Santiago González,David D.L. Bowtell,Peter J. Campbell,Shaolong Cao,Elizabeth L. Christie,Yupeng Cun,Kevin J. Dawson,Roland Eils,Dale W. Garsed,Gavin Ha,Lara Jerman,Henry Lee-Six,Thomas J. Mitchell,Layla Oesper,Myron Peto,Benjamin J. Raphael,Adriana Salcedo,Ruian Shi,Seung Jun Shin,Lincoln Stein,Oliver Spiro,Shankar Vembu,David A. Wheeler,Tsun-Po Yang
摘要
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.