Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes

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 RosebrockSteven E. Schumacher, Yu Fan, Matthew Fittall, Ruben M. Drews, Xiaotong Yao, Thomas B.K. 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, Santiago Gonzalez, David D. 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 D. Stein, Oliver Spiro, Shankar Vembu, David A. Wheeler, Tsun Po Yang

Research output: Contribution to journalArticlepeer-review

194 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2239-2254.e39
Issue number8
Publication statusPublished - 2021 Apr 15

Bibliographical note

Publisher Copyright:
© 2021 The Author(s)


  • branching evolution
  • cancer driver genes
  • cancer evolution
  • intra-tumor heterogeneity
  • pan-cancer genomics
  • subclonal reconstruction
  • tumor phylogeny
  • whole-genome sequencing

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology


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