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.
Dentro, Stefan C. and Leshchiner, Ignaty and Haase, Kerstin and Tarabichi, Maxime and Wintersinger, Jeff and Deshwar, Amit G. and Yu, Kaixian and Rubanova, Yulia and Macintyre, Geoff and Demeulemeester, Jonas and Vázquez-García, Ignacio and Kleinheinz, Kortine and Livitz, Dimitri G. and Malikic, Salem and Donmez, Nilgun and Sengupta, Subhajit and Anur, Pavana and Jolly, Clemency and Cmero, Marek and Rosebrock, Daniel and Schumacher, Steven and Fan, Yu and Fittall, Matthew and Drews, Ruben M. and Yao, Xiaotong and Lee, Juhee and Schlesner, Matthias and Zhu, Hongtu and Adams, David J. and Getz, Gad and Boutros, Paul C. and Imielinski, Marcin and Beroukhim, Rameen and Sahinalp, S. Cenk and Ji, Yuan and Peifer, Martin and Martincorena, Inigo and Markowetz, Florian and Mustonen, Ville and Yuan, Ke and Gerstung, Moritz and Spellman, Paul T. and Wang, Wenyi and Morris, Quaid and Wedge, David C. and Van Loo, Peter and Group, PCAWG Evolution and Heterogeneity Working and Consortium, PCAWG, Characterizing Genetic Intra-Tumor Heterogeneity Across 2,658 Human Cancer Genomes. Available at SSRN: https://ssrn.com/abstract=3582701 or http://dx.doi.org/10.2139/ssrn.3582701
This version of the paper has not been formally peer reviewed.
Download This Paper