Portraits of genetic intra-tumour heterogeneity and subclonal selection across cancer types

Stefan C. Dentro, Ignaty Leshchiner, Kerstin Haase, Maxime Tarabichi, Jeff Wintersinger, Amit G. Deshwar, Kaixian Yu, Yulia Rubanova, Geoff Macintyre, Ignacio Vázquez-García, Kortine Kleinheinz, Dimitri G. Livitz, Salem Malikic, Nilgun Donmez, Subhajit Sengupta, Jonas Demeulemeester, Pavana Anur, Clemency Jolly, Marek Cmero, Daniel Rosebrock, Steven Schumacher, Yu Fan, Matthew Fittall, Ruben M. Drews, Xiaotong Yao, Juhee Lee, Matthias Schlesner, Hongtu Zhu, David J. Adams, 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. 2018. bioRxiv 312041.


Ongoing cancer evolution gives rise to intra-tumour heterogeneity (ITH), which is a major mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin and drivers of ITH across cancer types are poorly understood. Here, we extensively characterise ITH across 2,778 cancer whole genome sequences from 36 cancer types. We demonstrate that nearly all tumours (94.7%) with sufficient sequencing depth contain evidence of recent subclonal expansions, and that most cancer types show clear signs of positive selection in both clonal and subclonal protein coding variants. We find distinctive subclonal patterns of driver gene mutations, fusions, structural variation and copy-number alterations across cancer types. Dynamic, tumour type-specific changes of mutational processes between subclonal expansions shape differences between clonal and subclonal events. Our results underline the importance of ITH and its drivers in tumour evolution, and provide an unprecedented pan-cancer resource of extensively annotated subclonal events, laying a foundation for future cancer genomic studies.