LAUSR

Cancer develops through a continuous process of somatic evolution. Whole genome sequencing provides a snapshot of the tumor genome at the point of sampling, however, the data can contain information that permits the reconstruction of a tumor9s evolutionary past. Here, we apply such life history analyses on an unprecedented scale, to a set of 2,658 tumors spanning 39 cancer types. We estimated the timing of large chromosomal gains during tumor evolution, by comparing the rates of doubled to non-doubled point mutations within gained regions. Although we find that such events typically occur in the second half of clonal evolution, we also observe distinctive and early chromosomal gains in some cancer types, such as gains of chromosomes 7, 19 and 20 in glioblastoma, and isochromosome 17q in medulloblastoma. By integrating these results with the qualitative timing of individual driver mutations, we obtained an overall ranking, from early to late, of frequent somatic events per cancer type, which both identified novel patterns of tumor evolution, and incorporated additional detail into known models, such as the progression of APC-KRAS-TP53 in colorectal cancer proposed by Vogelstein and Fearon. To estimate how mutational processes acting on the tumor genome change over time, we classified mutations in each sample according to three broad time periods (early clonal, late clonal, and subclonal), and quantified the activity of mutational signatures in each period. Most mutational processes appear to remain remarkably constant, however, certain signatures show clear and consistent changes during clonal evolution. Particularly, mutational signatures associated with exposure to carcinogens, such as smoking and UV light, tend to decrease over time. In contrast, signatures associated with defective endogenous processes, such as APOBEC mutagenesis and defective double strand break repair, show an increase between early and late phases of tumor evolution. Making use of clock-like mutational signatures, we converted mutational time estimates for large events, such as whole genome duplication (WGD), and the emergence of the most recent common ancestor (MRCA), into real time estimates, which allowed us to combine our analyses into overall timelines of cancer evolution, per tumor type. For example, the typical timeline of ovarian adenocarcinoma development shows that early tumor evolution is characterized by mutations in TP53, and widespread genome instability, with WGD events taking place on average 8 years prior to diagnosis. In later stages of evolution, signatures of defective repair processes increase, and the MRCA emerges on average 1 year before diagnosis. Taken together, these data reveal the common and divergent evolutionary trajectories available to a cancer, which might be crucial in understanding specific tumor biology, and in providing new opportunities for early detection and cancer prevention. Citation Format: Clemency Jolly, Moritz Gerstung, Ignaty Leshchiner, Stefan C. Dentro, Santiago Gonzalez, Thomas J. Mitchell, Yulia Rubanova, Pavana Anur, Daniel Rosebrock, Kaixian Yu, Maxime Tarabichi, Amit Deshwar, Jeff Wintersinger, Kortine Kleinheinz, Ignacio Vasquez-Garcia, Kerstin Haase, Subhajit Sengupta, Geoff Macintyre, Salem Malikic, Nilgun Donmez, Dimitri G. Livitz, Mark Cmero, Jonas Demeulemeester, Steve Schumacher, Yu Fan, Xiaotong Yao, Juhee Lee, Matthias Schlesner, Paul C. Boutros, David D. Bowtell, Hongtu Zhu, Gad Getz, Marcin Imielinski, Rameen Beroukhim, S Cenk Sahinalp, Yuan Ji, Martin Peifer, Florian Markowetz, Ville Mustonen, Ke Juan, Wenyi Wang, Quaid D. Morris, Paul T. Spellman, David C. Wedge, Peter Van Loo, PCAWG Evolution and Heterogeneity Working Group. The evolutionary history of 2,658 cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 218.