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Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes
- Authors
- Dentro, S.C.; Leshchiner, I.; Haase, K.; Tarabichi, M.; Wintersinger, J.; Deshwar, A.G.; Yu, K.; Rubanova, Y.; Macintyre, G.; Demeulemeester, J.; Vázquez-García, I.; Kleinheinz, K.; Livitz, D.G.; Malikic, S.; Donmez, N.; Sengupta, S.; Anur, P.; Jolly, C.; Cmero, M.; Rosebrock, D.; Schumacher, S.E.; Fan, Y.; Fittall, M.; Drews, R.M.; Yao, X.; Watkins, T.B.K.; Lee, J.; Schlesner, M.; Zhu, H.; Adams, D.J.; McGranahan, N.; Swanton, C.; Getz, G.; Boutros, P.C.; Imielinski, M.; Beroukhim, R.; Sahinalp, S.C.; Ji, Y.; Peifer, M.; Martincorena, I.; Markowetz, F.; Mustonen, V.; Yuan, K.; Gerstung, M.; Spellman, P.T.; Wang, W.; Morris, Q.D.; Wedge, D.C.; Van, Loo P.; Gonzalez, S.; Bowtell, D.D.; Campbell, P.J.; Cao, S.; Christie, E.L.; Cun, Y.; Dawson, K.J.; Eils, R.; Garsed, D.W.; Ha, G.; Jerman, L.; Lee-Six, H.; Mitchell, T.J.; Oesper, L.; Peto, M.; Raphael, B.J.; Salcedo, A.; Shi, R.; Shin, S.J.; Stein, L.D.; Spiro, O.; Vembu, S.; Wheeler, D.A.; Yang, T.-P.
- Issue Date
- 2021
- Publisher
- Elsevier B.V.
- Keywords
- branching evolution; cancer driver genes; cancer evolution; intra-tumor heterogeneity; pan-cancer genomics; subclonal reconstruction; tumor phylogeny; whole-genome sequencing
- Citation
- Cell, v.184, no.8, pp.2239 - 2254.e39
- Indexed
- SCIE
SCOPUS
- Journal Title
- Cell
- Volume
- 184
- Number
- 8
- Start Page
- 2239
- End Page
- 2254.e39
- ISSN
- 0092-8674
- Abstract
- 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. © 2021 The Author(s)
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