The repertoire of mutational signatures in human cancer
Ludmil B. Alexandrov, Jaegil Kim, Nicholas J. Haradhvala, Mi Ni Huang, Alvin Wei Tian Ng, Yang Wu, Arnoud Boot, Kyle R. Covington, Dmitry A. Gordenin, Erik N. Bergstrom, S. M. Ashiqul Islam, Núria López-Bigas, Leszek J. Klimczak, John R. McPherson, Sandro Morganella, Radhakrishnan Sabarinathan, David A. Wheeler, Ville Mustonen, PCAWG Mutational Signatures Working Group, Ludmil B. Alexandrov, Erik N. Bergstrom, Arnoud Boot, Paul C. Boutros, Kin Chan, Kyle R. Covington, Akihiro Fujimoto, Gad Getz, Dmitry A. Gordenin, Nicholas J. Haradhvala, Mi Ni Huang, S. M. Ashiqul Islam, Marat D. Kazanov, Jaegil Kim, Leszek J. Klimczak, Núria López-Bigas, Michael S. Lawrence, Iñigo Martincorena, John R. McPherson, Sandro Morganella, Ville Mustonen, Hidewaki Nakagawa, Alvin Wei Tian Ng, Paz Polak, Stephenie D. Prokopec, Steven A. Roberts, Steve Rozen, Radhakrishnan Sabarinathan, Natalie Saini, Tatsuhiro Shibata, Yuichi Shiraishi, Michael R. Stratton, Bin Tean Teh, Ignacio Vázquez-Garćıa, David A. Wheeler, Yang Wu, Fouad Yousif, Willie Yu, Gad Getz, Steven G. Rozen, Michael R. Stratton, Lauri A. Aaltonen, Federico Abascal, Adam Abeshouse, Hiroyuki Aburatani, David J. Adams, Nishant Agrawal, Keun Soo Ahn, Sung‐Min Ahn, Hiroshi Aikata, Rehan Akbani, Kadir C. Akdemir, Hikmat Al‐Ahmadie, Sultan T. Al‐Sedairy, Fátima Al‐Shahrour, Malik Alawi, Monique Albert, Kenneth Aldape, Ludmil B. Alexandrov, Adrian Ally, Kathryn Alsop, Eva G. Álvarez, Fernanda Amary, Samirkumar B. Amin, Brice Aminou, Ole Ammerpohl, Matthew J. Anderson, Yeng Ang, Davide Antonello, Pavana Anur, Samuel Aparício, Elizabeth L. Appelbaum, Yasuhito Arai, Axel Aretz, Koji Arihiro, Shun‐ichi Ariizumi, Joshua Armenia, Laurent Arnould, L. Sylvia, Yassen Assenov, Gurnit Atwal
Abstract
Abstract Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1 . Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses 3–15 , enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated—but distinct—DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.