s41586-020-1943-3.pdf (6.74 MB)
The repertoire of mutational signatures in human cancer
journal contribution
posted on 2024-01-29, 11:32 authored by 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, SM Ashiqul Islam, Nuria Lopez-Bigas, Leszek J Klimczak, John R McPherson, Sandro Morganella, Radhakrishnan Sabarinathan, David A Wheeler, Ville Mustonen, Paul Boutros, Kin Chan, Akihiro Fujimoto, Gad Getz, Marat Kazanov, Michael Lawrence, Iñigo Martincorena, Hidewaki Nakagawa, Paz Polak, Stephenie Prokopec, Steven A Roberts, Steven G Rozen, Natalie Saini, Tatsuhiro Shibata, Yuichi Shiraishi, Michael R Stratton, Bin Tean Teh, Ignacio Vázquez-García, Fouad Yousif, Willie Yu, 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, Fatima Al-Shahrour, Malik Alawi, Monique Albert, Kenneth Aldape, Adrian Ally, Kathryn Alsop, Eva G Alvarez, Fernanda Amary, Samirkumar B Amin, Brice Aminou, Ole Ammerpohl, Matthew J Anderson, Yeng Ang, Davide Antonello, Pavana Anur, Samuel Aparicio, Elizabeth L Appelbaum, Yasuhito Arai, Axel Aretz, Koji Arihiro, Shun-ichi Ariizumi, Joshua Armenia, Laurent Arnould, Sylvia Asa, Yassen Assenov, Gurnit Atwal, Sietse Aukema, J Todd Auman, Miriam RR Aure, Philip Awadalla, Marta Aymerich, Gary D Bader, Adrian Baez-Ortega, Matthew H Bailey, Peter J Bailey, Miruna Balasundaram, Saianand Balu, Pratiti Bandopadhayay, Rosamonde E Banks, Stefano Barbi, Andrew P Barbour, Jonathan Barenboim, Jill Barnholtz-Sloan, Hugh Barr, Elisabet Barrera, John Bartlett, Javier Bartolome, Claudio Bassi, Oliver F Bathe, Daniel Baumhoer, Prashant Bavi, Stephen B Baylin, Wojciech Bazant, Duncan Beardsmore, Timothy A Beck, Sam Behjati, Andreas Behren, Beifang Niu, Cindy Bell, Sergi Beltran, Christopher Benz, Andrew Berchuck, Anke K Bergmann, Benjamin P Berman, Daniel M Berney, Stephan H Bernhart, Rameen Beroukhim, Mario Berrios, Samantha Bersani, Johanna Bertl, Miguel Betancourt, Vinayak Bhandari, Shriram G Bhosle, Andrew V Biankin, Matthias Bieg, Darell Bigner, Hans Binder, Ewan Birney, Michael Birrer, Nidhan K Biswas, Bodil Bjerkehagen, Tom Bodenheimer, Lori Boice, Giada Bonizzato, Johann S De Bono, Moiz S Bootwalla, Ake Borg, Arndt Borkhardt, Keith A Boroevich, Ivan Borozan, Christoph Borst, Marcus Bosenberg, Mattia Bosio, Jacqueline Boultwood, Guillaume Bourque, Paul C Boutros, G Steven Bova, David T Bowen, Reanne Bowlby, David DL Bowtell, Sandrine Boyault, Rich Boyce, Jeffrey Boyd, Alvis Brazma, Paul Brennan, Daniel S Brewer, Arie B Brinkman, Robert G Bristow, Russell R Broaddus, Jane E Brock, Malcolm Brock, Annegien Broeks, Angela N Brooks, Denise Brooks, Benedikt Brors, Søren Brunak, Timothy JC Bruxner, Alicia L Bruzos, Alex Buchanan, Ivo Buchhalter, Christiane Buchholz, Susan Bullman, Hazel Burke, Birgit Burkhardt, Kathleen H Burns, John Busanovich, Carlos D Bustamante, Adam P Butler, Atul J Butte, Niall J Byrne, Anne-Lise Børresen-Dale, Samantha J Caesar-Johnson, Andy Cafferkey, Declan Cahill, Claudia Calabrese, Carlos Caldas, Fabien Calvo, Niedzica Camacho, Peter J Campbell, Elias Campo, Cinzia Cantù, Shaolong Cao, Thomas E Carey, Joana Carlevaro-Fita, Rebecca Carlsen, Ivana Cataldo, Mario Cazzola, Jonathan Cebon, Robert Cerfolio, Dianne E Chadwick, Dimple Chakravarty, Don Chalmers, Calvin Wing Yiu Chan, Michelle Chan-Seng-Yue, Vishal S Chandan, David K Chang, Stephen J Chanock, Lorraine A Chantrill, Aurélien Chateigner, Nilanjan Chatterjee, Kazuaki Chayama, Hsiao-Wei Chen, Jieming Chen, Ken Chen, Yiwen Chen, Zhaohong Chen, Andrew D Cherniack, Jeremy Chien, Yoke-Eng Chiew, Suet-Feung Chin, Juok Cho, Sunghoon Cho, Jung Kyoon Choi, Wan Choi, Christine Chomienne, Zechen Chong, Su Pin Choo, Angela Chou, Angelika N Christ, Elizabeth L Christie, Eric Chuah, Carrie Cibulskis, Kristian Cibulskis, Sara Cingarlini, Peter Clapham, Alexander Claviez, Sean Cleary, Nicole Cloonan, Marek Cmero, Colin C Collins, Ashton A Connor, Susanna L Cooke, Colin S Cooper, Leslie Cope, Vincenzo Corbo, Matthew G Cordes, Stephen M Cordner, Isidro Cortés-Ciriano, Kyle Covington, Prue A Cowin, Brian Craft, David Craft, Chad J Creighton, Yupeng Cun, Erin Curley, Ioana Cutcutache, Karolina Czajka, Bogdan Czerniak, Rebecca A Dagg, Ludmila Danilova, Maria Vittoria Davi, Natalie R Davidson, Helen Davies, Ian J Davis, Brandi N Davis-Dusenbery, Kevin J Dawson, Francisco M De La Vega, Ricardo De Paoli-Iseppi, Timothy Defreitas, Angelo P Dei Tos, Olivier Delaneau, John A Demchok, Jonas Demeulemeester, German M Demidov, Deniz Demircioğlu, Nening M Dennis, Robert E Denroche, Stefan C Dentro, Nikita Desai, Vikram Deshpande, Amit G Deshwar, Christine Desmedt, Jordi Deu-Pons, Noreen Dhalla, Neesha C Dhani, Priyanka Dhingra, Rajiv Dhir, Anthony DiBiase, Klev Diamanti, Li Ding, Shuai Ding, Huy Q Dinh, Luc Dirix, HarshaVardhan Doddapaneni, Nilgun Donmez, Michelle T Dow, Ronny Drapkin, Oliver Drechsel, Ruben M Drews, Serge Serge, Tim Dudderidge, Ana Dueso-Barroso, Andrew J Dunford, Michael Dunn, Lewis Jonathan Dursi, Fraser R Duthie, Ken Dutton-Regester, Jenna Eagles, Douglas F Easton, Stuart Edmonds, Paul A Edwards, Sandra E Edwards, Rosalind A Eeles, Anna Ehinger, Juergen Eils, Roland Eils, Adel El-Naggar, Matthew Eldridge, Kyle Ellrott, Serap Erkek, Georgia Escaramis, Shadrielle MG Espiritu, Xavier Estivill, Dariush Etemadmoghadam, Jorunn E Eyfjord, Bishoy M Faltas, Daiming Fan, Yu Fan, William C Faquin, Claudiu Farcas, Matteo Fassan, Aquila Fatima, Francesco Favero, Nodirjon Fayzullaev, Ina Felau, Sian Fereday, Martin L Ferguson, Vincent Ferretti, Lars Feuerbach, Matthew A Field, J Lynn Fink, Gaetano Finocchiaro, Cyril Fisher, Matthew W Fittall, Anna Fitzgerald, Rebecca C Fitzgerald, Adrienne M Flanagan, Neil E Fleshner, Paul Flicek, John A Foekens, Kwun M Fong, Nuno A Fonseca, Christopher S Foster, Natalie S Fox, Michael Fraser, Scott Frazer, Milana Frenkel-Morgenstern, William Friedman, Joan Frigola, Catrina C Fronick, Masashi Fujita, Masashi Fukayama, Lucinda A Fulton, Robert S Fulton, Mayuko Furuta, P Andrew Futreal, Anja Füllgrabe, Stacey B Gabriel, Steven Gallinger, Carlo Gambacorti-Passerini, Jianjiong Gao, Shengjie Gao, Levi Garraway, Øystein Garred, Erik Garrison, Dale W Garsed, Nils Gehlenborg, Josep LL Gelpi, Joshy George, Daniela S Gerhard, Clarissa Gerhauser, Jeffrey E Gershenwald, Mark Gerstein, Moritz Gerstung, Mohammed Ghori, Ronald Ghossein, Nasra H Giama, Richard A Gibbs, Bob Gibson, Anthony J Gill, Pelvender Gill, Dilip D Giri, Dominik Glodzik, Vincent J Gnanapragasam, Maria Elisabeth Goebler, Mary J Goldman, Carmen Gomez, Santiago Gonzalez, Abel Gonzalez-Perez, James Gossage, Kunihito Gotoh, Ramaswamy Govindan, Dorthe Grabau, Janet S Graham, Robert C Grant, Anthony R Green, Eric Green, Liliana Greger, Nicola Grehan, Sonia Grimaldi, Sean M Grimmond, Robert L Grossman, Adam Grundhoff, Gunes Gundem, Qianyun Guo, Manaswi Gupta, Shailja Gupta, Ivo G Gut, Marta Gut, Jonathan Göke, Gavin Ha, Andrea Haake, David Haan, Siegfried Haas, Kerstin Haase, James E Haber, Nina Habermann, Faraz Hach, Syed Haider, Natsuko Hama, Freddie C Hamdy, Anne Hamilton, Mark P Hamilton, Leng Han, George B Hanna, Martin Hansmann, Olivier Harismendy, Ivon Harliwong, Arif O Harmanci, Eoghan Harrington, Takanori Hasegawa, David Haussler, Steve Hawkins, Shinya Hayami, Shuto Hayashi, D Neil Hayes, Stephen J Hayes, Nicholas K Hayward, Steven Hazell, Yao He, Allison P Heath, Simon C Heath, David Hedley, Apurva M Hegde, David I Heiman, Michael C Heinold, Zachary Heins, Lawrence E Heisler, Eva Hellstrom-Lindberg, Mohamed Helmy, Seong Gu Heo, Austin J Hepperla, José María Heredia-Genestar, Carl Herrmann, Peter Hersey, Julian M Hess, Holmfridur Hilmarsdottir, Jonathan Hinton, Satoshi Hirano, Nobuyoshi Hiraoka, Katherine A Hoadley, Asger Hobolth, Ermin Hodzic, Jessica I Hoell, Steve Hoffmann, Oliver Hofmann, Andrea Holbrook, Aliaksei Z Holik, Michael A Hollingsworth, Oliver Holmes, Robert A Holt, Chen Hong, Eun Pyo Hong, Jongwhi H Hong, Gerrit K Hooijer, Henrik Hornshøj, Fumie Hosoda, Yong Hou, Volker Hovestadt, William Howat, Alan P Hoyle, Ralph H Hruban, Jianhong Hu, Taobo Hu, Xing Hua, Kuan-lin Huang, Mei Huang, Vincent Huang, Yi HuangSomatic 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.
