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Pan-cancer analysis of whole genomes
Nature. 2020 Feb;578(7793) :82-93
PMID: 32025007    PMCID: PMC7025898    URL: https://www.ncbi.nlm.nih.gov/pubmed/32025007
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Abstract
Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).
Notes
Campbell, Peter J. Getz, Gad Korbel, Jan O. Stuart, Joshua M. Jennings, Jennifer L. Stein, Lincoln D. Perry, Marc D. Nahal-Bose, Hardeep K. Ouellette, B. F. Francis Li, Constance H. Rheinbay, Esther Nielsen, G. Petur Sgroi, Dennis C. Wu, Chin-Lee Faquin, William C. Deshpande, Vikram Boutros, Paul C. Lazar, Alexander J. Hoadley, Katherine A. Louis, David N. Dursi, L. Jonathan Yung, Christina K. Bailey, Matthew H. Saksena, Gordon Raine, Keiran M. Buchhalter, Ivo Kleinheinz, Kortine Schlesner, Matthias Zhang, Junjun Wang, Wenyi Wheeler, David A. Ding, Li Simpson, Jared T. O'Connor, Brian D. Yakneen, Sergei Ellrott, Kyle Miyoshi, Naoki Butler, Adam P. Royo, Romina Shorser, Solomon, I Vazquez, Miguel Rausch, Tobias Tiao, Grace Waszak, Sebastian M. Rodriguez-Martin, Bernardo Shringarpure, Suyash Wu, Dai-Ying Demidov, German M. Delaneau, Olivier Hayashi, Shuto Imoto, Seiya Habermann, Nina Segre, Ayellet, V Garrison, Erik Cafferkey, Andy Alvarez, Eva G. Maria Heredia-Genestar, Jose Muyas, Francesc Drechsel, Oliver Bruzos, Alicia L. Temes, Javier Zamora, Jorge Baez-Ortega, Adrian Kim, Hyung-Lae Mashl, R. Jay Ye, Kai DiBiase, Anthony Huang, Kuan-lin Letunic, Ivica McLellan, Michael D. Newhouse, Steven J. Shmaya, Tal Kumar, Sushant Wedge, David C. Wright, Mark H. Yellapantula, Venkata D. Gerstein, Mark Khurana, Ekta Marques-Bonet, Tomas Navarro, Arcadi Bustamante, Carlos D. Siebert, Reiner Nakagawa, Hidewaki Easton, Douglas F. Ossowski, Stephan Tubio, Jose M. C. De La Vega, Francisco M. Estivill, Xavier Yuen, Denis Mihaiescu, George L. Omberg, Larsson Ferretti, Vincent Sabarinathan, Radhakrishnan Pich, Oriol Gonzalez-Perez, Abel Weiner, Amaro Taylor Fittall, Matthew W. Demeulemeester, Jonas Tarabichi, Maxime Roberts, Nicola D. Van Loo, Peter Cortes-Ciriano, Isidro Urban, Lara Park, Peter Bin Zhu Pitkaenen, Esa Li, Yilong Saini, Natalie Klimczak, Leszek J. Weischenfeldt, Joachim Sidiropoulos, Nikos Alexandrov, Ludmil B. Rabionet, Raquel Escaramis, Georgia Bosio, Mattia Holik, Aliaksei Z. Susak, Hana Prasad, Aparna Erkek, Serap Calabrese, Claudia Raeder, Benjamin Harrington, Eoghan Mayes, Simon Turner, Daniel Juul, Sissel Roberts, Steven A. Song, Lei Koster, Roelof Mirabello, Lisa Hua, Xing Tanskanen, Tomas J. Tojo, Marta Chen, Jieming Aaltonen, Lauri A. Ratsch, Gunnar Schwarz, Roland F. Butte, Atul J. Brazma, Alvis Chanock, Stephen J. Chatterjee, Nilanjan Stegle, Oliver Harismendy, Olivier Bova, G. Steven Gordenin, Dmitry A. Haan, David Sieverling, Lina Feuerbach, Lars Chalmers, Don Joly, Yann Knoppers, Bartha Molnar-Gabor, Fruzsina Phillips, Mark Thorogood, Adrian Townend, David Goldman, Mary Fonseca, Nuno A. Xiang, Qian Craft, Brian Pineiro-Yanez, Elena Munoz, Alfonso Petryszak, Robert Fullgrabe, Anja Al-Shahrour, Fatima Keays, Maria Haussler, David Weinstein, John Huber, Wolfgang Valencia, Alfonso Papatheodorou, Irene Zhu, Jingchun Fan, Yu Torrents, David Bieg, Matthias Chen, Ken Chong, Zechen Cibulskis, Kristian Eils, Roland Fulton, Robert S. Gelpi, Josep L. Gonzalez, Santiago Gut, Ivo G. Hach, Faraz Heinold, Michael Hu, Taobo Huang, Vincent Hutter, Barbara Jaeger, Natalie Jung, Jongsun Kumar, Yogesh Lalansingh, Christopher Leshchiner, Ignaty Livitz, Dimitri Ma, Eric Z. Maruvka, Yosef E. Milovanovic, Ana Nielsen, Morten Muhlig Paramasivam, Nagarajan Pedersen, Jakob Skou Puiggros, Montserrat Sahinalp, S. Cenk Sarrafi, Iman Stewart, Chip Stobbe, Miranda D. Wala, Jeremiah A. Wang, Jiayin Wendl, Michael Werner, Johannes Wu, Zhenggang Xue, Hong Yamaguchi, Takafumi N. Yellapantula, Venkata Davis-Dusenbery, Brandi N. Grossman, Robert L. Kim, Youngwook Heinold, Michael C. Hinton, Jonathan Jones, David R. Menzies, Andrew Stebbings, Lucy Hess, Julian M. Rosenberg, Mara Dunford, Andrew J. Gupta, Manaswi Imielinski, Marcin Meyerson, Matthew Beroukhim, Rameen Reimand, Juri Dhingra, Priyanka Favero, Francesco Dentro, Stefan Wintersinger, Jeff Rudneva, Vasilisa Park, Ji Wan Hong, Eun Pyo Heo, Seong Gu Kahles, Andre Kjong-Van Lehmann Soulette, Cameron M. Shiraishi, Yuichi Liu, Fenglin He, Yao Demircioglu, Deniz Davidson, Natalie R. Greger, Liliana Li, Siliang Liu, Dongbing Stark, Stefan G. Zhang, Fan Amin, Samirkumar B. Bailey, Peter Chateigner, Aurelien Frenkel-Morgenstern, Milana Hou, Yong Huska, Matthew R. Kilpinen, Helena Lamaze, Fabien C. Li, Chang Li, Xiaobo Li, Xinyue Liu, Xingmin Marin, Maximillian G. Markowski, Julia Nandi, Tannistha Ojesina, Akinyemi, I Pan-Hammarstrom, Qiang Park, Peter J. 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Wong, Wing Hing/0000-0003-2494-1721; Mustonen, Ville/0000-0002-7270-1792; Borozan, Ivan/0000-0002-3145-3550; Dutton-Regester, Ken/0000-0002-8884-6355; Kahraman, Abdullah/0000-0003-3523-4467; Rubio-Perez, Carlota/0000-0002-1921-168X; Schlomm, Thorsten/0000-0001-9557-4653; Underwood, Tim/0000-0001-9455-2188; Turkington, Richard/0000-0003-3164-1890; Jakrot, Valerie/0000-0002-8578-5964; Chen, Ken/0000-0003-4013-5279; Wang, Wenyi/0000-0003-0617-9438; Rooman, Ilse/0000-0001-7264-2246; Buchhalter, Ivo/0000-0003-0764-5832; Saito-Adachi, Mihoko/0000-0001-9213-0184; Newhouse, Steven/0000-0003-1531-5198 1476-4687