Patterns of somatic structural variation in human cancer genomes
Yilong Li, Nicola D. Roberts, Jeremiah A. Wala, Ofer Shapira, Steven E. Schumacher, Kiran Kumar, Ekta Khurana, Sebastian M. Waszak, Jan O. Korbel, James E. Haber, Marcin Imielinski, PCAWG Structural Variation Working Group, Kadir C. Akdemir, Eva G. Álvarez, Adrian Baez-Ortega, Rameen Beroukhim, Paul C. Boutros, David D.L. Bowtell, Benedikt Brors, Kathleen H. Burns, Peter J. Campbell, Kin Chan, Ken Chen, Isidro Cortés‐Ciriano, Ana Dueso-Barroso, Andrew J. Dunford, Paul A. Edwards, Xavier Estivill, Dariush Etemadmoghadam, Lars Feuerbach, J. Lynn Fink, Milana Frenkel‐Morgenstern, Dale W. Garsed, Mark Gerstein, Dmitry A. Gordenin, David Haan, James E. Haber, Julian M. Hess, Barbara Hutter, Marcin Imieliński, David T. W. Jones, Young Seok Ju, Marat D. Kazanov, Leszek J. Klimczak, Youngil Koh, Jan O. Korbel, Kiran Kumar, Eunjung Alice Lee, Jake June-Koo Lee, Yilong Li, Andy G. Lynch, Geoff Macintyre, Florian Markowetz, Iñigo Martincorena, Alexander Martinez-Fundichely, Matthew Meyerson, Satoru Miyano, Hidewaki Nakagawa, Fábio C. P. Navarro, Stephan Ossowski, Peter J. Park, John V. Pearson, Montserrat Puiggròs, Karsten Rippe, Nicola D. Roberts, Steven A. Roberts, Bernardo Rodriguez-Martin, Steven E. Schumacher, Ralph Scully, Mark Shackleton, Nikos Sidiropoulos, Lina Sieverling, Chip Stewart, David Torrents, José M. C. Tubío, Izar Villasante, Nicola Waddell, Jeremiah A. Wala, Joachim Weischenfeldt, Lixing Yang, Xiaotong Yao, Sung-Soo Yoon, Jorge Zamora, Cheng-Zhong Zhang, Joachim Weischenfeldt, Rameen Beroukhim, Peter J. Campbell, 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
Abstract
Abstract A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes 1–7 . Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types 8 . Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions—as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2–7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and—in liver cancer—frequently activate the telomerase gene TERT . A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.