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 cancerfrequently 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.

Authors	Li, Yilong; Roberts, Nicola D.; Wala, Jeremiah A.; Shapira, Ofer; Schumacher, Steven E.; Kumar, Kiran; Khurana, Ekta; Waszak, Sebastian; Korbel, Jan O.; Haber, James E.; Imielinski, Marcin; Weischenfeldt, Joachim; Beroukhim, Rameen; Campbell, Peter J.; Akdemir, Kadir C.; Alvarez, Eva G.; Baez-Ortega, Adrian; Boutros, Paul C.; Bowtell, David D. L.; Brors, Benedikt; Burns, Kathleen H.; Chan, Kin; Chen, Ken; Cortes-Ciriano, Isidro; Dueso-Barroso, Ana; Dunford, Andrew J.; Edwards, Paul A.; Estivill, Xavier; Etemadmoghadam, Dariush; Feuerbach, Lars; Fink, J. Lynn; Frenkel-Morgenstern, Milana; Garsed, Dale W.; Gerstein, Mark; Gordenin, Dmitry A.; Haan, David; Hess, Julian M.; Hutter, Barbara; Jones, David T. W.; Ju, Young Seok; Kazanov, Marat D.; Klimczak, Leszek J.; Koh, Youngil; Lee, Eunjung Alice; Lee, Jake June-Koo; Lynch, Andy G.; Macintyre, Geoff; Markowetz, Florian; Martincorena, Inigo; Martinez-Fundichely, Alexander; Meyerson, Matthew; Miyano, Satoru; Nakagawa, Hidewaki; Navarro, Fabio C. P.; Ossowski, Stephan; Park, Peter J.; Pearson, John, V; Puiggros, Montserrat; Rippe, Karsten; Roberts, Steven A.; Rodriguez-Martin, Bernardo; Scully, Ralph; Shackleton, Mark; Sidiropoulos, Nikos; Sieverling, Lina; Stewart, Chip; Torrents, David; Tubio, Jose M. C.; Villasante, Izar; Waddell, Nicola; Yang, Lixing; Yao, Xiaotong; Yoon, Sung-Soo; Zamora, Jorge; Zhang, Cheng-Zhong
Journal	NATURE
Pages	112-+
Volume	578
Date	1/02/2020
Grant ID
Funding Body	Wellcome Trust
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038/s41586-019-1913-9