Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition
Bernardo Rodríguez–Martín, Eva G. Alvarez, Adrian Baez‐Ortega, Jorge Zamora, Fran Supek, Jonas Demeulemeester, Martín Santamarina, Young Seok Ju, Javier Temes, Daniel García‐Souto, Harald Detering, Yilong Li, Jorge Rodríguez‐Castro, Ana Dueso-Barroso, Alicia L. Bruzos, Stefan C. Dentro, Miguel G. Blanco, Gianmarco Contino, Daniel Ardeljan, Marta Tojo, Nicola D. Roberts, Sonia Zumalave, Paul A. Edwards, Joachim Weischenfeldt, Montserrat Puiggròs, Zechen Chong, Ken Chen, Eunjung Alice Lee, Jeremiah A. Wala, Keiran M. Raine, Adam P. Butler, Sebastian M. Waszak, Fábio C. P. Navarro, Steven E. Schumacher, Jean Monlong, Francesco Maura, Niccolò Bolli, Guillaume Bourque, Mark Gerstein, Peter J. Park, David C. Wedge, Rameen Beroukhim, David Torrents, Jan O. Korbel, Iñigo Martincorena, Rebecca C. Fitzgerald, Peter Van Loo, Haig H. Kazazian, Kathleen H. Burns, PCAWG Structural Variation Working Group, Kadir C. Akdemir, Eva G. Alvarez, 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 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 Imielinski, David 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
Abstract
About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.