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Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition

Published version
Peer-reviewed

Change log

Authors

Alvarez, Eva G. 
Baez-Ortega, Adrian 
Zamora, Jorge 
Demeulemeester, Jonas  ORCID logo  https://orcid.org/0000-0002-2660-2478

Abstract

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.

Description

Funder: Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia (Ministry of Culture, Education and University Planning, Government of Galicia); doi: https://doi.org/10.13039/501100008425


Funder: Ministerio de Educación, Cultura y Deporte (Ministry of Education, Culture and Sports, Spain); doi: https://doi.org/10.13039/501100003176


Funder: EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council); doi: https://doi.org/10.13039/100010663


Funder: Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness); doi: https://doi.org/10.13039/501100003329


Funder: Korea Health Industry Development Institute (KHIDI); doi: https://doi.org/10.13039/501100003710


Funder: Danish Medical Research Council


Funder: NIH


Funder: Associazione Italiana Contro le Leucemie-Linfomi e Mieloma


Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289

Keywords

Article, /692/699/67, /631/208/212, /45/23, /45, article

Journal Title

Nature Genetics

Conference Name

Journal ISSN

1061-4036
1546-1718

Volume Title

52

Publisher

Nature Publishing Group US