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

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  • dc.contributor.author Rodríguez Martín, Bernardo
  • dc.contributor.author PCAWG Structural Variation Working Group
  • dc.contributor.author PCAWG Consortium
  • dc.contributor.author Ossowski, Stephan
  • dc.date.accessioned 2020-04-27T10:21:38Z
  • dc.date.available 2020-04-27T10:21:38Z
  • dc.date.issued 2020
  • dc.description.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.
  • dc.description.sponsorship J.M.C.T. is supported by European Research Council (ERC) Starting Grant 716290 ‘SCUBA CANCERS’, Ramon y Cajal grant RYC-2014-14999 and Spanish Ministry of Economy, Industry and Competitiveness (MINECO) grant SAF2015-66368-P. B.R.-M., E.G.A., M.S.G. and S.Z. are supported by PhD fellowships from Xunta de Galicia (Spain) ED481A-2016/151, ED481A-2017/299, ED481A-2017/306 and ED481A-2018/199, respectively. F.S. was supported by ERC Starting Grant 757700 ‘HYPER-INSIGHT’, MINECO grant BFU2017-89833-P ‘RegioMut’, and further acknowledges institutional funding from the MINECO Severo Ochoa award and from the CERCA Programme of the Catalan Government. Y.S.J. was supported by Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number HI16C2387). A.L.B. is supported by MINECO PhD fellowship BES-2016-078166. M.T. was supported by MINECO grant SAF2015-73916-JIN. R.B. received funding through the National Institutes of Health (U24CA210978 and R01CA188228). M.G.B. received funding through MINECO, AEI, Xunta de Galicia and FEDER (BFU2013-41554-P, BFU2016-78121-P, ED431F 2016/019). N.B. is supported by a My First AIRC grant from the Associazione Italiana Ricerca sul Cancro (number 17658). J.D. is a postdoctoral fellow of the Research Foundation Flanders (FWO) and the European Union’s Horizon 2020 research and innovation program (Marie Skłodowska-Curie grant agreement number 703594-DECODE). K.C. and Z.C. are supported by NIH R01 CA172652 and U41 HG007497. Z.C. is supported by an American Heart Association Institutional Data Fellowship Award (17IF33890015). P.A.W.E. is supported by Cancer Research UK. E.A.L. is supported by K01AG051791. I.M. is supported by Cancer Research UK (C57387/A21777). S.M.W. received funding through a SNSF Early Postdoc Mobility fellowship (P2ELP3_155365) and an EMBO Long-Term Fellowship (ALTF 755-2014). J.W. received funding from the Danish Medical Research Council (DFF-4183-00233). J.O.K. is supported by an ERC Starting Grant. This work is supported by The Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202) and the Wellcome Trust (FC001202). H.H.K. is supported by grants from the National Institute of General Medical Sciences (P50GM107632 and 1R01GM099875). K.H.B. is supported by P50GM107632, R01CA163705 and R01GM124531. This work was supported by the TransTumVar project PN013600.. This work was supported by the Wellcome Trust grant 09805
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Rodriguez-Martin B, Alvarez EG, Baez-Ortega A, Zamora J, Supek F, Demeulemeester J et al. Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition. Nat Genet. 2020 Mar; 52(3): 306-319. DOI: 10.1038/s41588-019-0562-0
  • dc.identifier.doi http://dx.doi.org/10.1038/s41588-019-0562-0
  • dc.identifier.issn 1061-4036
  • dc.identifier.uri http://hdl.handle.net/10230/44340
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nature Genetics. 2020 Mar;52(3):306-19
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/703594
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/716290
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/757700
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-66368-P
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2013-41554-P
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016-78121-P
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-73916-JIN
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BES2016-078166
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-89833-P
  • dc.rights © 2020 Bernardo Rodriguez-Martin et al. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.other Carcinogènesi
  • dc.subject.other Reordenament genètic
  • dc.subject.other Genoma humà
  • dc.subject.other Tumors
  • dc.subject.other Genètica
  • dc.title Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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