Systematic discovery of germline cancer predisposition genes through the identification of somatic second hits

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• dc.contributor.author Park, Solip
• dc.contributor.author Supek, Fran
• dc.contributor.author Lehner, Ben, 1978-
• dc.date.accessioned 2019-11-25T08:32:08Z
• dc.date.available 2019-11-25T08:32:08Z
• dc.date.issued 2018
• dc.description.abstract The genetic causes of cancer include both somatic mutations and inherited germline variants. Large-scale tumor sequencing has revolutionized the identification of somatic driver alterations but has had limited impact on the identification of cancer predisposition genes (CPGs). Here we present a statistical method, ALFRED, that tests Knudson's two-hit hypothesis to systematically identify CPGs from cancer genome data. Applied to ~10,000 tumor exomes the approach identifies known and putative CPGs - including the chromatin modifier NSD1 - that contribute to cancer through a combination of rare germline variants and somatic loss-of-heterozygosity (LOH). Rare germline variants in these genes contribute substantially to cancer risk, including to ~14% of ovarian carcinomas, ~7% of breast tumors, ~4% of uterine corpus endometrial carcinomas, and to a median of 2% of tumors across 17 cancer types.
• dc.description.sponsorship This work was supported by a European Research Council (ERC) Consolidator grant (616434), the AXA Research Fund, the Spanish Ministry of Economy and Competitiveness (BFU2011-26206 and ‘Centro de Excelencia Severo Ochoa 2013–2017’ SEV-2012-0208), the Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR), FP7 project 4DCellFate (277899), the EMBL-CRG Systems Biology Program and the CERCA Programme of the Generalitat de Catalunya. F.S. was also supported by FP7 grants MAESTRA (ICT-2013-612944) and InnoMol (FP7-REGPOT-2012-2013-1-316289). S.P. was funded by a Postdoctoral Fellowship from Novartis and by the Juan de la Cierva program (MINECO). The results published in this study are in part based upon data generated by The Cancer Genome Atlas project established by the NCI and NHGRI. Information about TCGA and the investigators and institutions who constitute the TCGA research network can be found at https://cancergenome.nih.gov/. We also acknowledge the 1000 genomes project, the Women’s Health Initiative, and UK10K as the sources of primary data.
• dc.format.mimetype application/pdf
• dc.identifier.citation Park S, Supek F, Lehner B. Systematic discovery of germline cancer predisposition genes through the identification of somatic second hits. Nat Commun. 2018;9(1):2601. DOI: 10.1038/s41467-018-04900-7
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-018-04900-7
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/42952
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nature Communications. 2018;9(1):2601
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/616434
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2011-26206
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/277899
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/612944
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/316289
• dc.rights © The Author(s) 2018. 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Cancer genetics
• dc.subject.keyword Cancer genomics
• dc.subject.keyword Computational biology and bioinformatics
• dc.subject.keyword Medical genetics
• dc.title Systematic discovery of germline cancer predisposition genes through the identification of somatic second hits
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion