The impact of rare germline variants on human somatic mutation processes

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  • dc.contributor.author Vali-Pour, Mischan
  • dc.contributor.author Lehner, Ben, 1978-
  • dc.contributor.author Supek, Fran
  • dc.date.accessioned 2022-11-07T07:30:19Z
  • dc.date.available 2022-11-07T07:30:19Z
  • dc.date.issued 2022
  • dc.description.abstract Somatic mutations are an inevitable component of ageing and the most important cause of cancer. The rates and types of somatic mutation vary across individuals, but relatively few inherited influences on mutation processes are known. We perform a gene-based rare variant association study with diverse mutational processes, using human cancer genomes from over 11,000 individuals of European ancestry. By combining burden and variance tests, we identify 207 associations involving 15 somatic mutational phenotypes and 42 genes that replicated in an independent data set at a false discovery rate of 1%. We associate rare inherited deleterious variants in genes such as MSH3, EXO1, SETD2, and MTOR with two phenotypically different forms of DNA mismatch repair deficiency, and variants in genes such as EXO1, PAXIP1, RIF1, and WRN with deficiency in homologous recombination repair. In addition, we identify associations with other mutational processes, such as APEX1 with APOBEC-signature mutagenesis. Many of the genes interact with each other and with known mutator genes within cellular sub-networks. Considered collectively, damaging variants in the identified genes are prevalent in the population. We suggest that rare germline variation in diverse genes commonly impacts mutational processes in somatic cells.
  • dc.description.sponsorship M.V.P. was supported by a Spanish Ministry of Science and Innovation FPI Fellowship (ref.: PRE2018-084410). Work in the lab of B.L. is funded by European Research Council (ERC) Advanced (883742) and Consolidator (616434) grants, the Spanish Ministry of Science and Innovation (BFU2017-89488-P, EMBL Partnership, Severo Ochoa Centre of Excellence), the Bettencourt Schueller Foundation, the AXA Research Fund, Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR, 2017 SGR 1322), and the CERCA Program/Generalitat de Catalunya. Work in the lab of F.S. is funded by the ERC Starting Grant HYPER-INSIGHT (757700), the Horizon2020 RIA grant DECIDER (965193), Spanish Ministry of Science and Innovation grant REPAIRSCAPE (PID2020-118795GB-I00), the EMBO YIP program, the Severo Ochoa Centre of Excellence award to IRB Barcelona, and the CERCA Program/Generalitat de Catalunya. We thank Solip Park for method consultations, comments, and discussions.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Vali-Pour M, Lehner B, Supek F. The impact of rare germline variants on human somatic mutation processes. Nat Commun. 2022 Jun 28;13(1):3724. DOI: 10.1038/s41467-022-31483-1
  • dc.identifier.doi http://dx.doi.org/10.1038/s41467-022-31483-1
  • dc.identifier.issn 2041-1723
  • dc.identifier.uri http://hdl.handle.net/10230/54718
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nat Commun. 2022 Jun 28;13(1):3724
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/883742
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/616434
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-89488-P
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/757700
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/965193
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-118795GB-I00
  • dc.rights © The Author(s) 2022. 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 Rare variants
  • dc.title The impact of rare germline variants on human somatic mutation processes
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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