Higher order genetic interactions switch cancer genes from two-hit to one-hit drivers

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  • dc.contributor.author Park, Solip
  • dc.contributor.author Supek, Fran
  • dc.contributor.author Lehner, Ben, 1978-
  • dc.date.accessioned 2022-03-25T07:06:12Z
  • dc.date.available 2022-03-25T07:06:12Z
  • dc.date.issued 2021
  • dc.description.abstract The classic two-hit model posits that both alleles of a tumor suppressor gene (TSG) must be inactivated to cause cancer. In contrast, for some oncogenes and haploinsufficient TSGs, a single genetic alteration can suffice to increase tumor fitness. Here, by quantifying the interactions between mutations and copy number alterations (CNAs) across 10,000 tumors, we show that many cancer genes actually switch between acting as one-hit or two-hit drivers. Third order genetic interactions identify the causes of some of these switches in dominance and dosage sensitivity as mutations in other genes in the same biological pathway. The correct genetic model for a gene thus depends on the other mutations in a genome, with a second hit in the same gene or an alteration in a different gene in the same pathway sometimes representing alternative evolutionary paths to cancer.
  • dc.description.sponsorship This work was funded by the European Research Council (ERC) Starting grant (HYPER-INSIGHT, 757700) to F.S. and ERC Consolidator (IR-DC, 616434) and Advanced (MUTANOMICS, 883742) grants to B.L. F.S. and B.L. are funded by the ICREA Research Professor program. S.P., F.S., and B.L. acknowledge the support of the Severo Ochoa Centres of Excellence program to the CNIO, IRB Barcelona, and to the CRG (MCIN/AEI/10.13039/50110001103), respectively. B.L. and F.S. Work is funded with the grants BFU2017-89488-P and RegioMut BFU2017-89833-P (MCIN/AEI /10.13039/501100011033/FEDER “A way to make Europe”), respectively. B.L. is further supported by the Bettencourt Schueller Foundation, the Agencia de Gestio d’Ajuts Universitaris i de Recerca (2017 SGR 1322), and the Centres de Recerca de Catalunya (CERCA) program/Generalitat de Catalunya. B.L. also acknowledges the support of the Spanish Ministry of Economy, Industry, and Competitiveness to the European Molecular Biology Laboratory (EMBL) partnership. The results shown here are in whole or part based upon data generated by the TCGA Research Network.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Park S, Supek F, Lehner B. Higher order genetic interactions switch cancer genes from two-hit to one-hit drivers. Nat Commun. 2021 Dec 3;12(1):7051. DOI: 10.1038/s41467-021-27242-3
  • dc.identifier.doi http://dx.doi.org/10.1038/s41467-021-27242-3
  • dc.identifier.issn 2041-1723
  • dc.identifier.uri http://hdl.handle.net/10230/52774
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nat Commun. 2021 Dec 3;12(1):7051
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/757700
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-109571RA-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/616434
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/883742
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-89488-P
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-89833-P
  • dc.rights © The Author(s) 2021. 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 Genetics
  • dc.title Higher order genetic interactions switch cancer genes from two-hit to one-hit drivers
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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