Nonhypermutator cancers access driver mutations through reversals in germline mutational bias

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• dc.contributor.author Tuffaha, Marwa Z.
• dc.contributor.author Castellano Esteve, David
• dc.contributor.author Serrano Colomé, Clàudia
• dc.contributor.author Gutenkunst, Ryan N.
• dc.contributor.author Wahl, Lindi M.
• dc.date.accessioned 2025-09-09T06:02:52Z
• dc.date.available 2025-09-09T06:02:52Z
• dc.date.issued 2025
• dc.description.abstract Cancer is an evolutionary disease driven by mutations in asexually reproducing somatic cells. In asexual microbes, bias reversals in the mutation spectrum can speed adaptation by increasing access to previously undersampled beneficial mutations. By analyzing tumors from 20 tissues, along with normal tissue and the germline, we demonstrate this effect in cancer. Nonhypermutated tumors reverse the germline mutation bias and have consistent spectra across tissues. These spectra changes carry the signature of hypoxia, and they facilitate positive selection in cancer genes. Hypermutated and nonhypermutated tumors thus acquire driver mutations differently: hypermutated tumors by higher mutation rates and nonhypermutated tumors by changing the mutation spectrum to reverse the germline mutation bias.
• dc.description.sponsorship This work was supported by the Natural Sciences and Engineering Research Council of Canada grant RGPIN-2019-06294, by the National Institute of General Medical Sciences of the National Institutes of Health through grants R01GM127348 and R35GM149235, and by the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049-S, MCIN/AEI /10.13039/501100011033), the Generalitat de Catalunya through the CERCA programme, and the European Union’s H2020 research and innovation program under Marie Sklodowska-Curie grant agreement No.754422.
• dc.format.mimetype application/pdf
• dc.identifier.citation Tuffaha MZ, Castellano D, Colomé CS, Gutenkunst RN, Wahl LM. Nonhypermutator cancers access driver mutations through reversals in germline mutational bias. Mol Biol Evol. 2025 Apr 30;42(5):msaf105. DOI: 10.1093/molbev/msaf105
• dc.identifier.doi http://dx.doi.org/10.1093/molbev/msaf105
• dc.identifier.issn 0737-4038
• dc.identifier.uri http://hdl.handle.net/10230/71158
• dc.language.iso eng
• dc.publisher Oxford University Press
• dc.relation.ispartof Mol Biol Evol. 2025 Apr 30;42(5):msaf105
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/754422
• dc.rights © The Author(s) 2025. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
• dc.subject.keyword Cancer
• dc.subject.keyword Hypermutator
• dc.subject.keyword Hypoxia
• dc.subject.keyword Mutation bias
• dc.subject.keyword Mutation spectrum
• dc.subject.keyword Positive selection
• dc.title Nonhypermutator cancers access driver mutations through reversals in germline mutational bias
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion