Tuffaha, Marwa Z.Castellano Esteve, DavidSerrano Colomé, ClàudiaGutenkunst, Ryan N.Wahl, Lindi M.2025-09-092025-09-092025Tuffaha 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/msaf1050737-4038http://hdl.handle.net/10230/71158Cancer 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.application/pdfeng© 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.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1093/molbev/msaf105CancerHypermutatorHypoxiaMutation biasMutation spectrumPositive selectioninfo:eu-repo/semantics/openAccess