Nonhypermutator cancers access driver mutations through reversals in germline mutational bias

Tuffaha, Marwa Z.; Castellano Esteve, David; Serrano Colomé, Clàudia; Gutenkunst, Ryan N.; Wahl, Lindi M.

doi:http://dx.doi.org/10.1093/molbev/msaf105

Nonhypermutator cancers access driver mutations through reversals in germline mutational bias

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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

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.