Nonhypermutator cancers access driver mutations through reversals in germline mutational bias

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.

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.