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Updated: Jun 26, 2025

Engineering Oncogenic Heterozygous Gain-of-Function Mutations in Human Hematopoietic Stem and Progenitor Cells
Published on: March 10, 2023
Non-hypermutator cancers access driver mutations through reversals in germline mutational bias
Marwa Z Tuffaha1, David Castellano2, Claudia Serrano Colome3
1Department of Mathematics, Western University, London, Ontario N6A 5B7, Canada.
None:
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. Non-hypermutated 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 non-hypermutated tumors thus acquire driver mutations differently: hypermutated tumors by higher mutation rates and non-hypermutated tumors by changing the mutation spectrum to reverse the germline mutation bias.
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