Mutant DNA polymerase-dependent mutagenesis in humans

We set out to test the contributions of mismatch repair (MMR) to mutant Pol ε-dependent mutagenesis in humans. To do this we used a combination of next generation sequencing on engineered model cell lines and publicly available tumor sequencing data from human patients. In MMR-deficient cells, Pol ε mutant alleles causes rapid increase in mutation signatures associated with Pol ε mutant/MMR-deficient tumors from patients with biallelic mismatch repair deficiency (bMMRD). A subset of Pol ε signature mutations occured even when MMR is functional. These results suggest that the Pol ε-dependent replication errors that dominate somatic tumor mutation spectra accumulate in patients due to their less efficient correction by the endogenous MMR. This further suggests that the Pol ε-dependent mutation accumulation is the driving event in these tumors, with MSI playing little if any role.