DNA mismatch repair promotes APOBEC3-mediated diffuse hypermutation in human cancers

Certain mutagens, including the APOBEC3 (A3) cytosine deaminase enzymes, can create multiple genetic changes in a single event. Activity of A3s results in striking ‘mutation showers’ occurring near DNA breakpoints, however less is known about mechanisms underlying the majority of A3 mutations. We classified the diverse patterns of clustered mutagenesis in tumor genomes, which identified a novel A3 pattern: nonrecurrent, diffuse hypermutation (omikli). This mechanism occurs independently of the known focal hypermutation (kataegis), and is associated with activity of the DNA mismatch repair (MMR) pathway, which can provide the single-stranded DNA substrate needed by A3 and contributes to a significant portion of A3 mutations genome-wide. Because MMR is directed towards early-replicating, gene-rich domains, A3 mutagenesis has a high propensity to generate impactful mutations, which exceeds other common carcinogens such as tobacco smoke and UV exposure. Cells direct their DNA repair capacity towards more important genomic regions, thus carcinogens that subvert DNA repair can be remarkably potent.