A panoply of errors: polymerase proofreading domain mutations in cancer

Key Points The proofreading exonuclease domains of the replicative DNA polymerases Pol δ and Pol ε perform an essential function in ensuring accurate DNA replication by proofreading and removing mispaired bases from the newly synthesized DNA strand. Recent studies have shown that mutations in the proofreading domains of POLD1 and POLE (which encode the catalytic subunits of Pol δ and Pol ε, respectively, in humans) predispose to colonic polyposis and cancer, and that somatic POLE proofreading domain mutations occur in several tumour types, most commonly those of the endometrium and colorectum. Interestingly, somatic POLD1 proofreading domain mutations seem to be uncommon. In several cases, the pathogenicity of these germline and somatic DNA polymerase proofreading domain mutations has been supported by studies using cell-free assays and Saccharomyces cerevisiae mutants, which confirm that they reduce or abolish exonuclease activity and increase the mutation rate. Consistent with these studies, the most striking feature of tumours with somatic POLE proofreading domain mutations is their exceptional burden of base substitution mutations — 'ultramutation'. Other notable features are their characteristic mutation spectrum, with overrepresentation of C→A transversions and, in general, a strong tendency to microsatellite stability. Endometrial cancers with somatic POLE proofreading domain mutations have an excellent prognosis, which may be because their ultramutation causes an abundance of antigenic neoepitopes, which in turn stimulate a potent antitumour immune response. The prognostic and immunological consequences of somatic POLE proofreading domain mutations in other tumour types await definition. Future studies of DNA polymerase proofreading domain mutations in cancer may provide further insights into the mechanisms and consequences of a mutator phenotype in cancer, and help to improve care for patients with endometrial, colorectal and other cancers.