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.

Abstract

Although it has long been recognized that the exonucleolytic proofreading activity intrinsic to the replicative DNA polymerases Pol δ and Pol ε is essential for faithful replication of DNA, evidence that defective DNA polymerase proofreading contributes to human malignancy has been limited. However, recent studies have shown that germline mutations in the proofreading domains of Pol δ and Pol ε predispose to cancer, and that somatic Pol ε proofreading domain mutations occur in multiple sporadic tumours, where they underlie a phenotype of 'ultramutation' and favourable prognosis. In this Review, we summarize the current understanding of the mechanisms and consequences of polymerase proofreading domain mutations in human malignancies, and highlight the potential utility of these variants as novel cancer biomarkers and therapeutic targets.

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Figure 1: Frequency and location of germline and somatic Pol δ and Pol ε proofreading exonuclease domain mutations in cancers.

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Acknowledgements

The authors thank J. Grimes for help in generating the Pol δ and Pol ε structures and N. de Wind for helpful comments on the manuscript. Work in the host laboratories is supported by an Academy of Medical Sciences/Health Foundation Clinician Scientist Fellowship Award (to D.N.C.), Cancer Research UK (programme grant C6199/A10417 to I.T.), the European Research Council (EVOCAN grant agreement: 340560 to I.T.), the Dutch Cancer Society (grant ref: UL2012-5719 to T.B.) and the Medical Research Council (grant Ref. MR/L016591/1 to S.E.K.) and core funding to the Wellcome Trust Centre for Human Genetics from the Wellcome Trust (ref: 090532/Z/09/Z). D.N.C. has received funding from the Oxford Cancer Centre, UK.

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Glossary

Mismatch repair

(MMR). A mechanism of post-replicative DNA repair that removes mismatched bases and small insertions and deletions (indels) from the newly synthesized DNA strand.

Ultramutated

Describes tumours with an exceptional frequency of mutations, often exceeding 100 mutations per megabase and often caused by mutations in the gene encoding the catalytic subunit of DNA polymerase ε (POLE).

Neoepitopes

Novel epitopes, created by somatic mutations in tumours, that are capable of eliciting an antitumour immune response.

B family polymerases

Replicative and repair DNA polymerases that are grouped on the basis of sequence and structural similarities, and include the prokaryotic DNA polymerase Pol II, and the eukaryotic DNA polymerases Pol ζ, Pol α, Pol δ and Pol ε.

GINS

A multiprotein complex essential for eukaryotic DNA replication. The name is derived from the Japanese go, ichi, ni and san (meaning five, one, two and three), and refers to the constituent components in budding yeast: Sld5, Psf1, Psf2 and Psf3.

Mutator phenotype

Elevation of the mutation rate above that expected for normally dividing cells. It has been argued that the acquisition of a mutator phenotype is a characteristic of many cancers.

Microsatellite-stable

Absence of small insertions and deletions (indels) at repetitive DNA microsatellites as a result of proficient DNA mismatch repair.

Intestinal polyposis

A phenotype of multiple colonic polyps and increased risk of colorectal cancer that may be due to a germline mutation in a known predisposition gene (for example, adenomatous polyposis coli (APC) or MUTYH) or may lack an obvious genetic cause.

Mutational hot spot

A genomic region that is the site of mutations in cancers at a frequency greater than that expected by chance: for example, codon 600 in the serine/threonine kinase BRAF.

Multinucleated giant cells

Abnormally large cells with multiple nuclei and typically bizarre morphology that are observed in association with chronic inflammation and some types of malignancy.

Microsatellite instability

(MSI). The presence of small insertions and deletions (indels) at repetitive DNA microsatellites that result from defective DNA mismatch repair.

Synthetically lethal

A type of genetic interaction in which the combination of mutations in two genes results in cell death, whereas cells harbouring only one of the mutations are viable.

Antimutator mutations

Mutations that result in an increase in the fidelity of DNA replication; examples have been reported in both Escherichia coli and Saccharomyces cerevisiae, although their occurrence in human cancer is currently not proved.

Polymerase proofreading-associated polyposis

(PPAP). A high-penetrance, dominantly inherited condition characterized by multiple colorectal adenomas and carcinomas, caused by germline mutations in the genes encoding the catalytic subunits of the DNA polymerases Pol δ and Pol ε (POLD1 and POLE, respectively).

Lynch syndrome

A tumour predisposition syndrome caused by germline mutation of mismatch repair genes, which manifests as increased risk of carcinomas of the colon and rectum, endometrium, ovary, stomach and several other organs.

MUTYH-associated polyposis

A syndrome characterized by multiple intestinal adenomas and an increased risk of colorectal carcinoma. It is caused by germline mutations in the base excision repair gene MUTYH.

Basket trial

Also known as a bucket trial. A study in which patients with a specific molecular marker are recruited for treatment with a corresponding targeted therapy, irrespective of tumour histology or tissue of origin.

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Rayner, E., van Gool, I., Palles, C. et al. A panoply of errors: polymerase proofreading domain mutations in cancer. Nat Rev Cancer 16, 71–81 (2016). https://doi.org/10.1038/nrc.2015.12

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