Germline and somatic polymerase ϵ and δ mutations define a new class of hypermutated colorectal and endometrial cancers

Abstract

Polymerases ϵ and δ are the main enzymes that replicate eukaryotic DNA . Accurate replication occurs through Watson–Crick base pairing and also through the action of the polymerases' exonuclease (proofreading) domains. We have recently shown that germline exonuclease domain mutations ( EDMs ) of POLE and POLD1 confer a high risk of multiple colorectal adenomas and carcinoma ( CRC ). POLD1 mutations also predispose to endometrial cancer ( EC ). These mutations are associated with high penetrance and dominant inheritance, although the phenotype can be variable. We have named the condition polymerase proofreading‐associated polyposis ( PPAP ). Somatic POLE EDMs have also been found in sporadic CRCs and ECs , although very few somatic POLD1 EDMs have been detected. Both the germline and the somatic DNA polymerase EDMs cause an ‘ultramutated’, apparently microsatellite‐stable, type of cancer, sometimes leading to over a million base substitutions per tumour. Here, we present the evidence for POLE and POLD1 as important contributors to the pathogenesis of CRC and EC , and highlight some of the key questions in this emerging field. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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