Journal
JOURNAL OF PATHOLOGY
Volume 230, Issue 2, Pages 148-153Publisher
WILEY
DOI: 10.1002/path.4185
Keywords
DNA polymerase; exonuclease; proofreading; germline mutation; somatic mutation; colorectal cancer; colorectal adenomas; polyposis; endometrial cancer
Funding
- Cancer Research UK
- Wellcome Trust [090532/Z/09/Z]
- Cancer Research UK [16459] Funding Source: researchfish
- National Institute for Health Research [ACF-2011-13-003] Funding Source: researchfish
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Polymerases E and are the main enzymes that replicate eukaryotic DNA. Accurate replication occurs through WatsonCrick 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 (c) 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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