Palles, C, Cazier, J-B, Howarth, KM et al. (36 more authors) (2013) Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nature Genetics, 45 (2). pp. 136-144. ISSN 1061-4036
Abstract
Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no controls. The variants associated with susceptibility, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases ε and δ and are predicted to cause a defect in the correction of mispaired bases inserted during DNA replication. In agreement with this prediction, the tumors from mutation carriers were microsatellite stable but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE mutations affecting the exonuclease domain.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2013 Nature America, Inc. This is an author produced version of a paper published in Nature Genetics. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Colorectal cancer; Genetic predisposition to disease; Mutation |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Epidemiology and Biostatistics (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 22 Aug 2016 14:32 |
Last Modified: | 22 Aug 2016 14:32 |
Published Version: | http://dx.doi.org/10.1038/ng.2503 |
Status: | Published |
Publisher: | Nature Publishing Group |
Identification Number: | 10.1038/ng.2503 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:101096 |