Show simple item record

dc.contributor.authorPalles, Claire
dc.contributor.authorGuarino Almeida, Estrella
dc.contributor.authorTomlinson, Ian
dc.date.accessioned2023-12-12T13:19:41Z
dc.date.available2023-12-12T13:19:41Z
dc.date.issued2012
dc.identifier.issn1061-4036spa
dc.identifier.urihttps://hdl.handle.net/10641/3564
dc.description.abstractMany 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 ɛ 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.spa
dc.language.isoengspa
dc.publisherNature Geneticsspa
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 España*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/es/*
dc.titleGermline mutations in the proof-reading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.spa
dc.typejournal articlespa
dc.type.hasVersionAMspa
dc.rights.accessRightsopen accessspa
dc.description.extent535 KBspa
dc.identifier.doi10.1038/ng.2503spa
dc.relation.publisherversionhttps://www.nature.com/articles/ng.2503spa


Files in this item

FilesSizeFormatView
emss-531222222.pdf534.2KbPDFView/Open

This item appears in the following Collection(s)

Show simple item record

Atribución-NoComercial-SinDerivadas 3.0 España
Except where otherwise noted, this item's license is described as Atribución-NoComercial-SinDerivadas 3.0 España