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Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. / UK IBD Genetics Consortium and COLORS in IBD and Oxford IBD cohort study investigators and WGS500 Consortium.

In: Nature Genetics, Vol. 45, No. 2, 01.02.2013, p. 136-143.

Research output: Contribution to journal › Article › peer-review

Harvard

UK IBD Genetics Consortium and COLORS in IBD and Oxford IBD cohort study investigators and WGS500 Consortium 2013, 'Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas', Nature Genetics, vol. 45, no. 2, pp. 136-143. https://doi.org/10.1038/ng.2503

APA

UK IBD Genetics Consortium and COLORS in IBD and Oxford IBD cohort study investigators and WGS500 Consortium (2013). Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nature Genetics, 45(2), 136-143. https://doi.org/10.1038/ng.2503

Vancouver

UK IBD Genetics Consortium and COLORS in IBD and Oxford IBD cohort study investigators and WGS500 Consortium. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nature Genetics. 2013 Feb 1;45(2):136-143. https://doi.org/10.1038/ng.2503

Author

UK IBD Genetics Consortium and COLORS in IBD and Oxford IBD cohort study investigators and WGS500 Consortium. / Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. In: Nature Genetics. 2013 ; Vol. 45, No. 2. pp. 136-143.

BibTeX

@article{686c134b94dd4f919a20f09b2953b63d,
title = "Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas",
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.",
author = "{UK IBD Genetics Consortium and COLORS in IBD and Oxford IBD cohort study investigators and WGS500 Consortium} and Claire Palles and Cazier, {Jean Baptiste} and Howarth, {Kimberley M.} and Enric Domingo and Jones, {Angela M.} and Peter Broderick and Zoe Kemp and Spain, {Sarah L.} and Almeida, {Estrella Guarino} and Israel Salguero and Amy Sherborne and Daniel Chubb and Carvajal-Carmona, {Luis G.} and Yusanne Ma and Kulvinder Kaur and Sara Dobbins and Ella Barclay and Maggie Gorman and Lynn Martin and Kovac, {Michal B.} and Sean Humphray and Anneke Lucassen and Holmes, {Christopher H.} and David Bentley and Peter Donnelly and Jenny Taylor and Christos Petridis and Rebecca Roylance and Sawyer, {Elinor J.} and Kerr, {David J.} and Susan Clark and Jonathan Grimes and Kearsey, {Stephen E.} and Thomas, {Huw J.W.} and Gilean McVean and Houlston, {Richard S.} and Ian Tomlinson and Thomas, {Huw J.W.} and Eamonn Maher and Gareth Evans and Carole Cummings and Margaret Stevens and Lisa Walker and Dorothy Halliday and Ruth Armstrong and Joan Paterson and Shirley Hodgson and Tessa Homfray and Lucy Side and Alexander Kanapin",
year = "2013",
month = feb,
day = "1",
doi = "10.1038/ng.2503",
language = "English",
volume = "45",
pages = "136--143",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "2",

}

RIS

TY - JOUR

T1 - Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas

AU - UK IBD Genetics Consortium and COLORS in IBD and Oxford IBD cohort study investigators and WGS500 Consortium

AU - Palles, Claire

AU - Cazier, Jean Baptiste

AU - Howarth, Kimberley M.

AU - Domingo, Enric

AU - Jones, Angela M.

AU - Broderick, Peter

AU - Kemp, Zoe

AU - Spain, Sarah L.

AU - Almeida, Estrella Guarino

AU - Salguero, Israel

AU - Sherborne, Amy

AU - Chubb, Daniel

AU - Carvajal-Carmona, Luis G.

AU - Ma, Yusanne

AU - Kaur, Kulvinder

AU - Dobbins, Sara

AU - Barclay, Ella

AU - Gorman, Maggie

AU - Martin, Lynn

AU - Kovac, Michal B.

AU - Humphray, Sean

AU - Lucassen, Anneke

AU - Holmes, Christopher H.

AU - Bentley, David

AU - Donnelly, Peter

AU - Taylor, Jenny

AU - Petridis, Christos

AU - Roylance, Rebecca

AU - Sawyer, Elinor J.

AU - Kerr, David J.

AU - Clark, Susan

AU - Grimes, Jonathan

AU - Kearsey, Stephen E.

AU - Thomas, Huw J.W.

AU - McVean, Gilean

AU - Houlston, Richard S.

AU - Tomlinson, Ian

AU - Thomas, Huw J.W.

AU - Maher, Eamonn

AU - Evans, Gareth

AU - Cummings, Carole

AU - Stevens, Margaret

AU - Walker, Lisa

AU - Halliday, Dorothy

AU - Armstrong, Ruth

AU - Paterson, Joan

AU - Hodgson, Shirley

AU - Homfray, Tessa

AU - Side, Lucy

AU - Kanapin, Alexander

PY - 2013/2/1

Y1 - 2013/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84873096362&partnerID=8YFLogxK

U2 - 10.1038/ng.2503

DO - 10.1038/ng.2503

M3 - Article

C2 - 23263490

AN - SCOPUS:84873096362

VL - 45

SP - 136

EP - 143

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 2

ER -

ID: 34671808