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

Claire Palles; Jean-Baptiste Cazier; Kimberley M Howarth; Enric Domingo; Angela M Jones; Peter Broderick; Zoe Kemp; Sarah L Spain; Estrella Guarino; Estrella Guarino Almeida; Israel Salguero; Amy Sherborne; Daniel Chubb; Luis G Carvajal-Carmona; Yusanne Ma; Kulvinder Kaur; Sara Dobbins; Ella Barclay; Maggie Gorman; Lynn Martin; Michal B Kovac; Sean Humphray; Anneke Lucassen; Christopher C Holmes; David Bentley; Peter Donnelly; Jenny Taylor; Christos Petridis; Rebecca Roylance; Elinor J Sawyer; David J Kerr; Susan Clark; Jonathan Grimes; Stephen E Kearsey; Huw J W Thomas; Gilean McVean; Richard S Houlston; Ian Tomlinson; Colorectal Tumour Gene Identification (CORGI) Consortium

doi:10.1038/ng.2503

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

Claire Palles, Jean-Baptiste Cazier, Kimberley M Howarth, Enric Domingo, Angela M Jones, Peter Broderick, Zoe Kemp, Sarah L Spain, Estrella Guarino, Estrella Guarino Almeida, Israel Salguero, Amy Sherborne, Daniel Chubb, Luis G Carvajal-Carmona, Yusanne Ma, Kulvinder Kaur, Sara Dobbins, Ella Barclay, Maggie Gorman, Lynn MartinMichal B Kovac, Sean Humphray, Anneke Lucassen, Christopher C Holmes, David Bentley, Peter Donnelly, Jenny Taylor, Christos Petridis, Rebecca Roylance, Elinor J Sawyer, David J Kerr, Susan Clark, Jonathan Grimes, Stephen E Kearsey, Huw J W Thomas, Gilean McVean, Richard S Houlston, Ian Tomlinson, Colorectal Tumour Gene Identification (CORGI) Consortium

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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 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.

Original language	English
Pages (from-to)	136-44
Number of pages	9
Journal	Nature Genetics
Volume	45
Issue number	2
DOIs	https://doi.org/10.1038/ng.2503
Publication status	Published - Feb 2013

Keywords

Adenoma
Colorectal Neoplasms
DNA Mismatch Repair
DNA Polymerase II
DNA Polymerase III
DNA Replication
Exodeoxyribonucleases
Genetic Linkage
Genome-Wide Association Study
Germ-Line Mutation
Humans
Microsatellite Repeats
Models, Molecular
Pedigree
Schizosaccharomyces
Sequence Analysis, DNA

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.2503

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Palles, C., Cazier, J.-B., Howarth, K. M., Domingo, E., Jones, A. M., Broderick, P., Kemp, Z., Spain, S. L., Guarino, E., Guarino Almeida, E., Salguero, I., Sherborne, A., Chubb, D., Carvajal-Carmona, L. G., Ma, Y., Kaur, K., Dobbins, S., Barclay, E., Gorman, M., ... Colorectal Tumour Gene Identification (CORGI) Consortium (2013). Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nature Genetics, 45(2), 136-44. https://doi.org/10.1038/ng.2503

@article{ea99208c5cff4234b91d83571fae0ca9,

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 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.",

keywords = "Adenoma, Colorectal Neoplasms, DNA Mismatch Repair, DNA Polymerase II, DNA Polymerase III, DNA Replication, Exodeoxyribonucleases, Genetic Linkage, Genome-Wide Association Study, Germ-Line Mutation, Humans, Microsatellite Repeats, Models, Molecular, Pedigree, Schizosaccharomyces, Sequence Analysis, DNA",

author = "Claire Palles and Jean-Baptiste Cazier and Howarth, {Kimberley M} and Enric Domingo and Jones, {Angela M} and Peter Broderick and Zoe Kemp and Spain, {Sarah L} and Estrella Guarino and {Guarino Almeida}, Estrella 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 C} 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 {Colorectal Tumour Gene Identification (CORGI) Consortium}",

year = "2013",

month = feb,

doi = "10.1038/ng.2503",

language = "English",

volume = "45",

pages = "136--44",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

}

Palles, C, Cazier, J-B, Howarth, KM, Domingo, E, Jones, AM, Broderick, P, Kemp, Z, Spain, SL, Guarino, E, Guarino Almeida, E, Salguero, I, Sherborne, A, Chubb, D, Carvajal-Carmona, LG, Ma, Y, Kaur, K, Dobbins, S, Barclay, E, Gorman, M, Martin, L, Kovac, MB, Humphray, S, Lucassen, A, Holmes, CC, Bentley, D, Donnelly, P, Taylor, J, Petridis, C, Roylance, R, Sawyer, EJ, Kerr, DJ, Clark, S, Grimes, J, Kearsey, SE, Thomas, HJW, McVean, G, Houlston, RS, Tomlinson, I & Colorectal Tumour Gene Identification (CORGI) 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. 136-44. https://doi.org/10.1038/ng.2503

TY - JOUR

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

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 - Guarino, Estrella

AU - Guarino Almeida, Estrella

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 C

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 - Colorectal Tumour Gene Identification (CORGI) Consortium

PY - 2013/2

Y1 - 2013/2

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 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.

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 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.

KW - Adenoma

KW - Colorectal Neoplasms

KW - DNA Mismatch Repair

KW - DNA Polymerase II

KW - DNA Polymerase III

KW - DNA Replication

KW - Exodeoxyribonucleases

KW - Genetic Linkage

KW - Genome-Wide Association Study

KW - Germ-Line Mutation

KW - Humans

KW - Microsatellite Repeats

KW - Models, Molecular

KW - Pedigree

KW - Schizosaccharomyces

KW - Sequence Analysis, DNA

U2 - 10.1038/ng.2503

DO - 10.1038/ng.2503

M3 - Article

C2 - 23263490

SN - 1061-4036

VL - 45

SP - 136

EP - 144

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

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

Abstract

Keywords

UN SDGs

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