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 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 H. Holmes; David Bentley; Peter Donnelly; Jenny Taylor; Christos Petridis; Rebecca Roylance; Elinor Sawyer; David J. Kerr; Susan Clark; Jonathan Grimes; Stephen E. Kearsey; Huw J W Thomas; Gilean McVean; Richard S. Houlston; Ian Tomlinson; Huw J W Thomas; Eamonn Maher; Gareth Evans; Carole Cummings; Margaret Stevens; Lisa Walker; Dorothy Halliday; Ruth Armstrong; Joan Paterson; Shirley Hodgson; Tessa Homfray; Lucy Side; Louise Izatt; Alan Donaldson; Susan Tomkins; Patrick Morrison; Selina Goodman; Carole Brewer; Alex Henderson; Rosemarie Davidson; Victoria Murday; Jaqueline Cook; Nneva Haites; Timothy Bishop; Eamonn Sheridan; Andrew Green; Christopher Marks; Sue Carpenter; Mary Broughton; Lynn Greenhalge; Mohnish Suri; John Bell; Peter Ratcliffe; Andrew Wilkie; John Broxholme; David Buck; Richard Cornall; Lorna Gregory; Julian Knight; Gerton Lunter; Zoya Kingsbury; Russell Grocock; Edouard Hatton; Christopher C. Holmes; Linda Hughes; Peter Humburg; Alexander Kanapin; Lisa Murray; Andy Rimmer

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 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. KovacSean Humphray, Anneke Lucassen, Christopher H. Holmes, David Bentley, Peter Donnelly, Jenny Taylor, Christos Petridis, Rebecca Roylance, Elinor Sawyer, David J. Kerr, Susan Clark, Jonathan Grimes, Stephen E. Kearsey, Huw J W Thomas, Gilean McVean, Richard S. Houlston, Ian Tomlinson^*, Huw J W Thomas, Eamonn Maher, Gareth Evans, Carole Cummings, Margaret Stevens, Lisa Walker, Dorothy Halliday, Ruth Armstrong, Joan Paterson, Shirley Hodgson, Tessa Homfray, Lucy Side, Louise Izatt, Alan Donaldson, Susan Tomkins, Patrick Morrison, Selina Goodman, Carole Brewer, Alex Henderson, Rosemarie Davidson, Victoria Murday, Jaqueline Cook, Nneva Haites, Timothy Bishop, Eamonn Sheridan, Andrew Green, Christopher Marks, Sue Carpenter, Mary Broughton, Lynn Greenhalge, Mohnish Suri, John Bell, Peter Ratcliffe, Andrew Wilkie, John Broxholme, David Buck, Richard Cornall, Lorna Gregory, Julian Knight, Gerton Lunter, Zoya Kingsbury, Russell Grocock, Edouard Hatton, Christopher C. Holmes, Linda Hughes, Peter Humburg, Alexander Kanapin, Lisa Murray, Andy Rimmer

^*Corresponding author for this work

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

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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 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.

Original language	English
Pages (from-to)	136-143
Number of pages	8
Journal	Nature Genetics
Volume	45
Issue number	2
DOIs	https://doi.org/10.1038/ng.2503
Publication status	Published - 1 Feb 2013

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Palles, C., Cazier, J. B., Howarth, K. M., Domingo, E., Jones, A. M., Broderick, P., Kemp, Z., Spain, S. L., Almeida, E. G., Salguero, I., Sherborne, A., Chubb, D., Carvajal-Carmona, L. G., Ma, Y., Kaur, K., Dobbins, S., Barclay, E., Gorman, M., Martin, L., ... Rimmer, A. (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

@article{fab84a72796145a599197ef7493bcee5,

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 = "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 Elinor Sawyer 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 Louise Izatt and Alan Donaldson and Susan Tomkins and Patrick Morrison and Selina Goodman and Carole Brewer and Alex Henderson and Rosemarie Davidson and Victoria Murday and Jaqueline Cook and Nneva Haites and Timothy Bishop and Eamonn Sheridan and Andrew Green and Christopher Marks and Sue Carpenter and Mary Broughton and Lynn Greenhalge and Mohnish Suri and John Bell and Peter Ratcliffe and Andrew Wilkie and John Broxholme and David Buck and Richard Cornall and Lorna Gregory and Julian Knight and Gerton Lunter and Zoya Kingsbury and Russell Grocock and Edouard Hatton and Holmes, {Christopher C.} and Linda Hughes and Peter Humburg and Alexander Kanapin and Lisa Murray and Andy Rimmer",

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doi = "10.1038/ng.2503",

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pages = "136--143",

journal = "Nature Genetics",

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Palles, C, Cazier, JB, Howarth, KM, Domingo, E, Jones, AM, Broderick, P, Kemp, Z, Spain, SL, Almeida, EG, 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, CH, Bentley, D, Donnelly, P, Taylor, J, Petridis, C, Roylance, R, Sawyer, E, Kerr, DJ, Clark, S, Grimes, J, Kearsey, SE, Thomas, HJW, McVean, G, Houlston, RS, Tomlinson, I, Thomas, HJW, Maher, E, Evans, G, Cummings, C, Stevens, M, Walker, L, Halliday, D, Armstrong, R, Paterson, J, Hodgson, S, Homfray, T, Side, L, Izatt, L, Donaldson, A, Tomkins, S, Morrison, P, Goodman, S, Brewer, C, Henderson, A, Davidson, R, Murday, V, Cook, J, Haites, N, Bishop, T, Sheridan, E, Green, A, Marks, C, Carpenter, S, Broughton, M, Greenhalge, L, Suri, M, Bell, J, Ratcliffe, P, Wilkie, A, Broxholme, J, Buck, D, Cornall, R, Gregory, L, Knight, J, Lunter, G, Kingsbury, Z, Grocock, R, Hatton, E, Holmes, CC, Hughes, L, Humburg, P, Kanapin, A, Murray, L & Rimmer, A 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

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 - 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

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 - Izatt, Louise

AU - Donaldson, Alan

AU - Tomkins, Susan

AU - Morrison, Patrick

AU - Goodman, Selina

AU - Brewer, Carole

AU - Henderson, Alex

AU - Davidson, Rosemarie

AU - Murday, Victoria

AU - Cook, Jaqueline

AU - Haites, Nneva

AU - Bishop, Timothy

AU - Sheridan, Eamonn

AU - Green, Andrew

AU - Marks, Christopher

AU - Carpenter, Sue

AU - Broughton, Mary

AU - Greenhalge, Lynn

AU - Suri, Mohnish

AU - Bell, John

AU - Ratcliffe, Peter

AU - Wilkie, Andrew

AU - Broxholme, John

AU - Buck, David

AU - Cornall, Richard

AU - Gregory, Lorna

AU - Knight, Julian

AU - Lunter, Gerton

AU - Kingsbury, Zoya

AU - Grocock, Russell

AU - Hatton, Edouard

AU - Holmes, Christopher C.

AU - Hughes, Linda

AU - Humburg, Peter

AU - Kanapin, Alexander

AU - Murray, Lisa

AU - Rimmer, Andy

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.

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U2 - 10.1038/ng.2503

DO - 10.1038/ng.2503

M3 - Article

C2 - 23263490

AN - SCOPUS:84873096362

SN - 1061-4036

VL - 45

SP - 136

EP - 143

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

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