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

Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas
Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas
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.
1061-4036
136-144
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Kearsey, Stephen E.
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McVean, Gilean
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Palles, Claire, Cazier, Jean-Baptiste, Howarth, Kimberley M., Domingo, Enric, Jones, Angela M., Broderick, Peter, Kemp, Zoe, Spain, Sarah L., Guarino, Estrella, Guarino Almeida, Estrella, Salguero, Israel, Sherborne, Amy, Chubb, Daniel, Carvajal-Carmona, Luis G., Ma, Yusanne, Kaur, Kulvinder, Dobbins, Sara, Barclay, Ella, Gorman, Maggie, Martin, Lynn, Kovac, Michal B., Humphray, Sean, Lucassen, Anneke, Holmes, Christopher C., Bentley, David, Donnelly, Peter, Taylor, Jenny, Petridis, Christos, Roylance, Rebecca, Sawyer, Elinor J., Kerr, David J., Clark, Susan, Grimes, Jonathan, Kearsey, Stephen E., Thomas, Huw J.W., McVean, Gilean, Houlston, Richard S. and Tomlinson, Ian (2012) Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nature Genetics, 45 (2), 136-144. (doi:10.1038/ng.2503). (PMID:23263490)

Record type: Article

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.

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e-pub ahead of print date: 23 December 2012
Published date: 23 December 2012
Organisations: Faculty of Medicine

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Local EPrints ID: 353452
URI: https://eprints.soton.ac.uk/id/eprint/353452
ISSN: 1061-4036
PURE UUID: 46e75dd8-bd28-44a8-8dee-581c8e4f19f7

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Date deposited: 06 Jun 2013 12:11
Last modified: 16 Sep 2019 18:36

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Contributors

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

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