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 journalArticlepeer-review

777 Citations (Scopus)


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 languageEnglish
Pages (from-to)136-143
Number of pages8
JournalNature Genetics
Issue number2
Publication statusPublished - 1 Feb 2013


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