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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601 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 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 languageEnglish
Pages (from-to)136-44
Number of pages9
JournalNature Genetics
Issue number2
Publication statusPublished - Feb 2013


  • 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


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