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.
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Palles
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Cazier
authors.forename: Kimberley M
authors.initials: KM
authors.lastname: Howarth
authors.forename: Enric
authors.initials: E
authors.lastname: Domingo
authors.forename: Angela M
authors.initials: AM
authors.lastname: Jones
authors.forename: Peter
authors.initials: P
authors.lastname: Broderick
authors.forename: Zoe
authors.initials: Z
authors.lastname: Kemp
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Spain
authors.forename: Estrella
authors.initials: E
authors.lastname: Guarino
authors.forename: Estrella
authors.initials: E
authors.lastname: Guarino Almeida
authors.forename: Israel
authors.initials: I
authors.lastname: Salguero
authors.forename: Amy
authors.initials: A
authors.lastname: Sherborne
authors.forename: Daniel
authors.initials: D
authors.lastname: Chubb
authors.forename: Luis G
authors.initials: LG
authors.lastname: Carvajal-Carmona
authors.forename: Yusanne
authors.initials: Y
authors.lastname: Ma
authors.forename: Kulvinder
authors.initials: K
authors.lastname: Kaur
authors.forename: Sara
authors.initials: S
authors.lastname: Dobbins
authors.forename: Ella
authors.initials: E
authors.lastname: Barclay
authors.forename: Maggie
authors.initials: M
authors.lastname: Gorman
authors.forename: Lynn
authors.initials: L
authors.lastname: Martin
authors.forename: Michal B
authors.initials: MB
authors.lastname: Kovac
authors.forename: Sean
authors.initials: S
authors.lastname: Humphray
authors.forename: Anneke
authors.initials: A
authors.lastname: Lucassen
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Holmes
authors.forename: David
authors.initials: D
authors.lastname: Bentley
authors.forename: Peter
authors.initials: P
authors.lastname: Donnelly
authors.forename: Jenny
authors.initials: J
authors.lastname: Taylor
authors.forename: Christos
authors.initials: C
authors.lastname: Petridis
authors.forename: Rebecca
authors.initials: R
authors.lastname: Roylance
authors.forename: Elinor J
authors.initials: EJ
authors.lastname: Sawyer
authors.forename: David J
authors.initials: DJ
authors.lastname: Kerr
authors.forename: Susan
authors.initials: S
authors.lastname: Clark
authors.forename: Jonathan
authors.initials: J
authors.lastname: Grimes
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Kearsey
authors.forename: Huw J W
authors.initials: HJ
authors.lastname: Thomas
authors.forename: Gilean
authors.initials: G
authors.lastname: McVean
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D000236:Adenoma / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D004257:DNA Polymerase II / Q000235:genetics*; D004258:DNA Polymerase III / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D005090:Exodeoxyribonucleases / Q000235:genetics; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D008958:Models, Molecular; D010375:Pedigree; D000075223:Poly-ADP-Ribose Binding Proteins; D012568:Schizosaccharomyces / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D000075223:Poly-ADP-Ribose Binding Proteins; C434055:POLD1 protein, human; D004257:DNA Polymerase II; D004258:DNA Polymerase III; C119525:POLE protein, human; D005090:Exodeoxyribonucleases