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 publication

DOI

10.1038/ng.2503

Type

Journal article

Journal

Nat Genet

Publication Date

02/2013

Volume

45

Pages

136 - 144

Keywords

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