Germline DNA Polymerase Mutations Increase Cancer Susceptibility

Germline mutations in at least 10 genes have been implicated in familial colorectal cancer predisposition syndromes, but some individuals with a family history of multiple benign colorectal adenomas or early-onset colorectal cancer do not have mutations in known cancer predisposition genes. To uncover additional risk variants, Palles and colleagues used linkage analysis to identify shared genomic regions among affected individuals within single families and searched for nonsilent coding variants within these regions. Analysis of one family identified a heterozygous germline mutation in POLE, which encodes the catalytic subunit of DNA polymerase ε, the enzyme responsible for synthesis and proofreading of the leading strand during DNA replication. This variant, which results in an amino acid substitution in the active site of the exonuclease domain that mediates proofreading, was identified in 12 additional unrelated individuals with a family history of colorectal tumors within a large validation set but was not identified in any control subjects. A similar analysis of another family identified a heterozygous mutation in POLD1 affecting the exonuclease domain of DNA polymerase δ, the enzyme that mediates lagging strand synthesis and proofreading. POLD1 mutation carriers were also prone to endometrial cancer, as is the case in patients with Lynch syndrome. The affected POLD1 and POLE residues are highly conserved, and the equivalent mutations led to a mutator phenotype in Schizosaccharomyces cerevisiae caused by increased base substitution arising from impaired exonuclease activity. Mapping of these mutations onto the structure of yeast DNA polymerase suggested that both likely induce detrimental exonuclease active site conformational changes. Consistent with these findings, POLD1- and POLE-mutant tumors were microsatellite stable but had an increased rate of base substitution mutations. POLD1 and POLE mutations should therefore be considered in patients with an unexplained history of multiple colorectal adenomas or early-onset cancers.

Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet 2012 Dec 23 [Epub ahead of print].

• ©2013 American Association for Cancer Research.