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 susceptibility variants appear to have high penetrance. POLD1 is also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proof-reading (exonuclease) domain of DNA polymerases ε and δ, and are predicted to impair correction of mispaired bases inserted during DNA replication. In agreement with this prediction, mutation carriers’ tumours 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 exonuclease domain mutations.

DNA Polymerase ε Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity

“…Further analysis of the CRCs with POLE exonuclease domain mutations (EDM) in the TCGA data demonstrated an increase in all types of base substitutions. C:G>T:A was the most common mutation type, but compared to other cancers the relative increase in G:C>T:A was most dramatic [2]. …”

Adenoma development in familial adenomatous polyposis and MUTYH‐associated polyposis: somatic landscape and driver genes

“…Germline variants in the genes LKB1 , SMAD4 , GREM1 , PTEN , BMPR1A and AXIN2 have also been implicated in predisposition to colorectal cancer and highlight a role for many pathways in tumourigenesis of the colon 5. More recently, germline variants in the exonuclease domains of the polymerase‐ϵ catalytic subunit gene ( POLE ) and in the DNA polymerase delta catalytic subunit ( POLD1 ) gene have been linked to colorectal adenoma and carcinoma development 6. Variants in POLE and POLD1 dramatically increase the somatic mutation rate, resulting in C:G → T:A somatic base changes 7.…”

GREM1 and POLE variants in hereditary colorectal cancer syndromes

“…Mutations in the DNA polymerase ɛ gene ( POLE ) were recently reported as predisposing for inherited colorectal cancer (Palles et al, 2013). In a previous study we present a mutation in the proof‐reading exonuclease domain of this protein in a large Swedish family with CRC (Rohlin et al, 2014), Supporting Information Table S1.…”

“…The reason for this additional sequencing was that heterozygote mutations in the DNA polymerase genes, POLD1 and POLE , were recently identified in patients with multiple adenoma and/or CRC. The mutations were restricted to the proofreading exonuclease domain of the proteins (Palles et al, 2013). We have recently reported a family with a mutation in the exonuclease domain of POLE in Sweden.…”

“…Syndromes characterized by polyposis include familial adenomatous polyposis (FAP), MUTYH ‐associated polyposis (MAP), juvenile polyposis (JPS), Cowden syndrome, Peutz–Jeghers syndrome, serrated polyposis (SPS), hereditary mixed polyposis (HMPS), and the recently described polymerase proofreading‐associated polyposis (PPAP). This syndrome is caused by germ‐line mutations in the exonuclease domain of POLE and POLD1 (Palles et al, 2013) and is recognized by multiple or very large adenomas and early onset CRC with microsatellite stable tumors (MSS). Exome studies have also recently identified high penetrant mutations in new CRC predisposing genes e.g.…”