Germline and somatic polymerase ε and δ mutations define a new class of hypermutated colorectal and endometrial cancers

Abstract

Polymerases ε and δ are the main enzymes that replicate eukaryotic DNA. Accurate replication occurs through Watson-Crick base pairing and also through the action of the polymerases' exonuclease (proofreading) domains. We have recently shown that germline exonuclease domain mutations (EDMs) of POLE and POLD1 confer a high risk of multiple colorectal adenomas and carcinoma (CRC). POLD1 mutations also predispose to endometrial cancer (EC). These mutations are associated with high penetrance and dominant inheritance, although the phenotype can be variable. We have named the condition polymerase proofreading-associated polyposis (PPAP). Somatic POLE EDMs have also been found in sporadic CRCs and ECs, although very few somatic POLD1 EDMs have been detected. Both the germline and the somatic DNA polymerase EDMs cause an 'ultramutated', apparently microsatellite-stable, type of cancer, sometimes leading to over a million base substitutions per tumour. Here, we present the evidence for POLE and POLD1 as important contributors to the pathogenesis of CRC and EC, and highlight some of the key questions in this emerging field.

Figure 1

Pedigree of a POLD1 p.Ser478Asn family. Shading denotes those affected with multiple (> 5) colorectal adenomas (adenomas) and/or early-onset colorectal cancer (CRC). In addition, three women developed endometrial carcinoma (EC). + denotes individuals tested and found to be gene carriers, and − denotes tested non-carriers. Ages denote the time interval over which colorectal polyps developed or the time at which cancer occurred. Note that one non-gene carrier developed a very small colorectal adenoma by age 43 years and that one carrier developed two astrocytomas, raising the possibility that POLD1 mutations also predispose to this tumour type.

Figure 2

The structure of POLE and POLD1 demonstrating the position of key mutations. Conserved exo motifs I–V within the exonuclease domain are highlighted in blue. Green circles denote germline mutations; grey circles denote somatic mutations.

Figure 3

Pymol-generated image of POLE and POLD1 EDMs on a composite structure of yeast Polδ (PDB 3IAY) and the ssDNA component (yellow) of the T4 polymerase complex (PDB 1NOY). Mutant amino acids are shown in red (POLE) or blue (POLD1). The key mutations generally cluster around the active site (D275) close to the ssDNA, an exception being V411 which lies some distance away and may act through affecting the positions of other residues closer to the active site.