Replicative DNA polymerase mutations in cancer

Abstract

Three DNA polymerases - Pol α, Pol δ and Pol ɛ - are essential for DNA replication. After initiation of DNA synthesis by Pol α, Pol δ or Pol ɛ take over on the lagging and leading strand respectively. Pol δ and Pol ɛ perform the bulk of replication with very high fidelity, which is ensured by Watson-Crick base pairing and 3'exonuclease (proofreading) activity. Yeast models have shown that mutations in the exonuclease domain of Pol δ and Pol ɛ homologues can cause a mutator phenotype. Recently, we identified germline exonuclease domain mutations (EDMs) in human POLD1 and POLE that predispose to 'polymerase proofreading associated polyposis' (PPAP), a disease characterised by multiple colorectal adenomas and carcinoma, with high penetrance and dominant inheritance. Moreover, somatic EDMs in POLE have also been found in sporadic colorectal and endometrial cancers. Tumors with EDMs are microsatellite stable and show an 'ultramutator' phenotype, with a dramatic increase in base substitutions.

Figure 1

Mutation spectra (upper) and numbers (lower) in exome sequence data from TCGA project colorectal cancers of three types. Note that MSI+ is used synonymously with MMR-deficient.

Figure 2

Mutations in colorectal cancer driver genes in the 17 POLE EDM TCGA project colorectal cancers (data from December 2013). Note the following: (i) bi-allelic mutations are shown for putative tumor suppressor genes, and additionally for PIK3CA; (ii) some filtering of variants with a low chance of being pathogenic has been performed on a gene-by-gene basis (e.g. for APC, only protein-truncating or splice-site mutations were considered pathogenic, for CTNNB1, only mutations affecting the exon 3 phosphorylation sites were considered pathogenic, et cetera); (iii) some highly atypical but potentially pathogenic mutations may therefore not be shown for some genes; (iv) LOH is not shown; (v) some of the mutations shown are highly likely to be passengers, especially missense changes in genes (e.g. MMR genes, SMAD4) where hotspots are not established; (vi) the presence of two mutations does not necessarily imply that these are bi-allelic changes.