title: DNA polymerase ε and δ exonuclease domain mutations in endometrial cancer.
abstract: Accurate duplication of DNA prior to cell division is essential to suppress mutagenesis and tumour development. The high fidelity of eukaryotic DNA replication is due to a combination of accurate incorporation of nucleotides into the nascent DNA strand by DNA polymerases, the recognition and removal of mispaired nucleotides (proofreading) by the exonuclease activity of DNA polymerases δ and ε, and post-replication surveillance and repair of newly synthesized DNA by the mismatch repair (MMR) apparatus. While the contribution of defective MMR to neoplasia is well recognized, evidence that faulty DNA polymerase activity is important in cancer development has been limited. We have recently shown that germline POLE and POLD1 exonuclease domain mutations (EDMs) predispose to colorectal cancer (CRC) and, in the latter case, to endometrial cancer (EC). Somatic POLE mutations also occur in 5-10% of sporadic CRCs and underlie a hypermutator, microsatellite-stable molecular phenotype. We hypothesized that sporadic ECs might also acquire somatic POLE and/or POLD1 mutations. Here, we have found that missense POLE EDMs with good evidence of pathogenic effects are present in 7% of a set of 173 endometrial cancers, although POLD1 EDMs are uncommon. The POLE mutations localized to highly conserved residues and were strongly predicted to affect proofreading. Consistent with this, POLE-mutant tumours were hypermutated, with a high frequency of base substitutions, and an especially large relative excess of G:C>T:A transversions. All POLE EDM tumours were microsatellite stable, suggesting that defects in either DNA proofreading or MMR provide alternative mechanisms to achieve genomic instability and tumourigenesis.
authors.affiliation: Molecular and Population Genetics Laboratory, University of Oxford, Roosevelt Drive, Oxford OX3 7BN. david.church@oncology.ox.ac.uk
authors.forename: David N
authors.initials: DN
authors.lastname: Church
authors.forename: Sarah E W
authors.initials: SE
authors.lastname: Briggs
authors.forename: Claire
authors.initials: C
authors.lastname: Palles
authors.forename: Enric
authors.initials: E
authors.lastname: Domingo
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kearsey
authors.forename: Jonathon M
authors.initials: JM
authors.lastname: Grimes
authors.forename: Maggie
authors.initials: M
authors.lastname: Gorman
authors.forename: Lynn
authors.initials: L
authors.lastname: Martin
authors.forename: Kimberley M
authors.initials: KM
authors.lastname: Howarth
authors.forename: Shirley V
authors.initials: SV
authors.lastname: Hodgson
authors.forename: Kulvinder
authors.initials: K
authors.lastname: Kaur
authors.forename: Jenny
authors.initials: J
authors.lastname: Taylor
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D004257:DNA Polymerase II / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004258:DNA Polymerase III / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000201:enzymology* / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D018895:Microsatellite Repeats; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D000075223:Poly-ADP-Ribose Binding Proteins; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D055815:Young Adult
chemical_list: D000075223:Poly-ADP-Ribose Binding Proteins; C434055:POLD1 protein, human; D004257:DNA Polymerase II; D004258:DNA Polymerase III; C119525:POLE protein, human