title: Common variants in mismatch repair genes and risk of invasive ovarian cancer.
abstract: Mismatch repair (MMR) is important for repairing of nucleotide mismatches during DNA replication. Germline mutations in MMR genes are associated with hereditary non-polyposis colorectal cancer (HNPCC). Ovarian cancer occurs as part of the HNPCC phenotype, and so common variants in MMR genes are candidates for ovarian cancer susceptibility. We performed a large multicentre case-control study to investigate associations of common variations in MMR genes and ovarian cancer using a single nucleotide polymorphism (SNP) tagging approach. A total of 2570 controls and 1531 cases from three separate studies were genotyped for 44 tagging SNPs (stSNP) in seven MMR genes (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2). Genotype frequencies were marginally different between cases and controls for PMS2 rs7797466 (P(2df) = 0.046) with a 1.17-fold (95% CI 1.03-1.33) increase in risk for each 'a' allele carried (P-trend = 0.013). Haplotype analysis of PMS2 also showed significant differences in frequencies between cases and controls (P(7df) = 0.005), with one haplotype accounting for most of the effect. There was also marginal evidence for a recessive protective effect with common homozygote as the baseline comparator for two SNPs--MSH6 rs3136245 (OR 0.67; 95% CI 0.46-0.98) and MSH3 rs6151662 (OR 0.28; 95% CI 0.08-0.91)--but the comparisons of genotype frequencies for these variants were not significant (P = 0.10 and 0.054). In conclusion, it is unlikely that common variants in MLH1, MLH3, PMS1, MSH2, MSH3 and MSH6 contribute significantly to ovarian cancer susceptibility. The observed association of PMS2 rs7797466 with ovarian cancer warrants confirmation in an independent study.
authors.affiliation: CR-UK Department of Oncology, University of Cambridge Strangeways Research Laboratory, Cambridge, UK. honglin@srl.cam.ac.uk
authors.forename: Honglin
authors.initials: H
authors.lastname: Song
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Ramus
authors.forename: Lydia
authors.initials: L
authors.lastname: Quaye
authors.forename: Richard A
authors.initials: RA
authors.lastname: DiCioccio
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tyrer
authors.forename: Emma
authors.initials: E
authors.lastname: Lomas
authors.forename: Danielle
authors.initials: D
authors.lastname: Shadforth
authors.forename: Estrid
authors.initials: E
authors.lastname: Hogdall
authors.forename: Claus
authors.initials: C
authors.lastname: Hogdall
authors.forename: Valerie
authors.initials: V
authors.lastname: McGuire
authors.forename: Alice S
authors.initials: AS
authors.lastname: Whittemore
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Bruce A J
authors.initials: BA
authors.lastname: Ponder
authors.forename: Susanne Kruger
authors.initials: SK
authors.lastname: Kjaer
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
authors.forename: Simon A
authors.initials: SA
authors.lastname: Gayther
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes