Common variants in mismatch repair genes and risk of invasive ovarian cancer.
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.
Song
Honglin
H
CR-UK Department of Oncology, University of Cambridge Strangeways Research Laboratory, Cambridge, UK. honglin@srl.cam.ac.uk
Ramus
Susan J
SJ
Quaye
Lydia
L
DiCioccio
Richard A
RA
Tyrer
Jonathan
J
Lomas
Emma
E
Shadforth
Danielle
D
Hogdall
Estrid
E
Hogdall
Claus
C
McGuire
Valerie
V
Whittemore
Alice S
AS
Easton
Douglas F
DF
Ponder
Bruce A J
BA
Kjaer
Susanne Kruger
SK
Pharoah
Paul D P
PD
Gayther
Simon A
SA
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
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes