Population-based study of the association of variants in mismatch repair genes with prostate cancer risk and outcomes.
BACKGROUND
Mismatch repair (MMR) gene activity may be associated with prostate cancer risk and outcomes. This study evaluated whether single nucleotide polymorphisms (SNP) in key MMR genes are related to prostate cancer outcomes.


METHODS
Data from two population-based case-control studies of prostate cancer among Caucasian and African-American men residing in King County, Washington were combined for this analysis. Cases (n = 1,458) were diagnosed with prostate cancer in 1993 to 1996 or 2002 to 2005 and were identified through the Seattle-Puget Sound Surveillance Epidemiology and End Results cancer registry. Controls (n = 1,351) were age-matched to cases and were identified through random digit dialing. Logistic regression was used to assess the relationship between haplotype-tagging SNPs and prostate cancer risk and disease aggressiveness. Cox proportional hazards regression was used to assess the relationship between SNPs and prostate cancer recurrence and prostate cancer-specific death.


RESULTS
Nineteen SNPs were evaluated in the key MMR genes: five in MLH1, 10 in MSH2, and 4 in PMS2. Among Caucasian men, one SNP in MLH1 (rs9852810) was associated with overall prostate cancer risk [odds ratio, 1.21; 95% confidence interval (95% CI), 1.02, 1.44; P = 0.03], more aggressive prostate cancer (odds ratio, 1.49; 95% CI, 1.15, 1.91; P < 0.01), and prostate cancer recurrence (hazard ratio, 1.83; 95% CI, 1.18, 2.86; P < 0.01), but not prostate cancer-specific mortality. A nonsynonymous coding SNP in MLH1, rs1799977 (I219V), was also found to be associated with more aggressive disease. These results did not remain significant after adjusting for multiple comparisons.


CONCLUSIONS
This population-based case-control study provides evidence for a possible association with a gene variant in MLH1 in relation to the risk of overall prostate cancer, more aggressive disease, and prostate cancer recurrence, which warrants replication.
Langeberg
Wendy J
WJ
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
Kwon
Erika M
EM
Koopmeiners
Joseph S
JS
Ostrander
Elaine A
EA
Stanford
Janet L
JL
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes