Recent experimental evidence has demonstrated that catechol estrogens can be activated through metabolism to form depurinating DNA adducts and thereby initiate cancer. Limited data are available regarding this pathway in epithelial ovarian cancer. We conducted a case-control study of incident epithelial ovarian cancer at the Mayo Clinic in Rochester Minnesota and Jacksonville Florida, and a 48-county region in North Carolina (Duke). Cancer-free controls were frequency matched to the cases on age, race, and residence. After an interview to obtain data on risk factors, a sample of blood or buccal cells was collected for DNA. A total of 503 incident cases (197 at Mayo and 306 at Duke) and 612 controls, were included in this analysis. Cases had earlier age at menarche than controls, and were more likely to be nulliparous, report difficulty becoming pregnant, and use hormone replacement therapy. Risk of ovarian cancer was also inversely associated with use of oral contraceptives and positively associated with body mass index, but there were no differences between cases and controls in family history of breast or ovarian cancer, or cigarette smoking (status or duration). Subjects were genotyped for 7 common single nucleotide polymorphisms (SNPs) in four genes involved in catechol estrogen formation (CYP1A1 V462I, CYP1B1 R48G, A119S, L432V, N453S) or conjugation (COMT V108/158M, SULT1A1 R213H). Data were analyzed using logistic regression, stratified by race, and with adjustment for design factors and potential confounders. Prior to analysis we compared genotype frequencies by race and study site and, among controls, against Hardy-Weinberg equilibrium expectations. African Americans and Caucasians had significantly different genotype frequencies for COMT and the four CYP1B1 SNPs. Odds ratios and 95% confidence intervals for the genotypes of interest by self-reported race were not confounded by any of the measured risk factors, so the race-specific results are adjusted for site and age only. None of the gene polymorphisms involved in catechol estrogen formation (CYP1A1, CYP1B1) or conjugation (COMT, SULT1A1) were strongly associated with risk among Caucasian cases and controls. Among the few African American subjects, no statistically significant associations were evident. We then examined all four genes in combination among the Caucasian subjects. Because of linkage disequilibrium among the CYP1B1 SNPs, we selected a haplotype-tag SNP for CYP1B1 (L432V). This multi-genic model provided evidence for an association between combinations of these SNPs and ovarian cancer risk (p=0.023). Although preliminary, this study provides some support for the hypothesis that low-penetrance susceptibility alleles may influence risk of epithelial ovarian cancer.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]