Case-control study of ovarian cancer and polymorphisms in genes involved in catecholestrogen formation and metabolism

Steroid hormones, such as estrogens, appear to be associated with ovarian c arcinogenesis, but the precise biological mechanisms are unclear. Polymorph isms in genes that regulate the concentration of estrogens and their metabo lites may contribute directly to the individual variation in ovarian cancer risk through a mechanism involving oxidative stress or indirectly by influ encing ovarian cancer susceptibility associated with ovulation and reproduc tion. We conducted a population-based, case-control study of primary ovaria n cancer between 1993 and 1999 in Hawaii to test several genetic and relate d hypotheses. A personal interview and blood specimen were obtained in the subjects' homes. In a sample of 129 epithelial ovarian cancer cases and 144 controls, we compared the frequencies of several polymorphisms in genes th at regulate steroid hormone metabolism and catecholestrogen formation. Mult ivariate unconditional logistic regression was used to model the associatio n of each genetic polymorphism separately after adjusting for age, ethnicit y, and other covariates, The high-activity Val432 allele of the CYP1B1 gene , which may be linked to oxidative stress through elevated 4-hydroxylated c atecholestrogen formation, was associated with an increased risk of ovarian cancer. The Val/Leu genotype for CYP1B1 was associated with an odds ratio of 1.8 (95% confidence interval, 1.0-3.3) and the Val/Val genotype with an odds ratio of 3.8 (95% confidence interval, 1.2-11.4) compared with the Leu /Leu genotype (P = 0,005), Tobacco smokers with at least one CYP1A1 (MspI) m2 allele, one CYP1B1 Val allele, one COMT Met allele, or two CYP1A2 A alle les were at significantly increased risk of ovarian cancer compared to neve r-smokers with CYP1A1 (Mspi) m1/m1, CYP1B1 Leu/Leu, COMT Val/Val, or CYP1A2 A/A genotypes, respectively. We found a positive statistical interaction ( P = 0.03) between tobacco smoking and the CYP1A1 (MspI) polymorphism on the risk of ovarian cancer. None of the other gene-environment (pregnancy, ora l contraceptive pill use) or gene-gene interactions were statistically sign ificant. Although not significant, there was a suggestion that the effect o f the CYP1B1 Val allele was reduced substantially in the presence of the hi gh-activity COMT Met allele, These findings suggest that the CYP1B1-Val all ele and perhaps other genetic polymorphisms in combination with environment al or hormonal exposures are susceptibility factors for ovarian cancer.