Ovarian cancer risk and polymorphisms involved in estrogen catabolism

Abstract

Polymorphisms within genes responsible for estrogen catabolism could alter cellular levels of genotoxic 4-hydroxylated catechol estrogens and antiangiogenic 2-methoxyestradiol, thus influencing risk of developing ovarian cancer. We carried out a population-based case-control study of 310 epithelial ovarian cancer cases and 585 controls in African-American and Caucasian women ages 35 to 54 years from Seattle, Atlanta, and Detroit metropolitan areas. Subjects were interviewed and genotyped for CYP1A1 m1, m2, m3, and m4; CYP1B1 Arg48Gly, Ala119Ser, Val32Leu, and Asn 453Ser; COMT Val158Met; UGT1A1 A(TA)nTAA; and SULT1A1 Arg213His polymorphisms. Unconditional logistic regression was used to calculate odds ratios (OR). Haplotypes were inferred and analyzed using models based on expectation-maximization with progressive ligation and Bayesian coalescence theory. CYP1B1 Leu432 carriers were at increased risk of ovarian cancer, with an adjusted OR of 1.5 (95% confidence interval, 1.1-2.3) compared with Val432 homozygotes. The most common CYP1B1 haplotype was Arg48-Ala119-Val432-Asn 453. All other haplotypes with frequencies >5% contained the Leu432 allele. In diplotype analyses, relative to women homozygous for Arg48-Ala119-Val432-Asn453, women with diplotypes containing at least one Leu432 allele had adjusted ORs ranging from 1.3 to 2.2. Among women homozygous for COMT Met 158, carriers of CYP1B1 Leu432 had a 2.6-fold increase in risk relative to CYP1B1 Val432 homozygotes (95% confidence interval, 1.1-5.9). This latter result is opposite in direction from a similar analysis conducted by other investigators in a different study population. No association of ovarian cancer risk was observed with any of the other polymorphisms examined, either alone or in combination. Copyright © 2007 American Association for Cancer Research.