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Ovarian Cancer Risk and Polymorphisms Involved in Estrogen Catabolism

¹ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center; ² Department of Epidemiology, School of Public Health and Community Medicine; and ³ Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Washington, Seattle, Washington

Requests for reprints: Sarah K. Holt, Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, P. O. Box 19024 (M4-C308), Seattle, WA 98109-1024. Phone: 206-667-7880; Fax: 206-667-5948. E-mail: sholt{at}u.washington.edu

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, Val⁴³²Leu, and Asn⁴⁵³Ser; 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-Asn⁴⁵³. 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 Met¹⁵⁸, 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. (Cancer Epidemiol Biomarkers Prev 2007;16(3):481–9)

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