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Pairwise Combinations of Estrogen Metabolism Genotypes in Postmenopausal Breast Cancer Etiology

¹ Center for Clinical Epidemiology and Biostatistics and Department of Biostatistics and Epidemiology; ² Abramson Cancer Center; ³ Department of Medicine; ⁴ Division of Oncology, Children's Hospital of Philadelphia; ⁵ Fox Chase Cancer Center, Philadelphia, Pennsylvania; and ⁶ Department of Obstetrics and Gynecology Oregon Health and Science University, Portland, Oregon

Requests for reprints: Timothy Rebbeck, Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, 904 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021. Phone: 215-898-1793; Fax: 215-898-2265. E-mail: trebbeck{at}cceb.med.upenn.edu

Estrogen exposures have been associated with breast cancer risk, and genes involved in estrogen metabolism have been reported to mediate that risk. Our goal was to better understand whether combinations of candidate estrogen metabolism genotypes are associated with breast cancer etiology. A population-based case-control study in three counties of the Philadelphia Metropolitan area was undertaken. We evaluated seven main effects and 21 first-order interactions in African Americans and European Americans for genotypes at COMT, CYP1A1, CYP1A2, CYP1B1, CYP3A4, SULT1A1, and SULT1E1 in 878 breast cancer cases and 1,409 matched random digit–dialed controls. In European Americans, we observed main effect associations of genotypes containing any CYP1A1*2C (odds ratio, 1.71; 95% confidence interval, 1.09-2.67) and breast cancer. No significant main effects were observed in African Americans. Three significant first-order interactions were observed. In European Americans, interactions between SULT1A1*2 and CYP1A1*2C genotypes (P_interaction < 0.001) and between SULT1E1 and CYP1A2*1F genotypes were observed (P_interaction = 0.006). In African Americans, an interaction between SULT1A1*2 and CYP1B1*4 was observed (P_interaction = 0.041). We applied the false-positive report probability approach, which suggested that these associations were noteworthy; however, we cannot rule out the possibility that chance led to these associations. Pending future confirmation of these results, our data suggest that breast cancer etiology in both European American and African American postmenopausal women may involve the interaction of a gene responsible for the generation of catecholestrogens with a gene involved in estrogen and catecholestrogen sulfation. (Cancer Epidemiol Biomarkers Prev 2007;16(3):444–50)

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