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V89L Polymorphism of the 5-Reductase Type II Gene (SRD5A2), Endogenous Sex Hormones, and Prostate Cancer Risk

¹ Program in Epidemiology and ² Program in Cancer Prevention, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center; ³ Department of Epidemiology, School of Public Health and Community Medicine, University of Washington; and ⁴ Swedish Medical Center Cancer Institute, Seattle, Washington

Requests for reprints: Chu Chen, Fred Hutchinson Cancer Research Center, Mailstop M5-C800, 1100 Fairview Avenue North, P.O. Box 19024, Seattle, WA 98109-1024. Phone: 206-667-6644; Fax: 206-667-2537. E-mail: cchen{at}fhcrc.org

We examined the combined effect of circulating sex hormones and SRD5A2 V89L polymorphism on prostate cancer risk in a case-control study (300 cases and 300 controls) nested within the Carotene and Retinol Efficacy Trial. A moderate increase in risk associated with above-median serum levels of androstenedione and dehydroepiandrosterone sulfate (DHEAS) was present irrespective of V89L genotype. However, in L/L or V/L men, above-median DHEAS levels were associated with an increased risk of aggressive tumors [odds ratios (OR), 3.12; 95% confidence interval (95% CI), 1.28-7.63] but not of nonaggressive ones (OR, 0.56; 95% CI, 0.25-1.25). Above-median serum levels of free estradiol were associated with a lower risk, especially for aggressive cancer. The association with aggressive disease was more pronounced in men with a V/V genotype (OR, 0.34; 95% CI, 0.14-0.81), than in men with an L/L or V/L genotype (OR, 0.77; 95% CI, 0.37-1.60). Above-median levels of 3-diol G were associated with an increased risk, but only in men with the L/L or V/L genotype (OR, 2.16; 95% CI, 1.31-3.56). The increase in risk in L/L and V/L men was restricted to aggressive tumors. Our study observed that only in men with the L/L or V/L genotype were increased serum levels of DHEAS and 3-diol G positively associated with a higher risk of aggressive prostate cancer. Free estradiol levels were negatively associated with risk of aggressive prostate cancer in men with the V/V genotype. However, the absence of an overall association between V89L genotype and aggressive prostate cancer argues for a cautious interpretation of these observations. (Cancer Epidemiol Biomarkers Prev 2008;17(2):286–91)