CYP17 POLYMORPHISMS IN RELATION TO RISKS OF PROSTATE CANCER AND BENIGN PROSTATIC HYPERPLASIA: A POPULATION-BASED STUDY IN CHINA M. Patricia MADIGAN 1 , Yu-Tang GAO 2 , Jie DENG 2 , Ruth M. PFEIFFER 1 , Bao-Li CHANG 3 , Siqun ZHENG 3 , Deborah A. MEYERS 3 , Frank Z. STANCZYK 4 , Jianfeng XU 3 and Ann W. HSING 1 * 1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA 2 Shanghai Cancer Institute, Shanghai, China 3 Human Genomic Center, Wake Forest University, Winston-Salem, NC, USA 4 Department of Obstetrics and Gynecology and Preventive Medicine, School of Medicine, University of Southern California, CA, USA Because androgens likely play a key role in prostate growth and prostate cancer development, variants of genes involved in androgen biosynthesis may be related to prostate cancer risk. The enzyme P450c17, encoded by the CYP17 gene, catalyzes the conversion of progesterone and pregnenolone into precursors of potent androgens. In the 5 promoter region of the CYP17 gene, a T (A1 allele) to C substitution (A2 allele) has been hypothesized to increase CYP17 gene expression, resulting in higher levels of androgens. To inves- tigate a possible role of CYP17 in prostate diseases, we eval- uated the risk of prostate cancer and benign prostatic hyper- plasia (BPH) in relation to variation in CYP17 genotype in a population-based case-control study conducted in Shanghai, China. The study included 174 prostate cancer cases, 182 BPH cases and 274 population controls. We observed no statistically significant overall associations of CYP17 geno- types with prostate cancer risk, although associations of the A1/A1 (odds ratio (OR) 1.42, 95% confidence interval (CI) 0.83–2.48) and A1/A2 (OR 1.41, 95% CI 0.91–2.17) genotypes with prostate cancer were suggested. A similar association of the A1/A1 genotype with BPH was suggested. We found no associations of CYP17 genotypes with serum sex hormone levels or other biomarkers after correction for multiple com- parisons. Large population-based studies are needed to clar- ify whether CYP17 plays a role in prostate cancer risk and whether genotype effects vary in different racial/ethnic and other subgroups. © 2003 Wiley-Liss, Inc. Key words: prostate cancer; benign prostatic hyperplasia; CYP17, genetic polymorphism; androgen; China Because androgens likely play a key role in prostate growth and prostate cancer development, variants of genes involved in andro- gen metabolism may be related to prostate disease risk. 1,2 The enzyme P450c17, encoded by the CYP17 gene on chromosome 10, catalyzes the conversion of progesterone and pregnenolone into the androgens androstenedione and dehydroepiandrosterone (DHEA), respectively, which are precursors of potent androgens. 3 In the 5' promoter region of the CYP17 gene, a T to C substi- tution (A2 allele) has been hypothesized to increase CYP17 gene expression, resulting in higher levels of androgens, relative to those associated with the A1 allele. 4 Results from molecular epi- demiologic studies of CYP17 and prostate cancer have been mixed (Table I): while one study reported an increased risk for the A1/A1 genotype, 5 results from other studies suggest either an increased risk for the A2/A2 genotype 6–9 or no association in homozygous genotype comparisons. 10 –13 One recent study found that in men with BMI under 24 kg/m 2 , an association with the A1/A1 genotype was suggested, while among men with BMI of 30 kg/m 2 or greater, an association with the A2/A2 genotype was observed. 14 Addi- tionally, a recent study in Japanese men found an increased risk of benign prostatic hyperplasia (BPH) in men with the A1/A1 geno- type. 5 To study further a possible role of CYP17 in prostate disease, we evaluated the risk of prostate cancer and BPH in relation to this variation in the CYP17 gene in a population-based case-control study conducted in Shanghai, China. MATERIAL AND METHODS Prostate cancer cases Details of the study have been reported elsewhere. 15–19 All study subjects were born in China. Briefly, cases of primary prostate cancer (ICD9 185) that were newly diagnosed between 1993 and 1995 were identified through a rapid reporting system that was established between the Shanghai Cancer Institute and 28 collab- orating hospitals in urban Shanghai. Cases were permanent resi- dents in 10 urban districts of Shanghai who did not have a history of any other cancer. A total of 268 eligible cases were identified, representing 95% of the cases diagnosed in urban Shanghai during this time period. Of the 268 eligible cases, 243 (91%) were interviewed. Since prostate cancer screening is not widespread in China, most of the identified cancer cases were symptomatic and clinically significant. After consensus review by U.S. and Shanghai pathology teams, 4 cancer cases were classified as having BPH and excluded from the study. Whenever possible, clinical stage and histologic grade were assessed. Localized cancer is defined as organ-confined can- cer (clinical stage A and B), and advanced cancer is defined as regional or remote cancer (stage C and D). Benign prostatic hyperplasia patients Upon identification of a prostate cancer case, the next BPH patient admitted to the same hospital as the index cancer case for either transurethral resection of the prostate or prostatectomy was invited to participate in the study. BPH cases underwent digital rectal exam, prostate specific antigen levels measurement and transurethral resection of the prostate. Pathology slides were re- viewed to confirm BPH status and assess whether there was histologic evidence of cancer. The study was limited to BPH cases who were permanent residents of Shanghai and who had no history of any cancer. In total, 206 (97%) of the 213 eligible BPH subjects were interviewed. *Correspondence to: Division of Cancer Epidemiology and Genetics, National Cancer Institute, EPS-MSC 7234, 6120 Executive Boulevard, Bethesda MD 20852-7234, USA. Fax: +001-301-402-0916. E-mail: hsinga@mail.nih.gov Received 12 December 2002; Revised 5 May 2003; Accepted 13 May 2003 DOI 10.1002/ijc.11378 Int. J. Cancer: 107, 271–275 (2003) © 2003 Wiley-Liss, Inc. Publication of the International Union Against Cancer