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Benzo(a)pyrene Diol Epoxide-Induced Chromosome 9p21 Aberrations Are Associated with Increased Risk of Bladder Cancer

Departments of ¹ Epidemiology and ² Urology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and ³ Department of Urology, Akita University School of Medicine, Akita, Japan

Requests for reprints: Jian Gu, Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Unit 1340, 1155 Pressler Boulevard, Houston, TX 77030. Phone: 713-792-8016; Fax: 713-792-4657. E-mail: jiangu{at}mdanderson.org

Purpose: Loss of chromosome 9p21 is one of the most frequent genomic alterations in bladder cancer. Alterations of 9p21 and p16 are also frequently seen in the epithelial cells of chronic smokers. We hypothesize that 9p21 is a molecular target of benzo(a)pyrene diol epoxide (BPDE), the metabolic product of tobacco carcinogen benzo(a)pyrene, and 9p21 BPDE sensitivity is a genetic susceptibility factor for bladder cancer.

Material and Methods: In this case-control study of 203 bladder cancer cases and 198 matched healthy controls, we compared the frequencies of BPDE-induced 9p21 aberrations in cultured peripheral blood lymphocytes using fluorescent in situ hybridization and evaluated the association between 9p21 BPDE sensitivity and bladder cancer risk.

Results: We found that BPDE-induced chromosome 9p21 aberrations were significantly higher in peripheral blood lymphocytes of bladder cancer cases (20.76 ± 6.97 per 1,000) than those of controls (16.58 ± 7.07 per 1,000; P < 0.0001). However, no difference was observed for CEP9, a control centromere locus on chromosome 9. Using the median aberration value in the controls as a cutoff point to dichotomize BPDE sensitivity and after adjustment by age, sex, ethnicity, and smoking status, 9p21 BPDE sensitivity was associated with a significantly increased risk of bladder cancer (odds ratio, 5.29; 95% confidence interval, 3.26-8.59), whereas the odds ratio for the CEP9 locus was 0.99 (95% confidence interval, 0.66-1.50). There was also a dose-response relationship between the 9p21 BPDE sensitivity and increased risk for bladder cancer.

Conclusion: 9p21 may be a molecular target for BPDE damage in bladder cancer cases and 9p21 BPDE sensitivity may be a marker of bladder cancer susceptibility. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2445–50)