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Role of Androgen Metabolism Genes CYP1B1, PSA/KLK3, and CYP11 in Prostate Cancer Risk and Aggressiveness

¹ Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Lerner School of Medicine, Cleveland, Ohio and ² Department of Epidemiology and Biostatistics, University of California, San Francisco, California

Requests for reprints: John S. Witte, Department of Epidemiology and Biostatistics, University of California, San Francisco, 500 Parnassus Avenue, MU-420 West San Francisco, CA 94143-0560. Phone: 415-476-1374; Fax: 415-476-6014. E-mail: jwitte{at}itsa.ucsf.edu

Candidate genes involved with androgen metabolism have been hypothesized to affect the risk of prostate cancer. To further investigate this, we evaluated the relationship between prostate cancer and multiple potentially functional polymorphisms in three genes involved in androgen metabolism: CYP1B1 (two single nucleotide polymorphisms: 355G/T and 4326C/G), prostate-specific antigen (PSA/KLK3 (three single nucleotide polymorphisms: –158A/G, –4643G/A, and –5412C/T), and CYP11 [(tttta)_n repeat], using a moderately large (n = 918) sibling-based case-control population. When looking at all subjects combined, no association was observed between any polymorphism—or their haplotypes—and prostate cancer risk. However, among men with more aggressive prostate cancer, the CYP1B1 355G/T variant was positively associated with disease: carrying one or two T alleles gave odds ratios (OR) of 1.90 [95% confidence interval (95% CI), 1.09-3.31; P = 0.02] and 3.73 (95% CI, 1.39-10.0; P = 0.009), respectively. Similarly, carrying the CYP1B1 355T-4326C haplotype was positively associated with prostate cancer among men with high aggressive disease (P = 0.01). In addition, the PSA –158G/–158G genotype was positively associated with prostate cancer among men with less aggressive disease (OR, 2.71; 95% CI, 1.06-6.94; P = 0.04). Our findings suggest that CYP1B1 and PSA variants may affect the risk of prostate cancer and tumor aggressiveness.

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