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Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio [S. J. P., P. L. P., A. P. C., G. C.], and Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106-4945 [D. V. C., J. S. W.]
Previous case-only studies have shown that men with the CYP3A4*1B promoter variant are at an increased risk of developing more aggressive forms of prostate cancer. However, no changes in CYP3A4 activity have been found in CYP3A4*1B carriers, suggesting that its association with disease may simply reflect linkage disequilibrium with another functional variant. CYP3A5 is located within 200 kb of CYP3A4, and a variant in CYP3A5 (*1/*3) correlates with function of the CYP3A5 enzyme. In this study, the potential effect of CYP3A4*1B and CYP3A5*1 on prostate cancer risk and aggressiveness were evaluated in a family-based case-control population. The CYP3A4*1B variant was positively associated with prostate cancer among Caucasians with more aggressive disease [odds ratio (OR), 1.91; 95% confidence interval (CI), 1.02–3.57; P = 0.04], and inversely associated with risk among Caucasians with less aggressive disease (OR, 0.08; 95% CI, 0.01–0.49; P = 0.006) and men with an age of diagnosis <63 (OR, 0.51; 95% CI, 0.26–1.00; P = 0.05). The CYP3A5*1 variant was inversely associated with prostate cancer, especially among Caucasians with less aggressive disease (OR, 0.42; 95% CI, 0.22–0.78; P = 0.006). As expected based on these genotype-level results, the CYP3A4*1B/CYP3A5*3 haplotype was positively associated with disease (OR, 2.91; 95% CI, 1.36–6.23; P = 0.006), and the CYP3A4*1B/CYP3A5*1 haplotype was inversely associated with risk among Caucasians with less aggressive disease (OR, 0.07; 95% CI, 0.01–0.51; P = 0.009). These findings suggest that the CYP3A4 and CYP3A5 variants, or other alleles on the haplotypes they help distinguish, are associated with prostate cancer risk and aggressiveness.
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