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Death Receptor 4 and Bladder Cancer Risk¹

Departments of Epidemiology [A. H., R. M. C., Y. Z., M. R. S., X. W.] and Urology [H. B. G.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Tumor necrosis factor-related apoptosis-inducing ligand stimulates the extrinsic apoptoticpathway by binding to death receptors 4 (DR4) and 5 (DR5). In DR4 exon 4, a CG polymorphism at amino acid 626 located immediately 3' to one of the main receptor ligand interface regions, results in a threoninearginine change. We found that the DR4 exon 4 G/G genotype was associated with an overall decreased risk of bladder cancer in Caucasians [odds ratio (OR) = 0.58; 95% confidence interval (CI), 0.38–0.88]. This protective effect was more apparent in younger individuals (OR = 0.42; 95% CI, 0.20–0.87) than in older individuals (OR = 0.60; 95% CI, 0.35–1.02) and in women (OR = 0.45; 95% CI, 0.20–0.99) than in men (OR = 0.60; 95% CI, 0.36–0.99). Moreover, the protective effect was greater for light smokers (OR = 0.19; 95% CI, 0.06–0.59) compared with heavy smokers (OR = 0.83; 95% CI, 0.41–1.69). These data provide the first large-scale molecular epidemiological evidence that the DR4 polymorphism is associated with environmental exposure and bladder cancer risk, possibly through modulating the capacity of the receptor ligand complex to engage the apoptotic pathway.

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