Abstract
BackgroundCigarette smoking is an established risk factor for bladder cancer. Epidemiological and biological data suggest that genetic polymorphisms in activating and detoxifying enzymes may play a role in determining an individual's susceptibility to bladder cancer in particular when in combination with specific environmental exposures such as cigarette smoking. N-acetyltransferase (NAT) enzymes, NAT1 and NAT2, are involved in the activation and detoxification of tobacco smoke constituents. Polymorphisms in these genes alter the ability of these enzymes to metabolize carcinogens, as certain allelic combinations result in a slow or rapid acetylation phenotype. Glutathione S-transferases (GSTs) also detoxify tobacco smoke constituents, and polymorphisms within the GSTM1 and GSTT1 genes can result in a complete lack of enzyme activity.MethodsWe assessed the association between common polymorphisms identified in the GSTM1, GSTT1, NAT1, and NAT2 genes and the risk of bladder cancer in two nested case-control studies within the Nurses' Health Study (n = 78 female cases, 234 female controls) and the Health Professionals' Follow-up Study (n = 139 male cases, 293 male controls). We also evaluated whether cigarette smoking modified the associations of the genotypes and bladder cancer risk in men and women.ResultsOverall, we observed no statistically significant associations between the polymorphisms and bladder cancer risk among men and women, although given our sample size, we had limited power to detect small to moderate effects. There was however the suggestion of an increased risk among female ever smokers with the NAT2 slow genotype and an increased risk in male never smokers with the GSTM1 null genotype.ConclusionIn summary, these prospective results are consistent with previous literature supporting associations between bladder cancer and the NAT2 slow acetylation and the GSTM1 null genotypes.
Highlights
Cigarette smoking is an established risk factor for bladder cancer
We examined the associations between polymorphisms within these key genes and bladder cancer risk in a nested case-control study of women participating in the Nurses' Health Study (NHS) and a nested case-control study of men participating in the Health Professionals' Follow-Up Study (HPFS)
Because the metabolism of tobaccorelated carcinogens may be influenced by the activity of Glutathione S-transferases (GSTs), polymorphisms in Glutathione S-transferase M1 (GSTM1) and Glutathione S-transferase T1 (GSTT1) may modify the risk of bladder cancer associated with these carcinogens
Summary
Cigarette smoking is an established risk factor for bladder cancer. Epidemiological and biological data suggest that genetic polymorphisms in activating and detoxifying enzymes may play a role in determining an individual's susceptibility to bladder cancer in particular when in combination with specific environmental exposures such as cigarette smoking. N-acetyltransferase (NAT) enzymes, NAT1 and NAT2, are involved in the activation and detoxification of tobacco smoke constituents. Polymorphisms in these genes alter the ability of these enzymes to metabolize carcinogens, as certain allelic combinations result in a slow or rapid acetylation phenotype. Cigarette smoking is the predominant risk factor for bladder cancer in males and females [1,2,3,4,5] Carcinogens such as aminobiphenyls (ABPs) found in tobacco have been implicated in bladder cancer etiology in smokers [6]. The slow NAT2 acetylation genotype compromises its detoxification ability, and studies have consistently observed an association between the slow NAT2 genotype and increased bladder cancer risk [11,12,13]. Fewer studies have formally evaluated whether the relationship of cigarette smoking and bladder cancer risk differed by acetylation status [11,16,18,19,20]
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