Because amine carcinogens require metabolic activation in order to exert their carcinogenic effect, genetic polymorphisms in the enzymes that metabolize them may significantly modify cancer risk. As recently reviewed (
Hein 2009), SNPs in
NAT1 can result in significant changes in acetylation rate. The presence of
NAT1*
10 allele or haplotype is associated with several cancers in which cigarette smoking and/or diet are implicated in their etiology, including lung cancer (
Abdel-Rahman et al. 1998;
Wikman et al. 2001;
Gemignani et al. 2007), urinary bladder cancer (
Taylor et al. 1998;
Katoh et al. 1999;
Gago-Dominguez et al. 2003;
Sanderson et al. 2007), colorectal cancer (
Bell et al. 1995a;
Chen et al. 1998;
Ishibe et al. 2002;
Lilla et al. 2006;
Shin et al. 2008), breast cancer (
Millikan et al. 1998;
Zheng et al. 1999;
Ambrosone et al. 2007), pancreatic cancer (
Li et al. 2006;
Jiao et al. 2007;
Suzuki et al. 2008) and non-Hodgkin lymphoma (
Morton et al. 2006,
2007;
Kilfoy et al. 2010). In comparison, the role of
NAT1*
10 in prostate cancer has been understudied. Cigarette smoking is generally not associated with prostate cancer risk, but recent reviews (
Zu and Giovannucci 2009) suggest that it is associated with aggressive prostate cancer. Thus, we investigated whether
NAT1*
10 was associated not only with prostate cancer risk but also with tumor grade and stage in a pilot case–control study of smokers in Finland.
The
NAT1*
10 allele or haplotype, resulting from two single nucleotide substitutions (1088T→A and 1095C→A), causes a shift in the position of the mRNA polyadenylation signal. Studies show that the
NAT1*
10 may represent a rapid acetylator allele, as it was associated with slightly increased acetylation activity in the bladder and colonic mucosa elevated DNA adduct formation in the urinary bladder (
Badawi et al. 1995;
Bell et al. 1995b), and increased
N-acetylation activity in vivo (
Hein et al. 2000), whereas other studies have failed to confirm these observations in other tissues (
Bruhn et al. 1999).
Individuals with rapid acetylator genotypes may have increased capacity to activate pro-carcinogens to their ultimate genotoxic forms within the prostate. Three small studies have suggested an association between
NAT1*
10 and prostate cancer (
Fukutome et al. 1999;
Hein et al. 2002;
Rovito et al. 2005). Although this study observed a slight increase in prostate cancer risk estimates among individuals with the
NAT1*
10 variant allele, our findings were not statistically significant. Furthermore, among cases,
NAT1*
10 was not significantly related to either tumor grade or stage of disease.
Study limitations were considered within our study. First, the low frequency of the NAT1*10 variant allele among our controls (9%) may have limited our statistical power to detect modest associations (OR < 1.5) with prostate cancer susceptibility. Given our sample size and the prevalence of NAT1*10 within our control population, there was 80% power to detect an odds ratio of 2.3. Second, inadequate data did not enable us to examine whether meat-derived mutagens can modify the association between polymorphic NAT1 and prostate cancer. Failure to observe statistically significant associations is partially due to insufficient sample size and the use of a dietary questionnaire as a surrogate of well-done meat intake, which may under/overestimate actual arylamine carcinogen exposures, thereby biasing risk estimates. Overall, larger studies are needed to assess gene–environment interactions effectively. Third, our genotyping method does not preclude the possibility of minor genotype misclassification of our participants, since we did not account for either rare or slow acetylator genotypes or genetic polymorphisms of other metabolism genes. Each of these would not have been informative because of the small sample size.
In conclusion, the current study did not observe a significant association between functional polymorphisms in the NAT1 gene and the risk of prostate cancer within a cohort of Finnish middle-aged male smokers. Given the limited data in the literature, the potential role of polymorphic NAT1 and prostate cancer risk remains inconclusive. Thus, large prospective studies are necessary to validate the findings of this nested case–control study.
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