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Biochem Genet. Author manuscript; available in PMC Aug 15, 2011.
Published in final edited form as:
PMCID: PMC3155982
NIHMSID: NIHMS296570
Lack of Association of the N-acetyltransferase NAT1*10 Allele with Prostate Cancer Incidence, Grade, or Stage Among Smokers in Finland
LaCreis R. Kidd
Department of Pharmacology and Toxicology, James Graham Brown Cancer Center, University of Louisville Health Sciences Center, Clinical and Translational Research Building, 505 S. Hancock St., Louisville, KY 40202, USA
Cancer Prevention Studies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
David W. Hein
Department of Pharmacology and Toxicology, James Graham Brown Cancer Center, University of Louisville Health Sciences Center, Clinical and Translational Research Building, 505 S. Hancock St., Louisville, KY 40202, USA
Karen Woodson
Cancer Prevention Studies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
Philip R. Taylor
Cancer Prevention Studies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
Demetrius Albanes
Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA
Jarmo Virtamo
Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland
Joseph A. Tangrea
Cancer Prevention Studies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
lrkidd01/at/louisville.edu
Genetic variations in xenobiotic metabolizing genes can influence susceptibility to many environmentally induced cancers. Inheritance of the N-acetyltransferase 1 allele (NAT1*10), linked with increased metabolic activation of pro-carcinogens, is associated with an increased susceptibility to many cancers in which cigarette- or meat-derived carcinogens have been implicated in their etiology. The role of NAT1*10 in prostate cancer is under studied. Although cigarette smoking is not considered a risk factor for prostate cancer, a recent review suggests it may play a role in disease progression. Consequently, we examined the association of NAT1*10 with prostate cancer risk, grade, and stage among 400 Finnish male smokers using a case–control study design. Following genotyping of 206 patients and 196 healthy controls, our results do not support the role of NAT1*10 in relation to prostate cancer risk (OR = 1.28; 95% CI, 0.66–2.47), aggressive disease (OR = 0.58; 95% CI, 0.13–2.67), or advanced disease (OR = 1.19; 95% CI, 0.49–2.91).
Keywords: N-acetyltransferase 1, Prostate cancer, Disease progression, Arylamine carcinogens
Humans are exposed to arylamine carcinogens such as 2-amino-l-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) in well-done meats (Keating and Bogen 2004), cigarette smoke (Manabe et al. 1991), and airborne particulates (Manabe et al. 1993). PhIP induces prostate tumors in rats (Shirai et al. 1997) and is classified as a probable human carcinogen (National Toxicology Program 2005). A related arylamine carcinogen (3,2-dimethyl-4-aminobiphenyl) also induces prostate tumors in rats (Katayama et al. 1982; Ito et al. 1988; Kohno et al. 2005).
Multiple studies report associations between meat intake, including well-done meat intake, and prostate cancer (Cross et al. 2005; Koutros et al. 2008; Sinha et al. 2009). In contrast, evidence for an association between cigarette smoking and prostate cancer risk was not found in a systematic review of prospective, nested case–control and retrospective cohort studies (Hickey et al. 2001). More recent studies suggest that risk factors for prostate cancer progression differ from those for prostate cancer risk (Giovannucci et al. 2007) raising the possibility that cigarette smoking may be associated with prostate cancer severity (Watters et al. 2009).
Regardless of exposure source, arylamine carcinogens require metabolic activation by hepatic and/or extrahepatic derived enzymes, such as cytochrome P-450 and N-acetyltransferases. Human prostate epithelial cells can activate arylamine carcinogens (Williams et al. 2000; Lawson and Kolar 2002) and their N-hydroxylated metabolites (Wang et al. 1999; Williams et al. 2000) to DNA adducts, which if not repaired may lead to mutations and tumors. Syrian hamster N-acetyltransferase 1 (NAT1) partially purified from prostate cytosol catalyzes the O-acetylation of N-hydroxylated arylamine metabolites leading to DNA adducts (Hein et al. 2003). Human NAT1 is ubiquitously expressed in virtually all tissues (Husain et al. 2007) including prostate (Agundez et al. 1998; Lawson and Kolar 2002; Al-Buheissi et al. 2006; John et al. 2009).
Genetic polymorphisms in enzymes catalyzing the metabolism of arylamine carcinogens may influence susceptibility to cancer (Hein 2009). The human NAT1 gene confers its most common genetic polymorphisms in its 3′-untranslated region. NAT1*10 is a variant allele (haplotype) that differs from the NAT1*4 reference allele (haplotype) by two single nucleotide polymorphisms (SNP): 1088T→A; rs1057126 and 1095C→A; rs15561 (Hein et al. 2008b). Functional expression of genetic polymorphism in prostate N-acetyltransferase capacity has been reported in the Syrian hamster and rat (Hein et al. 2003, 2008a). DNA adduct levels in the prostate were higher in rapid than in slow acetylator rats following administration of PhIP (Purewal et al. 2000), whereas the opposite finding was observed with 3,2-dimethyl-4-aminobiphenyl (Jiang et al. 1999). Since NAT1 activates arylamine carcinogens that induce prostate cancer in the rat and is expressed in human prostate, a pilot nested case–control study was designed to examine the association of NAT1*10 with prostate cancer risk, grade, and stage among male smokers in Finland.
Study Subjects
Cases and controls were identified among participants of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study, a randomized cancer prevention trial study conducted in Finland as previously described (Albanes et al. 1995; Heinonen et al. 1998). Briefly, 29,133 current smokers (five or more cigarettes per day) were recruited from a total smoking population of 290,406 male residents of Southwestern Finland (age range 50–69 years). Participants were randomized to receive alpha-tocopherol alone, beta-carotene alone, alpha-tocopherol and beta-carotene combined, or a placebo for 5–8 years (1985–1993) to test the efficacy of antioxidant supplementation on prostate cancer. At baseline, demographic, meat intakes, smoking history, and other characteristics were collected. Dietary information was obtained from a validated self-administered food-use questionnaire given to all participants prior to randomization. The questionnaire was linked to the food composition database of the National Public Health Institute of Finland. All study participants provided informed consent for participation in the ATBC Study under a protocol approved by the institutional review boards of both the National Cancer Institute (USA) and the National Public Health Institute of Finland.
Selection of Cases and Controls
Based on the availability of whole blood collected among 20,305 men, the nested case–control sample consisted of 206 incident prostate cancer cases (ICD-185) and 194 controls (frequency matched to cases on age, ±5 years). Prostate cancer diagnostic information was obtained through the Finnish Cancer Registry and Register of Causes of Death based on review of medical records and histopathologic/cytologic specimens by study oncologists and pathologists, respectively. Information on prostate tumor grade and TNM stage was available for 85 and 100% of the cases, respectively. Prostate cancer cases were diagnosed with localized (stage 0–II), regional (stage III), or remote (stage IV) disease. In addition, cases were diagnosed with well differentiated (41%; Grade 1, roughly equivalent to Gleason grade 1–4), moderately differentiated (42%; Grade 2, Gleason grade 5–7), and poorly differentiated (17%; Grade 3, Gleason grade 8–10) disease.
NAT1 Genotyping
Following isolation of genomic DNA, two SNPs (1088T→A; rs1057126 and 1095C→A; rs15561), diagnostic for the presence of the NAT1*10 allele, were detected by polymerase chain reaction assay combined with matrix assisted laser desorption/ionization time-of-flight mass spectrometry. The following amplification primers were used: forward (5′-acg ttg gat gac ata ace aca aac ctt ttc-3′), reverse (5′-acg ttg gat gtt tec aag ata ace aca ggc-3′), and extension (5′-cag gcc ate ttt aaa aga cat tt-3′) primers to detect 1088T→A; and forward (5′-acg ttg gat gac ata ace aca aac ctt ttc-3′), reverse (5′-acg ttg gat gtt tec aag ata ace aca ggc-3′ reverse), and extension (5′-taa cca cag gcc ate ttt aaa a-3′) to detect 1095C→A. Genotype data were successfully obtained for 200 cases and 184 controls. Assay failures or insufficient DNA prevented genotyping of a small percentage of cases (3%; n = 6) and controls (5%; n = 10).
Statistical Analyses
Descriptive analyses for categorical and continuous traits at baseline used the χ2 test of heterogeneity and Wilcoxon rank sum test, respectively. The χ2 test was used to test the hypothesis that the distribution of NAT1*10 was similar between prostate cancer cases and controls. Associations between NAT1*10 and prostate cancer risk or tumor grade or stage were evaluated using odds ratios and corresponding 95% confidence intervals (CI) estimated using unconditional logistic regression analyses controlled for age, intervention group, study clinic, meat intake, and other potential confounders. Individuals without the NAT1*10 allele were used as the reference group. The odds ratios for poorly differentiated (tumor grade = 3) or regional/remote (TNM tumor stages 3 and 4) prostate cancer were computed versus well or moderately differentiated (tumor grade<2) and localized (TNM stage<2) prostate cancer as the referent groups, respectively. A likelihood ratio test was used to evaluate whether meat intake (e.g., beef, broiled chicken, fish, pork, and poultry) modified the association of NAT1*10 with prostate cancer by comparing a reduced model with an extended model containing relevant interaction terms in addition to the main effects. Covariates were included in regression models if they changed the risk estimates by greater than 20% or significantly altered the likelihood ratio statistic. Two-sided P values were used with a statistical significance level of P<0.05. All statistical tests were performed using SAS 8.0 (Cary, NC).
No significant differences in baseline characteristics were observed between cases and controls (Table 1). Prostate cancers were diagnosed an average of 5.5 ± 2.0 years after study entry, when the cases were 66.4 ± 5.4 years old. Within this Finnish cohort, the prevalence of NAT1*10 did not differ significantly between prostate cancer cases and controls (Table 2). Since the odds ratios did not change significantly when age, study clinic, intervention group, lifestyle factors (e.g., meat intake), and other covariates were included in the logistic regression model; univariate risk estimates are presented throughout this report. Additionally, within a case–case analysis, a significant association was not observed between NAT1*10 and disease progression assessed by tumor grade (Table 3) and stage (Table 4).
Table 1
Table 1
Demographic, lifestyle, and other characteristics of participants.
Table 2
Table 2
Association between NAT1*10 and prostate cancer incidence
Table 3
Table 3
Association between NAT1*10 and prostate cancer grade
Table 4
Table 4
Association between NAT1*10 and prostate cancer stage
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.
Acknowledgments
We thank Rama Modali and Kirsten Taylor for technical support and Mike Barrett, Kirk Snyder, and Tan Carly for data management. This study was supported in part by Public Health Service contracts NOl CN45165 and 45035 from the National Cancer Institute, United States Department of Health and Human Services.
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