UMLS:C0005684 - FACTA Search

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Query: UMLS:C0005684 (bladder cancer)
16,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aromatic amines from cigarette smoking or occupational exposure, recognized risk factors for bladder cancer, are metabolized by N-acetyltransferases (NAT). This study examined the association of (NAT) 1 and 2 genotypes with the risk of smoking-related bladder cancer. A total of 74 pathologically confirmed bladder cancer patients and 184 controls were serially recruited from the National Taiwan University Hospital. History of cigarette smoking and other risk factors for bladder cancer was obtained through standardized questionnaire interview. Peripheral blood lymphocytes were collected from each subject and genotyped for NAT1 and NAT2 by DNA sequencing and polymerase chain reaction-restriction fragment length polymorphism methods. Allele frequency distributions of NAT1 and NAT2 were similar between cases and controls. There was a significant dose-response relationship between the risk of bladder cancer and the quantity and duration of cigarette smoking. The biological gradients were significant among subjects carrying NAT1*10 allele or NAT2 slow acetylators, but not among NAT2 rapid acetylators without NAT1*10 allele. The results are consistent with the hypothesis that NAT1 and NAT2 might modulate the susceptibility to bladder cancer associated with cigarette smoking.
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PMID:Genetic polymorphisms of N-acetyltransferase 1 and 2 and risk of cigarette smoking-related bladder cancer. 1050 82

The 'Mediterranean diet', a diet rich in cereals, fruit and vegetables, has been associated with lowering the risk of a variety of cancers of the digestive tract and the bladder. In a previous study, we showed that the high phenolic content these dietary components produce in the urine could be associated with higher antimutagenic properties of the urine and lower arylamine-DNA adducts in exfoliated bladder cells. We have conducted a case-control study on 162 bladder cancer patients and 104 hospital controls. Total aromatic DNA adducts were measured in white blood cells (WBC) of all subjects by (32)P-post-labelling. Genetically based metabolic polymorphisms were analysed by PCR-RFLP (NAT2, GSTM1, GSTT1, GSTP1, COMT and NQO1). All subjects were interviewed about their tobacco use, dietary habits and other risk factors. The odds ratio (OR) for the risk of bladder cancer according to the presence/absence of WBC DNA adducts (detection limit 0.1 RALx10(8)) was 3.7 [95% confidence interval (CI) 2.2-6.3] and a dose-response relationship with levels of adducts was apparent. The association between case/control status and the presence of WBC DNA adducts was significantly stronger in the subjects who consumed fewer portions of fruit or vegetables per day (OR 7.80, 95% CI 3.0-20.30 for 0-1 portions of vegetables) than in the heavy consumers (OR 4.98 for consumers of 2 portions daily, OR 1.97 for consumers of > or =3 portions; similar but lower estimates were found for the intake of fruit). No association was noticed between tobacco smoking and WBC DNA adducts. Only NAT-2, among the several genotypes considered, was associated in a statistically significant way with the risk of bladder cancer (OR 1.72, 95% CI 1.03-2.87) and with the levels of WBC DNA adducts. Our report suggests that fruit and vegetables could protect against bladder cancer by inhibiting the formation of DNA adducts.
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PMID:White blood cell DNA adducts and fruit and vegetable consumption in bladder cancer. 1065 56

The focus of this review is the molecular genetics, including consensus NAT1 and NAT2 nomenclature, and cancer epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Two N-acetyltransferase isozymes, NAT1 and NAT2, are polymorphic and catalyze both N-acetylation (usually deactivation) and O-acetylation (usually activation) of aromatic and heterocyclic amine carcinogens. Epidemiological studies suggest that the NAT1 and NAT2 acetylation polymorphisms modify risk of developing urinary bladder, colorectal, breast, head and neck, lung, and possibly prostate cancers. Associations between slow NAT2 acetylator genotypes and urinary bladder cancer and between rapid NAT2 acetylator genotypes and colorectal cancer are the most consistently reported. The individual risks associated with NAT1 and/or NAT2 acetylator genotypes are small, but they increase when considered in conjunction with other susceptibility genes and/or aromatic and heterocyclic amine carcinogen exposures. Because of the relatively high frequency of some NAT1 and NAT2 genotypes in the population, the attributable cancer risk may be high. The effect of NAT1 and NAT2 genotype on cancer risk varies with organ site, probably reflecting tissue-specific expression of NAT1 and NAT2. Ethnic differences exist in NAT1 and NAT2 genotype frequencies that may be a factor in cancer incidence. Large-scale molecular epidemiological studies that investigate the role of NAT1 and NAT2 genotypes and/or phenotypes together with other genetic susceptibility gene polymorphisms and biomarkers of carcinogen exposure are necessary to expand our current understanding of the role of NAT1 and NAT2 acetylation polymorphisms in cancer risk.
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PMID:Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms. 1066 61

The NAT2 gene is involved in phase II detoxification of aromatic monoamines, a class of known bladder carcinogens. Certain allelic combinations result in the slow acetylation phenotype, which is thought to increase bladder cancer risk. We conducted a meta-analysis of all identifiable published case-control studies conducted in the general population that had examined the relationship of acetylation status and bladder cancer risk (22 studies, 2496 cases, 3340 controls). Using meta-analysis techniques that employed weighting based on individual-study variation, slow acetylators had an approximately 40% increase in risk compared with rapid acetylators [odds ratio (OR) 1.4, 95% confidence interval (CI) 1.2-1.6]. Statistical tests indicated, however, that pooling of all studies, or of studies conducted in Caucasian populations, hid potentially important heterogeneity in the individual study results, and suggested that the relationship of NAT2 slow acetylation and bladder cancer risk might differ by geographical region. Studies conducted in Asia generated a summary OR of 2.1 (CI 1.2-3.8), in Europe, a summary OR of 1.4 (CI 1.2-1.6), and in the USA, a summary OR of 0.9 (CI 0.7-1.3). Among European studies, the relationship between NAT2 slow acetylation and bladder cancer risk did not differ by method used to assess acetylation status (older drug-based phenotyping methods: 10 studies, OR 1.5, CI 1.2-1.8; more recent NAT2 genotyping methods: four studies, OR 1.4, CI 1.1-1.7). Our results suggest that in most populations studied to date, NAT2 slow acetylation status is associated with a modest increase in bladder cancer risk.
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PMID:NAT2 slow acetylation and bladder cancer risk: a meta-analysis of 22 case-control studies conducted in the general population. 1076 99

N-acetyltransferases are the enzymes present in the cells of most mammal species. In human cells, the activity of two N-acetyltransferases, known as NAT1 and NAT2, is expressed. These enzymes are coded by two different genes: NAT1 and NAT2. Gene NAT1 is expressed in the cells of the majority of tissues and organs, whereas gene NAT2 only in the liver and intestine. Acetylation polymorphism and resultant division into the fast and free acetylators is caused by the occurrence of gene wild allele NAT2 and its mutated forms. A given person shows the fast acetylation phenotype if at least one allele NAT2 is wild. The presence of mutation in both alleles NAT2 is manifested by a free acetylation phenotype. It was indicated that gene NAT1 is also polymorphic, and together with its wild form, the mutated forms are also observed. Genetic polymorphism of NAT1 and NAT2 has serious pharmacological and toxicological consequences. Epidemiological studies show that the free acetylation phenotypes are more susceptible to bladder cancer than the fast ones if they smoke or work under exposure to bicyclic aromatic amines. It has also been evidenced that the fast acetylation phenotypes show enhanced risk of large intestine cancer in conditions of environmental and occupational exposure to heterocyclic amines. It has not as yet been found out whether the acetylation status may be linked with the increased risk of lung cancer.
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PMID:[N-acetyltransferase genetic polymorphism and its role in the development of neoplastic disease]. 1100 74

Arylamines such as 2-naphthylamine and 4-aminobiphenyl are suspected human bladder procarcinogens that require bioactivation to DNA-reactive species to exert their carcinogenic potential. The goals of the present study were (i) to assay for the presence of the arylamine acetyltransferases NAT1 and NAT2, and of the cytochrome P450 isoform CYP1A2, in human bladder epithelium; and (ii) to determine whether the activities of these arylamine biotransforming enzymes differ between bladder cancer patients and control subjects. We measured in-vitro enzyme activities in biopsies of normal, undiseased bladder epithelium obtained from 103 bladder cancer patients. NAT1 activity was detectable in all samples, with mean levels higher than those found in human liver. Kinetic evidence also suggested low levels of NAT2 expression in this tissue, but there was no detectable CYP1A2 by either enzymatic or immunochemical measurements. We also compared several probe drug indices of in-vivo NAT1, NAT2 and CYP1A2 activity between 53 bladder cancer patients and 96 cancer-free control subjects who were carefully matched for age, gender and smoking status. NAT1 and NAT2 genotypes were also determined. No significant differences were found between bladder cancer patients and control subjects for a number of individual phenotypic or genotypic predictors of enzyme function. Our results suggest that although expression of particular arylamine biotransforming enzymes within the bladder tissue could play a significant role in locally bioactivating arylamine procarcinogens in theory, interindividual variations in CYP1A2, NAT1 and NAT2 activities do not significantly differ between bladder cancer patients and control subjects when potential arylamine exposures are controlled for
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PMID:Variation in enzymes of arylamine procarcinogen biotransformation among bladder cancer patients and control subjects. 1120 33

The role of hereditary polymorphisms of the arylamine N-acetyltransferase 1 (NAT1) gene in the etiology of urinary bladder cancer is controversial. NAT1 is expressed in the urothelium and may O-acetylate hydroxyl amines, particularly in subjects with low NAT2 activity. Thus, NAT1 polymorphisms may affect the individual bladder cancer risk by interacting with environmental factors (smoking and occupational risks) and by interacting with the NAT2 gene. We studied the frequencies of the NAT1 haplotypes *3, *4, *10, *11, *14, *15, *17, and *22 in 425 German bladder cancer patients and 343 controls by PCR-RFLP. NAT1*10 allelic frequency was lower in bladder cancer patients (15.1%) compared with controls (20.4%; P = 0.012). Genotypes that included NAT1*10 were significantly less frequent among the cases (odds ratio adjusted for age, gender, and smoking, 0.65; 95% confidence interval, 0.46-0.91; P = 0.013). Two subtypes of NAT1*11 were detected: *11A (-344T, -40T, 445A, 459A, 640G, and 1095A) and *11C (-344T, -40T, 459A, 640G, and 1095A). The allele frequency of NAT1*11 was 4.3% in the cases versus 3.9% in the controls. The rare low-active NAT1*14A was overrepresented in the cases (P = 0.026). With regard to the NAT2 genotype, our data showed: (a) a partial linkage of NAT1*10 to NAT2*4; (b) a clear underrepresentation of NAT1*10 genotypes among rapid NAT2 genotypes in the cases studied (odds ratio, 0.39; 95% confidence interval, 0.22-0.68; P = 0.001), and (c) a gene-gene-environment interaction. NAT2*slow/NAT1*4 genotype combinations with a history of occupational exposure were 5.96 (2.96-12.0) times more frequent in cancer cases than in controls without risk occupation (P < 0.0001). Hence, our data suggest that individuals provided with NAT2*4 and NAT1*10 are at a significantly lower risk for bladder cancer, particularly when exposed to environmental risk factors.
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PMID:Association of NAT1 and NAT2 polymorphisms to urinary bladder cancer: significantly reduced risk in subjects with NAT1*10. 1143 40

The aim of this study was to investigate the association of NAT2 gene polymorphism with bladder cancer using the data derived from the International Project on Genetic Susceptibility to Environmental Carcinogens. Four case control studies conducted in four European countries, plus two case series, one from England and one from Germany, for a total of 1530 cases and 731 controls (all Caucasian) were included. The interaction between NAT2 and bladder cancer considering smoking habits and occupational exposure was studied. There was a significant association between NAT2 and bladder cancer (odds ratio: 1.42, 95% confidence interval: 1.14-1.77), with a slightly significant heterogeneity among studies. However, heterogeneity disappeared when smokers were divided into current and ex-smokers. The risk of cancer was elevated in smokers and occupationally exposed subjects, with the highest risk among slow acetylators. The increase in risk was limited, in fact, to current smokers (odds ratio = 1.74, 95% confidence interval: 0.96-3.15). This analysis confirms that the NAT2 genotype is a risk factor for bladder cancer by interacting with smoking or occupational exposures. Our observation suggests that NAT2 is not a risk factors per se but modulates the effect of carcinogens contained in tobacco smoke (probably arylamines) or associated with occupational exposures.
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PMID:Current smoking, occupation, N-acetyltransferase-2 and bladder cancer: a pooled analysis of genotype-based studies. 1175 41

Aromatic and heterocyclic amines require metabolic activation to electrophilic intermediates that initiate carcinogenesis. N-Acetyltransferase 1 (NAT1) and 2 (NAT2) are important enzymes in the biotransformation of these carcinogens and exhibit genetic polymorphism. Human NAT1 and NAT2 alleles are listed at: http://www.louisville.edu/medschool/pharmacology/NAT.html by an international gene nomenclature committee. The high frequency of the NAT1 and NAT2 acetylation polymorphisms in human populations together with ubiquitous exposure to aromatic and heterocyclic amines suggest that NAT1 and NAT2 acetylator genotypes are important modifiers of human cancer susceptibility. For cancers in which N-acetylation is a detoxification step such as aromatic amine-related urinary bladder cancer, NAT2 slow acetylator phenotype is at higher risk. Multiple studies have shown that the urinary bladder cancer risk is particularly high in the slowest NAT2 acetylator phenotype or genotype (NAT2(*)5). In contrast, for cancers in which N-acetylation is negligible and O-acetylation is an activation step such as for heterocyclic amine-related colon cancer, NAT2 rapid acetylator phenotype is at higher risk. Although studies have found associations between NAT1 genotype and various cancers, the findings are less consistent and are not well understood. Since cancer risk requires exposure to aromatic and/or heterocyclic amine carcinogens modified by NAT1 and/or NAT2 acetylator genotype, the results from human epidemiology studies are dependent upon the quality and accuracy of the exposure assessment and genotype determination. Conclusions require understanding the relationship between genotype and phenotype, as well as the role of genetic variation in carcinogen metabolism, DNA repair, and host susceptibility. Investigations have been carried out in rapid and slow acetylator rodent models in which both exposure and genetic variability are tightly controlled. Human NAT1 and NAT2 alleles have been characterized by recombinant expression to further understand the effects of nucleotide polymorphisms on function and phenotype.
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PMID:Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis. 1235 Nov 46

Cigarette smoking is the main risk factor for bladder cancer, accounting for at least 50% of bladder cancer in men. Cigarette smoke is a rich source of arylamines, which are detoxified by the NAT2 enzyme and activated by the NAT1 enzyme to highly reactive species that can form bulky adducts on DNA. DNA damage from such adducts is mainly repaired by the nucleotide excision repair pathway, in which the XPD protein functions in opening the DNA helix. We hypothesized that an XPD codon 751 polymorphism (Lys-to-Gln amino acid change) could affect the repair of smoking-induced DNA damage and could be associated with bladder-cancer risk. We also hypothesized that allelic variants of the NAT1 and NAT2 genes might modify the effect of the XPD codon 751 polymorphism on smoking-associated bladder-cancer risk. We determined the XPD codon 751 genotype for 228 bladder-cancer cases and 210 controls who were frequency-matched to cases by age, sex, and ethnicity, and we used our previously published data on the NAT1 and NAT2 genotypes for these same individuals (J. A. Taylor et al., Cancer Res., 58: 3603-3610, 1998). We found a slight decrease in risk for the XPD codon 751 Gln/Gln genotype (adjusted odds ratio: 0.8; 95% confidence interval: 0.4-1.3) compared with subjects with the Lys/Lys or Lys/Gln genotypes. The analysis with smoking showed that smokers with the Lys/Lys or Lys/Gln genotypes were twice as likely to have bladder cancer than smokers with the Gln/Gln genotype (test of interaction P = 0.03). The combined presence of the NAT1/NAT2 high-risk genotype and the XPD Lys/Lys or Lys/Gln genotypes ignoring smoking had an odds ratio that was only slightly higher than expected, assuming no genotype-genotype interaction (P = 0.52). We found little evidence for a gene-gene-exposure, three-way interaction among the XPD codon 751 genotype, smoking, and the NAT1/NAT2 genotype.
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PMID:XPD codon 751 polymorphism, metabolism genes, smoking, and bladder cancer risk. 1237

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