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.

https://cebp.aacrjournals.org/content/cebp/9/1/29.full.pdf

Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q131, 19q12 and 2q371: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q131, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q371 We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p163, 8q2421 and 8q243, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci

Foreign compound-metabolizing enzymes may modify the risk of chemically induced cancer. We wanted to examine enzymes with putative relevance in urinary bladder cancer using molecular genetic analyses of heritably polymorphic enzymes. Arylamine N-acetyltransferase (NAT2); glutathione S-transferases (GSTs) M1 and T1; microsomal epoxide hydrolase; and cytochrome P-450 enzymes (CYP) 1A1, 2C19, 2D6, and 2E1 were analyzed in 374 cases and in 373 controls in a hospital-based case-control study in Berlin. Slow acetylation was a significant risk factor in heavy smokers [odds ratio (OR), 2.7; 95% confidence interval (CI), 1.0–7.4], with the greatest risk noted for the allele NAT2*5B. GSTM1 deficiency was a risk factor independent of smoking and occupation (OR, 1.6; CI, 1.2–2.2). GSTT1 was associated with cancer risk in the nonsmoker subgroup (OR, 2.6; CI, 1.1–6.0). The two amino acid polymorphisms that are known in microsomal epoxide hydrolase were not associated with bladder cancer risk. CYP2D6 activity was rejected as a risk factor by phenotyping and by detailed molecular genetic analyses. CYP2C19 may have a role in bladder cancer risk, but polymorphisms in CYP1A1 and 2E1 had no statistically significant impact. Deficiencies in both NAT2 and GSTM1 failed to show significant synergistic or antagonistic interactions. In conclusion, molecular genetic analysis of a large sample specified the increased bladder cancer risk of those who are deficient in NAT2 and GSTM1; the other traits proved to be of minor impact.

https://cancerres.aacrjournals.org/content/canres/56/17/3915.full.pdf

Combined Analysis of Inherited Polymorphisms in Arylamine N-Acetyltransferase 2, Glutathione S-Transferases M1 and T1, Microsomal Epoxide Hydrolase, and Cytochrome P450 Enzymes as Modulators of Bladder Cancer Risk

Acetylator genotype and arylamine-induced carcinogenesis.

Establishing causal relationships between environmental exposures and common diseases is beset with problems of unresolved confounding, reverse causation and selection bias that may result in spurious inferences. Mendelian randomization, in which a functional genetic variant acts as a proxy for an environmental exposure, provides a means of overcoming these problems as the inheritance of genetic variants is independent of-that is randomized with respect to-the inheritance of other traits, according to Mendel's law of independent assortment. Examples drawn from exposures and outcomes as diverse as milk and osteoporosis, alcohol and coronary heart disease, sheep dip and farm workers' compensation neurosis, folate and neural tube defects are used to illustrate the applications of Mendelian randomization approaches in assessing potential environmental causes of disease. As with all genetic epidemiology studies there are problems associated with the need for large sample sizes, the non-replication of findings, and the lack of relevant functional genetic variants. In addition to these problems, Mendelian randomization findings may be confounded by other genetic variants in linkage disequilibrium with the variant under study, or by population stratification. Furthermore, pleiotropy of effect of a genetic variant may result in null associations, as may canalisation of genetic effects. If correctly conducted and carefully interpreted, Mendelian randomization studies can provide useful evidence to support or reject causal hypotheses linking environmental exposures to common diseases.

/pdf/mendelian-randomization-can-genetic-epidemiology-help-29g9rz4ofw.pdf

Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology?

A variable but often significant proportion of urinary bladder cancer in urban areas can be attributed to occupational and cultural (cigarette smoking) situations associated with exposures to vario...

/pdf/n-acetyltransferase-phenotype-and-risk-in-urinary-bladder-5f9m6pqzzp.pdf

N-acetyltransferase phenotype and risk in urinary bladder cancer: approaches in molecular epidemiology. Preliminary results in Sweden and Denmark.

A variable but often significant proportion of urinary bladder cancer in urban areas can be attributed to occupational and cultural (cigarette smoking) situations associated with exposures to various arylamines. The variable N-acetylation of carcinogenic arylamines by human hepatic enzyme systems, the known genetic regulation and polymorphic distribution of this enzyme activity in humans, and the known enhanced susceptibility of individuals with the genetically distinct ‘slowacetylator’ phenotype to various arylamine toxicities, has prompted examination of possible correlations between N-acetyltransferase phenotype and urinary bladder cancer risk in rural and urban populations. In this context, N-acetylation is viewed as a component of detoxication pathways with respect to arylamine bladder carcinogenesis. In preliminary utilizations of this approach, a population of urban urinary bladder cancer patients from Copenhagen, Denmark displayed a 13% excess (P ¼ 0.065) of individuals with the slow acetylator phenotype (46/71 ¼ 64.8%) when compared with a Danish control population (38/74 ¼ 51.4%). These data are consistent with the possibility that arylamines may play an etiological role in bladder cancer in this locale and that slow acetylator individuals may be at higher relative risk (1.74) than rapid acetylator individuals. As 95% of patients reported histories of smoking, it was not possible to isolate and examine smoking factors. In contrast, a population of rural urinary bladder cancer patients from Lund, Sweden, where bladder cancer incidence (20/100 000) (1971) is lower than in Copenhagen (43.8/100 000) (1968–72), no difference in slow acetylator distribution was observed between bladder cancer (80/115 ¼ 69.6%) and Swedish control (79/118 ¼ 66.9%) populations, indicating a relative lack of involvement of arylamines in the etiology of rural bladder cancer. Populations of ‘spontaneous’ bladder cancer patients would be expected to contain variable portions of disease related to arylamine exposure and would be less likely to display a detectable correlation than would an industrial population with documentable arylamine exposure. Consequently, confirmation of this hypothesis is being pursued by examination of industrial populations in an effort to obtain an empirical estimate of relative risk for slow and rapid acetylator phenotypes. These studies involve exposure-matched workmen both with and without bladder cancer.

/pdf/n-acetyltransferase-phenotype-and-risk-in-urinary-bladder-3gp79m5ct0.pdf

C. E. Nelson

Papers

N-acetyltransferase phenotype and risk in urinary bladder cancer: approaches in molecular epidemiology. Preliminary results in Sweden and Denmark.

N-acetyltransferase phenotype and risk in urinary bladder cancer: approaches in molecular epidemiology. Preliminary results in Sweden and Denmark