Gene Summary

Gene:NAT2; N-acetyltransferase 2
Aliases: AAC2, PNAT, NAT-2
Summary:This gene encodes an enzyme that functions to both activate and deactivate arylamine and hydrazine drugs and carcinogens. Polymorphisms in this gene are responsible for the N-acetylation polymorphism in which human populations segregate into rapid, intermediate, and slow acetylator phenotypes. Polymorphisms in this gene are also associated with higher incidences of cancer and drug toxicity. A second arylamine N-acetyltransferase gene (NAT1) is located near this gene (NAT2). [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:arylamine N-acetyltransferase 2
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NAT2 (cancer-related)

Zhu X, Liu Y, Chen G, et al.
Association between NAT2 polymorphisms and acute leukemia risk: A meta-analysis.
Medicine (Baltimore). 2019; 98(12):e14942 [PubMed] Related Publications
BACKGROUND: N-acetyl-transferase 2 (NAT2) polymorphisms have been demonstrated to be associated with acute leukemia (AL); however, the results remain controversial. The present meta-analysis was performed to provide more precise results.
METHODS: Pubmed, Embase, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases were used to identify eligible studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between NAT2 polymorphisms and AL risk.
RESULTS: Increased risk was found under both heterozygous (OR 1.24, 95% CI 1.02-1.51) and recessive model (OR 1.28, 95% CI 1.06-1.55) for rs1801280. The slow acetylator phenotype (OR 1.22, 95% CI 1.07-1.40) also increased AL risk. Subgroup analysis demonstrated that rs1801280 increased AL risk under the recessive model (OR 1.14, 95% CI 0.93-1.41) in Caucasian population and the co-dominant (OR 1.77, 95% CI 1.40-2.23), homozygous (OR 3.06, 95% CI 1.88-4.99), dominant (OR 2.22, 95% CI 1.56-3.17), recessive model (OR 2.06, 95% CI 1.35-3.16) in the Mixed populations. Association between rs1799929 and decreased AL risk was found in the co-dominant (OR 0.82, 95% CI 0.70-0.97), homozygous (OR 0.65, 95% CI 0.46-0.93), heterozygous (OR 0.71, 95% CI 0.51-1.00), and the recessive model (OR 0.68, 95% CI 0.49-0.94) in the Caucasian group. As for rs1799931, the same effects were found in the co-dominant (OR 0.68, 95% CI 0.49-0.94) and the dominant model (OR 0.68, 95% CI 0.48-0.97) in the mixed group.
CONCLUSION: rs1801280 and the slow acetylator phenotype are risk factors for AL.

Berrandou T, Mulot C, Cordina-Duverger E, et al.
Association of breast cancer risk with polymorphisms in genes involved in the metabolism of xenobiotics and interaction with tobacco smoking: A gene-set analysis.
Int J Cancer. 2019; 144(8):1896-1908 [PubMed] Related Publications
Single nucleotide polymorphisms (SNPs) in genes involved in xenobiotics metabolism (XM) are suspected to play a role in breast cancer risk. However, previous findings based on a SNP by SNP approach need to be replicated taking into account the combined effects of multiple SNPs. We used a gene-set analysis method to study the association between breast cancer risk and genetic variation in XM genes (seen as a set of SNPs) and in the XM pathway (seen as a set of genes). We also studied the interaction between variants in XM genes and tobacco smoking. The analysis was conducted in a case-control study of 1,125 cases and 1,172 controls. Using a dedicated chip, genotyping data of 585 SNPs in 68 XM genes were available. Genetic variation in the whole XM pathway was significantly associated with premenopausal breast cancer risk (p = 0.008). This association was mainly driven by genetic variation in NAT2, CYP2C18, CYP2C19, AKR1C2 and ALDH1A3. The association between the XM gene pathway and breast cancer was observed among current and previous smokers, but not among never smokers (p = 0.013 for interaction between XM genes and tobacco smoking status). The association with breast cancer risk indicates that XM genes variants may play a role in breast carcinogenesis through their detoxification function of environmental pollutants, such as those contained in tobacco smoke.

Farvid MS, Stern MC, Norat T, et al.
Consumption of red and processed meat and breast cancer incidence: A systematic review and meta-analysis of prospective studies.
Int J Cancer. 2018; 143(11):2787-2799 [PubMed] Related Publications
Prior studies on red and processed meat consumption with breast cancer risk have generated inconsistent results. We performed a systematic review and meta-analysis of prospective studies to summarize the evidence regarding the relation of red meat and processed meat consumption with breast cancer incidence. We searched in MEDLINE and EMBASE databases through January 2018 for prospective studies that reported the association between red meat and processed meat consumption with incident breast cancer. The multivariable-adjusted relative risk (RR) was combined comparing the highest with the lowest category of red meat (unprocessed) and processed meat consumption using a random-effect meta-analysis. We identified 13 cohort, 3 nested case-control and two clinical trial studies. Comparing the highest to the lowest category, red meat (unprocessed) consumption was associated with a 6% higher breast cancer risk (pooled RR,1.06; 95% confidence intervals (95%CI):0.99-1.14; I

Carta A, Pavanello S, Mastrangelo G, et al.
Impact of Occupational Exposures and Genetic Polymorphisms on Recurrence and Progression of Non-Muscle-Invasive Bladder Cancer.
Int J Environ Res Public Health. 2018; 15(8) [PubMed] Free Access to Full Article Related Publications

Carlisle SM, Hein DW
Retrospective analysis of estrogen receptor 1 and N‑acetyltransferase gene expression in normal breast tissue, primary breast tumors, and established breast cancer cell lines.
Int J Oncol. 2018; 53(2):694-702 [PubMed] Free Access to Full Article Related Publications
The expression levels of estrogen receptor 1 (ESR1), arylamine N‑acetyltransferase 1 (NAT1), and arylamine N‑acetyltransferase 2 (NAT2) are implicated in breast cancer; however, their co-expression profiles in normal breast tissue, primary breast tumors and established breast cancer cell lines are undefined. NAT1 expression is widely reported to be associated with ESR1 expression and is frequently investigated in breast cancer etiology. Furthermore, the NAT2 phenotype has been reported to modify breast cancer risk in molecular epidemiological association studies. Understanding the relationships between the expression levels of these genes is essential to understand their role in breast cancer etiology and treatment. In the present study, NAT1, NAT2 and ESR1 expression data were accessed from repositories of RNA‑Seq data covering 57 breast cancer cell lines, 1,043 primary breast tumors and 99 normal breast tissues. The relationships between gene expression, and between NAT1 activity and RNA expression in breast cancer cell lines were evaluated using non-parametric statistical analyses. Differences in gene expression in each dataset, as well as gene expression differences in normal breast tissue compared to primary breast tumors, and stratification by estrogen receptor status were determined. NAT1 and NAT2 mRNA expression were detected in normal and primary breast tumor tissues; NAT1 expression was much higher than NAT2. NAT1 and ESR1 expression were strongly associated, whereas NAT2 and ESR1 expression were not. Although NAT1 and NAT2 expression were associated, the magnitude was moderate. NAT1, NAT2, and ESR1 expression were increased in primary breast tumor tissue compared with normal breast tissue; however, the magnitude and significance of the differences were lower for NAT2. Analysis of NAT1, NAT2, and ESR1 expression in normal and primary breast tissues and breast cancer cell lines suggested that NAT1 and NAT2 expression are regulated by distinctive mechanisms, whereas NAT1 and ESR1 expression may have overlapping regulation. Defining these relationships is important for future investigations into breast cancer prevention.

Pál I, Illés Á, Gergely L, et al.
The Impact of Drug Metabolism Gene Polymorphisms on Therapeutic Response and Survival in Diffuse Large B-Cell Lymphoma Patients.
Isr Med Assoc J. 2018; 20(4):217-221 [PubMed] Related Publications
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) accounts for 30% of all non-Hodgkin lymphomas (NHL) and 80% of agressive lymphomas. Besides the traditional International Prognostic Index (IPI), some other factors may also influence the prognosis of DLBCL patients.
OBJECTIVES: To study how the genetic polymorphisms in the metabolic pathway influence the event-free and overall survivals and therapeutic responses in DLBCL.
METHODS: The study was comprised of 51 patients (32 men, 19 women). The average age was 53.1 years. DLBCL was diagnosed between 2011 and 2016 and the average follow-up time was 3.78 years. These patients received 1-8 cycles (an average of 6.2 cycles) of rituximab, cyclophosphamide, doxorubicin, vincristin, prednisolon (R-CHOP) immunochemotherapy. Real-time polymerase chain reaction was used to determine the genetic polymorphisms of CYP2E1, GSTP1, NAT1, and NAT2 genes.
RESULTS: Our results showed that the polymorphisms of CYP2E1, GSTP1, and NAT1 genes did not influence the prognosis of DLBCL patients significantly. In terms of the NAT2 gene, GG homozygous patients showed slightly better therapeutic response and survival results compared to those bearing an A allele; however, the differences were not statistically significant.
CONCLUSIONS: Our results could not confirm that genetic polymorphism in metabolic pathways has any predictive role in DLBCL.

Milne E, Greenop KR, Petridou E, et al.
Maternal consumption of coffee and tea during pregnancy and risk of childhood ALL: a pooled analysis from the childhood Leukemia International Consortium.
Cancer Causes Control. 2018; 29(6):539-550 [PubMed] Related Publications
PURPOSE: The early onset of childhood acute lymphoblastic leukemia (ALL) suggests that critical exposures occurring during pregnancy may increase risk. We investigated the effects of maternal coffee and tea consumption during pregnancy on ALL risk by pooling data from eight case-control studies participating in the Childhood Leukemia International Consortium.
METHOD: Data on maternal coffee intake were available for 2,552 cases and 4,876 controls, and data on tea intake were available for 2,982 cases and 5,367 controls. Coffee and tea intake was categorized into 0, > 0-1, > 1-2, and > 2 cups/day, and covariates were combined and harmonized. Data on genetic variants in NAT2, CYP1A1, and NQO1 were also available in a subset. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression, and linear trends across categories were assessed.
RESULTS: No association was seen with 'any' maternal coffee consumption during pregnancy, but there was evidence of a positive exposure-response; the pooled OR for > 2 cups/day versus none was 1.27 (95% CI 1.09-1.43), p trend = 0.005. No associations were observed with tea consumption. No interactions were seen between coffee or tea intake and age, maternal smoking or genotype, and there was little or no evidence that associations with coffee or tea differed among cases with and without chromosomal translocations.
CONCLUSIONS: Despite some limitations, our findings suggest that high coffee intake during pregnancy may increase risk of childhood ALL. Thus, current advice to limit caffeine intake during pregnancy to reduce risk of preterm birth may have additional benefits.

Bellamri M, Xiao S, Murugan P, et al.
Metabolic Activation of the Cooked Meat Carcinogen 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine in Human Prostate.
Toxicol Sci. 2018; 163(2):543-556 [PubMed] Free Access to Full Article Related Publications
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), an heterocyclic aromatic amine (HAA) formed in cooked meat, is a rodent and possible human prostate carcinogen. Recently, we identified DNA adducts of PhIP in the genome of prostate cancer patients, but adducts of 2-amino-3, 8-dimethylmidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-9 H-pyrido[2,3-b]indole (AαC), other prominent HAAs formed in cooked meats, were not detected. We have investigated the bioactivation of HAAs by Phase I and II enzymes in the human prostate (LNCaP) cell line using cytotoxicity and DNA adducts as endpoints. PhIP, MeIQx, and 2-amino-3-methylimidazo[4,5-f]quinoline, another HAA found in cooked meats, were poorly bioactivated and not toxic. The synthetic genotoxic N-hydroxylated-HAAs were also assayed in LNCaP cells with Phase II enzyme inhibitors. Notably, 2-hydroxy-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (HONH-PhIP), but not other HONH-HAAs, induced cytotoxicity. Moreover, PhIP-DNA adduct formation was 20-fold greater than adducts formed with other HONH-HAAs. Pretreatment of LNCaP cells with mefenamic acid, a specific inhibitor of sulfotransferase (SULT1A1), decreased PhIP-DNA adducts by 25%, whereas (Z)-5-(2'-hydroxybenzylidene)-2-thioxothiazolidin-4-one and pentachlorophenol, inhibitors of SULTs and N-acetyltransferases (NATs), decreased the PhIP-DNA adduct levels by 75%. NATs in cytosolic fractions of LNCaP cells and human prostate catalyzed DNA binding of HONH-PhIP by up to 100-fold greater levels than for SULT and kinase activities. Recombinant NAT2 is catalytically superior to recombinant NAT1 in the bioactivation of HONH-PhIP; however, the extremely low levels of NAT2 activity in prostate suggest that NAT1 may be the major isoform involved in PhIP-DNA damage. Thus, the high susceptibility of LNCaP cells recapitulates the DNA-damaging effect of HONH-PhIP in rodent and human prostate.

Stepp MW, Doll MA, Carlisle SM, et al.
Genetic and small molecule inhibition of arylamine N-acetyltransferase 1 reduces anchorage-independent growth in human breast cancer cell line MDA-MB-231.
Mol Carcinog. 2018; 57(4):549-558 [PubMed] Free Access to Full Article Related Publications
Arylamine N-acetyltransferase 1 (NAT1) expression is reported to affect proliferation, invasiveness, and growth of cancer cells. MDA-MB-231 breast cancer cells were engineered such that NAT1 expression was elevated or suppressed, or treated with a small molecule inhibitor of NAT1. The MDA-MB-231 human breast cancer cell lines were engineered with a scrambled shRNA, a NAT1 specific shRNA or a NAT1 overexpression cassette stably integrated into a single flippase recognition target (FRT) site facilitating incorporation of these different genetic elements into the same genomic location. NAT1-specific shRNA reduced NAT1 activity in vitro by 39%, increased endogenous acetyl coenzyme A levels by 35%, and reduced anchorage-independent growth (sevenfold) without significant effects on cell morphology, growth rates, anchorage-dependent colony formation, or invasiveness compared to the scrambled shRNA cell line. Despite 12-fold overexpression of NAT1 activity in the NAT1 overexpression cassette transfected MDA-MB-231 cell line, doubling time, anchorage-dependent cell growth, anchorage-independent cell growth, and relative invasiveness were not changed significantly when compared to the scrambled shRNA cell line. A small molecule (5E)-[5-(4-hydroxy-3,5-diiodobenzylidene)-2-thioxo-1,3-thiazolidin-4-one (5-HDST) was 25-fold more selective towards the inhibition of recombinant human NAT1 than N-acetyltransferase 2. Incubation of MDA-MB-231 cell line with 5-HDST resulted in 60% reduction in NAT1 activity and significant decreases in cell growth, anchorage-dependent growth, and anchorage-independent growth. In summary, inhibition of NAT1 activity by either shRNA or 5-HDST reduced anchorage-independent growth in the MDA-MB-231 human breast cancer cell line. These findings suggest that human NAT1 could serve as a target for the prevention and/or treatment of breast cancer.

Pavanello S, Carta A, Mastrangelo G, et al.
Relationship between Telomere Length, Genetic Traits and Environmental/Occupational Exposures in Bladder Cancer Risk by Structural Equation Modelling.
Int J Environ Res Public Health. 2017; 15(1) [PubMed] Free Access to Full Article Related Publications

Hernández-González O, Ortiz-Zamudio JJ, Rodríguez-Pinal CJ, et al.
Genetic polymorphisms of arylamine N-acetyltransferases 1 and 2 and the likelihood of developing pediatric acute lymphoblastic leukemia.
Leuk Lymphoma. 2018; 59(8):1968-1975 [PubMed] Related Publications
Acute lymphoblastic leukemia (ALL) is one of the main causes of death in children and is associated with both genetic susceptibility and environmental factors. Genes encoding the arylamine N-acetyltransferases 1 and 2 (NAT1 and NAT2) isoenzymes are highly polymorphic among populations. Single-nucleotide polymorphism analysis was performed by real-time polymerase chain reaction from the genomic DNA of 225 healthy subjects and 57 children with ALL diagnoses. Significant associations were found between the development of ALL and the presence of the haplotypes NAT1*3 (Odds ratio [OR], 2.1), NAT1*4 (OR, 1.92), NAT2*6B (OR, 3.30), NAT2*6J (OR, 3.25) and NAT2*7A (OR, 2.45) and the NAT1 rapid (OR, 6.69) and NAT2 slow phenotypes (OR, 2.95). Our results indicate that haplotypes that provide rapid NAT1 and slow NAT2 acetylating phenotypes may influence the development of ALL in children.

Szymańska B, Pawlik KJ, Sawicka E, et al.
Evaluation of NMP22 in bladder cancer patients sensitive to environmental toxins.
Adv Clin Exp Med. 2017; 26(7):1069-1075 [PubMed] Related Publications
BACKGROUND: Bladder cancer (BC) is recognized as environmentally related. The interaction of environmental exposure to chemicals and genetic susceptibility seem to play important roles in BC development. In order to improve diagnosis and the recognition of BC risk, a group of markers which combine genetic susceptibility with detoxification and nuclear matrix protein (NMP22) is proposed.
OBJECTIVES: The aim of the study was to examine the utility of nuclear matrix protein (NMP22) as a diagnostic marker in BC in genetic susceptibility (NAT2 slow acetylators) combined with detoxification abilities (glutathione S-transferase GST and isoenzyme GST-π).
MATERIAL AND METHODS: The NMP22 level in urine, N-acetyltransferase 2 (NAT2) genotype and GST activity in hemolysate blood, as well as isoenzyme GST-π level, were determined in the urine and serum of 43 patients with BC and from 25 non-cancer controls. NMP22 and isoenzyme GST-π levels were measured by ELISA. The NAT2 genotype was examined in DNA isolated from whole blood using the PCR (Polymerase Chain Reaction) technique, while the activity of GST was determined with the spectrophotometric method.
RESULTS: In the BC group, NMP22 (p = 0.005) concentration, GST-π (p = 0.003) in urine and GST (p = 0.009) activity in blood were statistically significantly higher than in the healthy controls. The majority of BC patients were slow acetylators (NAT2 genotype). A correlation between the level of nuclear matrix protein NMP22 and GST was found in all BC group (p = 0.007) and also slow acetylators (p = 0.0147).
CONCLUSIONS: The results support the utility of a marker combination, which covers the genetic susceptibility to chemicals with the level of detoxification and nuclear matrix protein in BC patients. A relationship between NMP22 level in urine, GST level in blood and NAT2 genotype was observed. Also the isoenzyme GST-π in urine seems useful as a marker of BC.

Hein DW, Zhang X, Doll MA
Role of N-acetyltransferase 2 acetylation polymorphism in 4, 4'-methylene bis (2-chloroaniline) biotransformation.
Toxicol Lett. 2018; 283:100-105 [PubMed] Free Access to Full Article Related Publications
Arylamine N-acetyltransferase 1 (NAT1) and 2 (NAT2) catalyze the acetylation of arylamine carcinogens. Single nucleotide polymorphisms in the NAT2 coding exon present in NAT2 haplotypes encode allozymes with reduced N-acetyltransferase activity towards the N-acetylation of arylamine carcinogens and the O-acetylation of their N-hydroxylated metabolites. NAT2 acetylator phenotype modifies urinary bladder cancer risk following exposures to arylamine carcinogens such as 4-aminobiphenyl. 4, 4'-methylene bis (2-chloroaniline) (MOCA) is a Group 1 carcinogen for which a role of the NAT2 acetylation polymorphism on cancer risk is unknown. We investigated the role of NAT2 and the genetic acetylation polymorphism on both MOCA N-acetylation and N-hydroxy-MOCA O-acetylation. MOCA N-acetylation exhibited a robust gene dose response in rabbit liver cytosol and in cryopreserved human hepatocytes derived from individuals of rapid, intermediate and slow acetylator NAT2 genotype. MOCA exhibited about 4-fold higher affinity for recombinant human NAT2 than NAT1. Recombinant human NAT2*4 (reference) and 15 variant recombinant human NAT2 allozymes catalyzed both the N-acetylation of MOCA and the O-acetylation of N-hydroxy-MOCA. Human NAT2 5, NAT2 6, NAT2 7 and NAT2 14 allozymes catalyzed MOCA N-acetylation and N-hydroxy-O-acetylation at rates much lower than the reference NAT2 4 allozyme. In conclusion, our results show that NAT2 acetylator genotype has an important role in MOCA metabolism and suggest that risk assessments related to MOCA exposures consider accounting for NAT2 acetylator phenotype in the analysis.

Koda M, Iwasaki M, Yamano Y, et al.
Association between NAT2, CYP1A1, and CYP1A2 genotypes, heterocyclic aromatic amines, and prostate cancer risk: a case control study in Japan.
Environ Health Prev Med. 2017; 22(1):72 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Heterocyclic aromatic amines (HAAs) may confer prostate cancer risk; however, the evidence is inconclusive and the activity of HAA-metabolizing enzymes is modulated by gene variants. The purpose of our study was to determine whether there was evidence of an association between HAA intake, polymorphisms in NAT2, CYP1A1, and CYP1A2 and prostate cancer risk in Japanese men.
METHODS: Secondary data analysis of an observational case control study was performed. Among 750 patients with prostate cancer and 870 healthy controls, 351 cases and 351 age-matched controls were enrolled for analysis. HAA intake was estimated using a food frequency questionnaire and genotypes were scored by TaqMan real-time PCR assay. Logistic regression analysis was conducted according to affected/control status.
RESULTS: We found that high HAA intake was significantly associated with an increased risk of prostate cancer (odds ratio (OR), 1.90; 95% confidence interval (95% CI), 1.40-2.59). The increased risk of prostate cancer was observed among individuals with the NAT2 slow acetylator phenotype (OR, 1.65; 95% CI, 1.04-2.61), CYP1A1 GA + GG genotype (OR, 1.27; 95% CI, 1.02-1.59), and CYP1A2 CA + AA genotype (OR, 1.43; 95% CI, 1.03-2.00). In addition, CYP1A1 GA + GG genotypes were associated with increased cancer risk in low (OR, 2.05; 95% CI, 1.19-3.63), moderate (OR, 1.72; 95% CI, 1.07-2.76), and high (OR, 2.86; 95% CI, 1.83-4.47) HAA intake groups.
CONCLUSIONS: Our results suggest that high HAA intake is a risk factor of prostate cancer, and genotypes related to HAA metabolic enzymes can modulate the degree of the risk.

Regev-Avraham Z, Baron-Epel O, Hammond SK, Keinan-Boker L
Passive smoking, NAT2 polymorphism, and breast cancer risk in Israeli Arab women: a case-control study.
Breast Cancer. 2018; 25(2):176-184 [PubMed] Related Publications
BACKGROUND: The effect of passive smoking (PS) on breast cancer (BC) is controversial, and may be modified by polymorphism of the N-Acetyl-transferase (NAT) 2 enzyme which is involved in tobacco carcinogen metabolism. We aimed to evaluate the relationship between PS and BC by NAT2 variants in Arab-Israeli women, a unique population with low active smoking rates, and high exposure to PS.
METHODS: A population-based case-control study was carried out on non-smoking 137 prevalent breast cancer patients and 274 population-based controls, aged 30-70 years. Data on past and current PS, sociodemographic, and other characteristics were retrieved through interviews, and buccal smears were provided for NAT2 analyses. Logistic regression models adjusting for potential confounders assessed the odds ratios (ORs) and 95% confidence intervals (95% CI) of the association between PS and BC.
RESULTS: Ever PS was associated with increased BC risk: OR = 2.22, 95% CI 1.28-3.87. Higher lifetime PS exposure was associated with higher BC risk: Compared to never exposed women, women exposed to PS most of their lives had a threefold higher BC risk (OR = 3.16, 95% CI 1.70-5.87, P
CONCLUSIONS: PS exposure in non-smoking Israeli Arab women is significantly associated with increased risk for BC, potentially allowing for specific intervention; NAT2 polymorphism does not modify this association.

Zou Y, Dong S, Xu S, et al.
Genetic polymorphisms of NAT2 and risk of acute myeloid leukemia: A case-control study.
Medicine (Baltimore). 2017; 96(42):e7499 [PubMed] Free Access to Full Article Related Publications
Our purpose was to investigate the possible associations between N-acetyltransferase-2 (NAT2) gene polymorphisms and the risk of acute myeloid leukemia (AML) in Chinese Han population.A case-control study was conducted including 98 AML cases and 112 healthy controls. NAT2 gene 2 polymorphisms rs1799930 and rs1799931 were genotyped using direct sequencing. Chi-square test was performed to compare the genotype and allele distribution differences between groups. Odds ratio (OR) with 95% confidence interval (CI) was calculated to estimate the association between NAT2 gene polymorphisms and AML onset.A remarkable decrease trend of rs1799931 GA genotype was detected in AML patients compared with controls, whereas the ancestral GG genotype frequency increased in cases (P < .05). And the mutant A allele of rs1799931 significantly reduced the risk of AML by 0.585-fold versus the ancestral G allele carriers (OR = 0.585, 95% CI = 0.361-0.950). But the distributions of rs1799930 genotype and allele were similar between groups (P > .05).Our findings suggested that NAT2 gene polymorphism rs1799931 was associated with decreased risk of AML and was likely to be a protective factor against AML development.

Szymańska B, Sawicka E, Guzik A, et al.
The Diagnostic Value of Nuclear Matrix Proteins in Bladder Cancer in the Aspect of Environmental Risk from Carcinogens.
Biomed Res Int. 2017; 2017:9643139 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The interaction of environmental factors with genetic susceptibility and detoxification level seems to be an important causative factor in bladder cancer (BC). The aim of this study was to look for a BC marker panel which reflects the environmental risk. The nuclear matrix protein 22 (NMP22), bladder cancer-4 (BLCA-4), and total level proteins NMP22 and BLCA-4 (NMBL) in BC patients with genetic predisposition NAT2 (classified as slow acetylators, SA), DNA damage (8-OHdG), and detoxification by isoenzyme GST
MATERIALS AND METHODS: The urine and blood from 91 BC patients and controls were examined, also according to tumor stage (T) and grade (G). The participants completed a questionnaire in order to evaluate environmental risk.
RESULTS: Most patients (75.3%) were previous or actual smokers. The levels of 8-OHdG, NMP22, BLCA-4, NMBL, and GST
CONCLUSIONS: The total pool of nuclear matrix proteins in the urine (NMBL) has a higher diagnostic value in bladder cancer than single proteins. The particular value of BLCA-4 and GST

Lévi F, Karaboué A, Saffroy R, et al.
Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228).
Br J Cancer. 2017; 117(7):965-973 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The hepatic artery infusion (HAI) of irinotecan, oxaliplatin and 5-fluorouracil with intravenous cetuximab achieved outstanding efficacy in previously treated patients with initially unresectable liver metastases from colorectal cancer. This planned study aimed at the identification of pharmacogenetic predictors of outcomes.
METHODS: Circulating mononuclear cells were analysed for 207 single-nucleotide polymorphisms (SNPs) from 34 pharmacology genes. Single-nucleotide polymorphisms passing stringent Hardy-Weinberg equilibrium test were tested for their association with outcomes in 52 patients (male/female, 36/16; WHO PS, 0-1).
RESULTS: VKORC1 SNPs (rs9923231 and rs9934438) were associated with early and objective responses, and survival. For rs9923231, T/T achieved more early responses than C/T (50% vs 5%, P=0.029) and greatest 4-year survival (46% vs 0%, P=0.006). N-acetyltransferase-2 (rs1041983 and rs1801280) were associated with up to seven-fold more macroscopically complete hepatectomies. Progression-free survival was largest in ABCB1 rs1045642 T/T (P=0.026) and rs2032582 T/T (P=0.035). Associations were found between toxicities and gene variants (P<0.05), including neutropenia with ABCB1 (rs1045642) and SLC0B3 (rs4149117 and rs7311358); and diarrhoea with CYP2C9 (rs1057910), CYP2C19 (rs3758581), UGT1A6 (rs4124874) and SLC22A1 (rs72552763).
CONCLUSION: VKORC1, NAT2 and ABCB1 variants predicted for HAI efficacy. Pharmacogenetics could guide the personalisation of liver-targeted medico-surgical therapies.

Feki-Tounsi M, Khlifi R, Louati I, et al.
Polymorphisms in XRCC1, ERCC2, and ERCC3 DNA repair genes, CYP1A1 xenobiotic metabolism gene, and tobacco are associated with bladder cancer susceptibility in Tunisian population.
Environ Sci Pollut Res Int. 2017; 24(28):22476-22484 [PubMed] Related Publications
Other than the established environmental risk factors associated with bladder cancer (BC), little is known about the genetic variations determining the individual susceptibility of this complex disease. This study aimed to investigate the relationship of BC with environmental agents and polymorphisms in XRCC1, ERCC2, and ERCC3 DNA repair genes and CYP1A1, CYP2D6, NAT1, and NAT2 xenobiotic metabolism genes through a hospital-based case-control study in Tunisia. The selection of the single nucleotide polymorphisms (SNPs) (rs25487, rs 13181, rs415407, rs446421, rs1058172, rs4921880, and rs1208) was performed using the dbSNP database. DNA genotyping was determined by PCR-RFLP after DNA extraction from whole blood. The risks of BC associated with every polymorphism as well as the studied environmental factors were estimated by multivariate-adjusted logistic regression using R software. In addition, gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) methods. Results showed that tobacco smoking and chewing parameters were significantly associated with BC risk. Single-gene variant analysis showed significant associations of the TT genotype of CYP1A1 and the rare GG genotype of ERCC2 with bladder cancer susceptibility (OR = 1.34, 95% CI 1.22-1.40, P < 0.0001). According to GMDR analysis, our findings indicated a significant association between BC and gene-gene interaction among the CYP1A1, ERCC3, and XRCC1. The present results suggest a potential role of XRCC1, ERCC2, ERCC3, and CYP1A1 besides tobacco intake in susceptibility to BC.

Ebbinghaus D, Bánfi G, Selinski S, et al.
Polymorphisms of xenobiotic metabolizing enzymes in bladder cancer patients of the Semmelweis University Budapest, Hungary.
J Toxicol Environ Health A. 2017; 80(7-8):423-429 [PubMed] Related Publications
Polymorphic xenobiotic metabolizing enzymes such as N-acetyltransferase 2 (NAT2) or glutathione S-transferase M1 (GSTM1) are known to modulate bladder cancer risk. As no apparent data were available from Hungary, a former member of the eastern European economic organization, a study was performed in Budapest. In total, 182 bladder cancer cases and 78 cancer-free controls were investigated by questionnaire. Genotypes of NAT2, GSTM1, GSTT1, rs1058396 and rs17674580 were determined by standard methods. Current smokers' crude odds ratio (OR) (3.43) and former smokers crude OR (2.36) displayed a significantly increased bladder cancer risk. The risk rose by a factor of 1.56 per 10 pack years. Exposure to fumes was associated with an elevated bladder cancer risk (23% cases, 13% controls). Sixty-four % of the cases and 59% of controls were slow NAT2 acetylators. It was not possible to establish a particular impact of NAT2*6A and *7B genotypes (15 cases, 8%, 5 controls, 7%). GSTT1 exerted no marked influence on bladder cancer (negative 21% cases vs. 22% controls). The portion of GSTM1 negative bladder cancer patients was increased (63% cases vs. 54% controls). The SLC14A1 SNPs rs1058396[AG/GG] and the nearby rs17674580[CT/TT] occurred more frequently in cases (79% and 68%) than controls (77% and 55%). The portion of GSTM1 negative bladder cancer patients is comparable with portions reported from other industrialized areas like Lutherstadt Wittenberg/Germany (58%), Dortmund/Germany (70%), Brescia/Italy (66%) or an occupational case-control series in Germany (56%). Data indicate that GSTM1 is a susceptibility factor for environmentally triggered bladder cancer rather than for smoking-mediated bladder cancer.

Krech E, Selinski S, Blaszkewicz M, et al.
Urinary bladder cancer risk factors in an area of former coal, iron, and steel industries in Germany.
J Toxicol Environ Health A. 2017; 80(7-8):430-438 [PubMed] Related Publications
This study was performed to investigate the frequency of bladder cancer in patients with an occupational history such as underground hard coal mining and/or painting after the structural change in the local industry. A total of 206 patients with bladder cancer and 207 controls were enlisted regarding occupational and nonoccupational bladder cancer risk factors by questionnaire. The phase II enzymes N-acetyltransferase 2 (NAT2), glutathione S-transferases M1 (GSTM1), and T1 (GSTT1) and the single nucleotide polymorphism (SNP) rs11892031[A/C] reported to be associated with bladder cancer in genome-wide association studies were genotyped. The bladder cancer risk in varnishers and underground hard coal miners was increased as previously shown in a study in this area performed in the 1980s. The occupation of a car mechanic was associated with a significantly elevated bladder cancer risk and higher in the case of underground hard coal miners even though the mine was closed in 1987. The frequency of GSTM1 negative genotype was comparable in cases and controls (53% versus 54%). In the case of NAT2, the slow NAT2 genotype was more frequent (62% versus 58%) and ultra-slow NAT2 genotype (NAT2*6A and/or *7B alleles only) was 23% versus 15%. An occupational history of a varnisher or an underground hard coal miner remains a risk factor for bladder cancer occurrence. Data indicate that in the case of bladder cancer, GSTM1 is a susceptibility factor related to environmental and/or occupational exposure.

Lukas C, Selinski S, Prager HM, et al.
Occupational bladder cancer: Polymorphisms of xenobiotic metabolizing enzymes, exposures, and prognosis.
J Toxicol Environ Health A. 2017; 80(7-8):439-452 [PubMed] Related Publications
Approximately 7% of all bladder cancer cases in males are associated with occupation. The question arises whether the use of genome-wide association studies was able to identify bladder cancer risk factors that may modulate occupational bladder cancer risk and prognosis. One hundred and forty-three bladder cancer cases with suspected occupational bladder cancer and 337 controls were genotyped for the following polymorphisms: N-acetyltransferase 2 (NAT2), glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), UDP-glucuronyltransferase 1A rs11892031 (UGT1A), rs9642880 (close to c-MYC), and rs710521 (close to TP63). The most relevant polymorphisms for occupational bladder cancer risk were GSTM1 and UGT1A, especially when co-occurring (GSTM1 negative and rs11892031[A/A]: 48% cases vs. 38% controls, OR 1.47, 95% CI 0.99-2.20). The effect was more pronounced in smokers. GSTM1 negative genotype occurred more frequently in cancer cases exposed to aromatic amines, carbolineum, and in painters and varnishers. UGT1A (rs11892031[A/A]) was found frequently in cases exposed to carbolineum, crack test spray, PAH, and in painters and varnishers. All investigated polymorphisms except rs710521 (TP63) seemed to exert an impact on recurrence risk. Relapse-free times were shorter for NAT2 slow and ultra-slow, GSTT1 positive and GSTM1 negative cases. Occupational bladder cancer cases with a number of risk variants displayed significantly shorter relapse-free times compared to cases with few, less relevant risk alleles as evidenced by median difference 8 months. In conclusion, in the present, suspected occupational bladder cancer cases phase II polymorphisms involved in bladder carcinogen metabolism modulate bladder cancer recurrence. Most relevant for bladder cancer risk were GSTM1 and UGT1A but not NAT2.

Otsubo K, Nosaki K, Imamura CK, et al.
Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer.
Cancer Sci. 2017; 108(9):1843-1849 [PubMed] Free Access to Full Article Related Publications
Spliced variant isoforms of CD44 (CD44v) are a marker of cancer stem cells in solid tumors. They stabilize the xCT subunit of the transporter system xc(-) and thereby promote synthesis of the antioxidant glutathione. Salazosulfapyridine (SASP) is an inhibitor of xCT and suppresses the proliferation of CD44v-positive cancer cells. Chemotherapy-naïve patients with advanced non-squamous non-small-cell lung cancer were enrolled in a dose-escalation study (standard 3 + 3 design) of SASP in combination with cisplatin and pemetrexed. The primary end-point was the percentage of patients who experience dose-limiting toxicity. Fifteen patients were enrolled in the study. Dose-limiting toxicity was observed in one of six patients at a SASP dose of 1.5 g/day (elevation of aspartate and alanine aminotransferase levels, each of grade 3), two of five patients at 3 g/day (hypotension or pneumonitis, each of grade 3), and two of three patients at 4.5 g/day (anorexia of grade 3). The maximum tolerated dose was thus 3 g/day, and the recommended dose was 1.5 g/day. The overall response rate was 26.7% and median progression-free survival was 11.7 months, much longer than that for cisplatin-pemetrexed alone in previous studies. Exposure to SASP varied markedly among individuals according to ABCG2 and NAT2 genotypes. The serum concentration of free CD44v protein was increased after the first cycle of treatment, possibly reflecting death of cancer stem cells. Salazosulfapyridine was thus given safely in combination with cisplatin-pemetrexed, with the addition of SASP tending to prolong progression-free survival. This trial is registered in the UMIN Clinical Trials Registry as UMIN000017854.

Thakkar N, Guptill JT, Aleš K, et al.
Population Pharmacokinetics/Pharmacodynamics of 3,4-Diaminopyridine Free Base in Patients With Lambert-Eaton Myasthenia.
CPT Pharmacometrics Syst Pharmacol. 2017; 6(9):625-634 [PubMed] Free Access to Full Article Related Publications
Lambert-Eaton myasthenia (LEM) is a rare autoimmune disorder associated with debilitating muscle weakness. There are limited treatment options and 3,4-diaminopyridine (3,4-DAP) free base is an investigational orphan drug used to treat LEM-related weakness. We performed a population pharmacokinetic/pharmacodynamic (PK/PD) analysis using 3,4-DAP and metabolite concentrations collected from a phase II study in patients with LEM. The Triple Timed Up & Go (3TUG) assessment, which measures lower extremity weakness, was the primary outcome measure. A total of 1,270 PK samples (49 patients) and 1,091 3TUG data points (32 randomized patients) were included in the PK/PD analysis. A two-compartment and one-compartment model for parent and metabolite, respectively, described the PK data well. Body weight and serum creatinine partially explained the variability in clearance for the final PK model. A fractional inhibitory maximum effect (E

Stojanovic J, Milovanovic S, Pastorino R, et al.
Occupational exposures and genetic susceptibility to urinary tract cancers: a systematic review and meta-analysis.
Eur J Cancer Prev. 2018; 27(5):468-476 [PubMed] Related Publications
This study aims to summarize the current knowledge on the relationship between genetic polymorphisms, occupational exposures, and urinary tract cancers. We searched MEDLINE, ISI Web of science, and SCOPUS online databases for all articles published in English language up to September 2016. A meta-analysis was performed to provide summary estimates for the association between a certain genetic polymorphism, occupational exposure and bladder cancer (BC) or kidney cancer (KC), when appropriate. Fifteen studies on BC and six on KC were deemed eligible for the review. With regard to BC, an overall odds ratio (OR) of 2.07 [95% confidence interval (CI): 1.38-3.09] for those with GSTM1 and an OR of 2.07 (95% CI: 1.38-3.09) for those with GSTT1 null genotype were reported when exposed to polycyclic aromatic hydrocarbons (PAHs). NAT2 slow genotype carriers had an OR of 3.59 (95% CI: 2.62-4.93) for BC when exposed to aromatic amines and an OR of 2.07 (95% CI: 1.36-3.15) when exposed to PAHs. With regard to KC and pesticide exposure, the meta-analysis reported an OR of 4.38 (95% CI: 2.28-8.41) for GSTM1 present genotype, an OR of 2.59 (95% CI: 1.62-4.15) for GSTT1-present genotype and an OR of 6.51 (95% CI: 2.85-14.89) for combined effects of GSTM1 and GSTT1 active genotypes. This meta-analysis indicates a possible association between the variant genotypes of GSTM1, GSTT1, NAT2 and SULT1A1, occupational exposure to aromatic amines or PAHs, and development of BC. Our results suggest that polymorphisms in GSTM1 and GSTT1 genes could influence the risk for developing KC in individuals occupationally exposed to pesticides.

Procopciuc LM, Osian G, Iancu M
Colorectal Cancer Carcinogenesis: a Multivariate Genetic Model in a Cohort of Romanian Population.
Clin Lab. 2017; 63(4):647-658 [PubMed] Related Publications
BACKGROUND: The molecular mechanism of carcinogenesis of sporadic colorectal cancer (CRC) involves genes with roles in folate metabolism, genes involved in metabolization of carcinogenic compounds from diet and tobacco smoke, and genes related to the DNA repair process. The aim of the study was to examine whether the MTHFRC677T, MTHFR- A1298C, TS-2rpt/3rpt, TS-1494del6bp, NAT2*5C-C481T, NAT2*5A-T341C, NAT2*6B-G590A, NAT2*7B-G857A, NAT2*18-A845C, GSTM1-null, XRCC1-Arg399Gln, XRCC3-Thr241Met, XPD-Lys751Gln genetic variations are associated with CRC prognosis, in the presence of environmental and demographic factors.
METHODS: We genotyped 150 patients diagnosed with sporadic CRC using PCR-RFLP and sequencing methods. The performance of the final model was quantified using Nagelkerke's coefficient, the Hosmer-Lemeshow test, C statistics, and Somers' (D) index, capable of describing the model's goodness-of-fit and discrimination.
RESULTS: Multiple logistic regression analysis established a significant independent association of NAT2*18-A845C, MTHFR-C677T, XRCC3-Thr241Met, NAT2*7B-G857A, XPD-Lys751Gln, XRCC1-Arg399Gln and NAT2*6BG590A with an increased prevalence of sporadic CRC, regardless of the presence/absence of colonic tumors. After an adjustment for other polymorphisms and environmental risk factors, the risk to develop sporadic CRC was 2.25 (p = 0.011) and 2.31 (p = 0.01) in association with the NAT2*18-A845C and MTHFR-C677T genetic variants, respectively. The risk increased to 3.22 (p = 0.0005) and 3.69 (p = 0.0009) in association with the XRCC3Thr241Met and NAT2*7B-G857A polymorphisms. Also, patients carrying the XPD-Lys751Gln, XRCC1Arg399Gln, and NAT2*6B-G590A polymorphisms had a 4.16 (p < 0.0001), 5.16 (p < 0.0001), and 5.46-fold (p < 0.0001) increased risk for sporadic CRC, under the dominant genetic comparison model. In addition, we found an interaction between gender and alcohol, the effect of alcohol consumption on the risk of developing sporadic CRC being different in female and male patients.
CONCLUSIONS: Our study confirmed the predictive role of some polymorphisms associated with DNA methylation and procarcinogen transformation into carcinogenic compounds in sporadic CRC risk and, also, the influence of environmental risk factors such as diet, smoking, and alcohol consumption on this association.

Ohnami S, Nagashima T, Urakami K, et al.
Whole exome sequencing detects variants of genes that mediate response to anticancer drugs.
J Toxicol Sci. 2017; 42(2):137-144 [PubMed] Related Publications
Certain interindividual differences affecting the efficacy of drug treatment and adverse drug reactions are caused by genetic variants, and their phenotypic effects differ among ethnic groups. In this study, we used whole exome sequencing (WES) systematically to identify germline mutations that influence the activities of drug-metabolizing enzymes, as well as that of a transporter. We analyzed DNA isolated from blood samples from 2,042 Japanese patients with diverse cancers. We identified sequence variants of CYP2B6 (rs3745274), CYP2C9 (rs1057910), CYP2C19 (rs4986893), CYP2C19 (rs4244285), TPMT (rs1142345), NAT2 (rs1799930), NAT2 (rs1799931), UGT1A1 (rs4148323), COMT (rs4680), ABCB1 (rs1045642), and CDA (rs60369023). Wider application of WES will help to determine the effects of mutations on the activities of proteins encoded by drug response genes, and the information gained will accelerate the development of personalized therapies for patients with cancer. Moreover, this knowledge may provide clues for preventing cancer before the onset of symptoms.

Xu WJ, Wen LP, Jiang XX, et al.
Association between N-Acetyltransferase 2 Polymorphism and Bladder Cancer Risk: a Meta-Analysis in a Single Ethnic Group.
Clin Lab. 2017; 63(2):287-293 [PubMed] Related Publications
BACKGROUND: Many studies have evaluated the correlation between N-acetyltransferase 2 (NAT2) slow acetylation genotype and bladder cancer risk. However, the results are inconsistent and remain to be confirmed in each ethnic group. To assess the effects of NAT2 acetylation status on the risk of bladder cancer in the Chinese population, a meta-analysis was performed.
METHODS: Studies were identified using PubMed and Chinese databases through February 2016. The associations were assessed with pooled odds ratios (ORs) and 95% confidence intervals (CIs).
RESULTS: This meta-analysis included 10 studies with 896 bladder cancer cases and 1188 controls. In the overall analysis, NAT2 slow acetylation phenotype was significantly associated with an increased risk of bladder cancer in the Chinese population (OR = 1.68, 95% CI = 1.11 - 2.53). In the subgroup analyses by geographic areas and sources of controls, significant risk was found in Mainland China (OR = 1.83, 95% CI = 1.04 - 3.20) and hospitalbased studies (OR = 1.74, 95% CI = 1.27 - 2.38), but not in Taiwan China.
CONCLUSIONS: This meta-analysis suggested that the NAT2 slow acetylation genotype is associated with an increased bladder cancer risk in Chinese individuals.

Procopciuc LM, Osian G, Iancu M
N-acetyl transferase 2/environmental factors and their association as a modulating risk factor for sporadic colon and rectal cancer.
J Clin Lab Anal. 2017; 31(5) [PubMed] Related Publications
OBJECTIVES: The aim of this study was to evaluate the association between environmental factors and colon or rectal cancer after adjusting for N-acetyl transferase 2 (NAT2) phenotypes.
METHODS: Ninety-six patients with sporadic colon cancer, 54 with sporadic rectal cancer and 162 control subjects were genotyped for NAT2-T341C, G590A, G857A, A845C, and C481T using sequencing and PCR-RFLP analysis.
RESULTS: The risk for colon cancer was increased in carriers of the homozygous negative genotypes for NAT2*5C-T341C, NAT2*6B-G590A, NAT2*7B-G857A, NAT2*18-A845C, and NAT2*5A-C481T. The risk for rectal cancer was increased in carriers of the homozygous negative genotypes for NAT2*5C-T341C, NAT2*7B-G857A, and NAT2*5A-C481T. High fried red meat intake associated with NAT2-T341C, G590A, G857A, A845C, and C481T rapid acetylator allele determines a risk of 2.39 (P=.002), 2.39 (P=.002), 2.37 (P=.002), 2.28 (P=.004), and 2.51 (P=.001), respectively, for colon cancer, whereas in the case of rectal cancer, the risk increased to 7.55 (P<.001), 7.7 (P<.001), 7.83 (P<.001), 7.51 (P<.001), and 8.62 (P<.001), respectively. Alcohol consumption associated with the NAT2 -T341C, G590A, G857A, A845C, and C481T rapid acetylator allele induces a risk of 10.63 (P<.001), 12.04 (P<.001), 9.76 (P<.001), 10.25 (P<.001), and 9.54 (P<.001), respectively, for colon cancer, whereas the risk for rectal cancer is 9.72 (P<.001), 11.24 (P<.001), 13.07 (P<.001), 10.04 (P<.001), and 9.43 (P<.001), respectively. Smokers with NAT2-T341C, G590A, G857A, A845C, and C481T rapid acetylator allele have a risk of 4.87, 4.25, 4.18, 3.81, and 3.82, respectively, to develop colon cancer.
CONCLUSIONS: Fried red meat, alcohol, and smoking increase the risk of sporadic CRC, especially of colon cancer, in the case of rapid acetylators for the NAT2 variants.

Quan L, Chattopadhyay K, Nelson HH, et al.
Differential association for N-acetyltransferase 2 genotype and phenotype with bladder cancer risk in Chinese population.
Oncotarget. 2016; 7(26):40012-40024 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: N-acetyltransferase 2 (NAT2) is involved in both carcinogen detoxification through hepatic N-acetylation and carcinogen activation through local O-acetylation. NAT2 slow acetylation status is significantly associated with increased bladder cancer risk among European populations, but its association in Asian populations is inconclusive.
METHODS: NAT2 acetylation status was determined by both single nucleotide polymorphisms (SNPs) and caffeine metabolic ratio (CMR), in a population-based study of 494 bladder cancer patients and 507 control subjects in Shanghai, China.
RESULTS: The CMR, a functional measure of hepatic N-acetylation, was significantly reduced in a dose-dependent manner among both cases and controls possessing the SNP-inferred NAT2 slow acetylation status (all P-values<5.0×10-10). The CMR-determined slow N-acetylation status (CMR<0.34) was significantly associated with a 50% increased risk of bladder cancer (odds ratio = 1.50, 95% confidence interval = 1.10-2.06) whereas the SNP-inferred slow acetylation statuses were significantly associated with an approximately 50% decreased risk of bladder cancer. The genotype-disease association was strengthened after the adjustment for CMR and was primarily observed among never smokers.
CONCLUSIONS: The apparent differential associations for phenotypic and genetic measures of acetylation statuses with bladder cancer risk may reflect dual functions of NAT2 in bladder carcinogenesis because the former only measures the capacity of carcinogen detoxification pathway while the latter represents both carcinogen activation and detoxification pathways. Future studies are warranted to ascertain the specific role of N- and O-acetylation in bladder carcinogenesis, particularly in populations exposed to different types of bladder carcinogens.

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