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. 2015 Dec 11;94(49):e1947. doi: 10.1097/MD.0000000000001947

Association Between NAT2 Polymorphisms and Lung Cancer Susceptibility

Chang Liu 1, Wei Cui 1, Lin Cong 1, Li Wang 1, Xinjian Ruan 1, Jia Jia 1, Yanfang Liu 1, Xiaoyan Jia 1, Xia Zhang 1
Editor: Gouri Shankar Bhattacharyya1
PMCID: PMC5008471  PMID: 26656326

Abstract

To further investigate the association between NAT2 polymorphisms and lung cancer susceptibility.

In terms of phenotypes, we investigated the acetylator status of NAT2 polymorphisms associated with lung cancer risk. Additionally, in view of genotypes, we mainly analyzed 5 single nucleotide polymorphisms (SNPs) in NAT2 gene, namely C282T, A803G, C481T, G590A, and G857A. Twenty-six eligible studies were included in our meta-analysis by searching PubMed, Embase, and CNKI databases. We used odds ratios (ORs) with corresponding 95% confidence intervals (CIs) to evaluate the susceptibility to lung cancer associated with NAT2 polymorphisms.

Overall, based on phenotypes, the pooled ORs showed no significant association between NAT2 polymorphisms and lung cancer susceptibility. In the subgroup analyses by ethnicity and source of control, there was still no significant association. In terms of genotypes, overall, no obvious relationship was observed between NAT2 polymorphisms and lung cancer risk. But increased risk of lung cancer was found in association with NAT2 C282T polymorphism (TT vs. CC + TC: OR = 1.58, 95% CI = 1.11–2.25).

Our meta-analysis demonstrates that TT genotype in NAT2 C282T polymorphism may be a risk factor for lung cancer susceptibility. Additionally, the acetylator status of 5 SNPs in NAT2 gene may not be associated with lung cancer risk.

INTRODUCTION

Lung cancer is the most common cancer and the leading cause of cancer death in the world.1,2 It consists of 3 major histological subtypes, adenocarcinoma, squamous cell carcinoma, and small cell carcinoma. The exposure to tobacco smoke is known as a crucial cause of lung cancer.3 Additionally, genetic factors are considered to play an important role in lung cancer risk.4,5

N-acetyltransferase 2 (NAT2) gene, located on the short arm of chromosome 8 (8q22), encodes a phase II xenobiotic-metabolizing enzyme.6,7NAT2 gene is essentially involved in the metabolism of aromatic, heterocyclic amines, and hydrazines.8,9 Five known polymorphisms in NAT2 gene, namely C282T, A803G, C481T, G590A, and G857A, are associated with decreased enzyme activity and variable stability, leading to imbalance of the process of xenobiotics detoxification and consequently affecting lung cancer susceptibility.10

The alteration of NAT2 acetylator status caused by polymorphisms in NAT2 gene may lead to decreased enzyme activity and absence of efficiency in detoxification, and further contribute to elevated cancer risk.11 There are 2 major NAT2 phenotypes, including rapid acetylator phenotype and slow acetylator phenotype. Wild-type homozygotes and heterozygotes in NAT2 gene are categorized into rapid acetylator phenotype whereas mutant homozygotes are categorized into slow acetylator phenotype.12 The rapid acetylator phenotype was reported to increase the risk of bladder, colon, and prostate cancers.13–15 Whereas slow acetylator phenotype was in association with increased risk of bladder cancer and decreased risk of colon cancer.16,17

In 1995, Martinez et al first explored NAT2 polymorphisms in malignancies among Caucasians. However, no significant association was observed.18 Since then, several phenotyping studies have investigated the association between acetylator status of NAT2 polymorphisms and lung cancer risk.12,19–38 However, the results were inconclusive. With respect to genotypes, quite a few studies focused on the relationship between genetic polymorphisms in NAT2 gene and lung cancer susceptibility.39–42 Therefore, we conducted this meta-analysis to gain more precise evidence for the association from genotype and phenotype aspects.

METHODS

Search Strategy

We searched PubMed, Embase, and CNKI databases using the terms “NAT2,” “polymorphism,” and “lung cancer.” The reference lists of the selected papers were also screened for other potential articles. The following inclusion criteria were used to select the eligible studies for this meta-analysis: case–control studies; enough data for estimating odds ratio (OR) with 95% confidence interval (CI). Additionally, when the same data were included in several publications, only the largest or most recent study was selected in our meta-analysis. All patients provided written or oral consent for participation in the registry, in accordance with local ethics committee requirements.

Data Extraction

All the following data were independently extracted from each study by 2 investigators: single nucleotide polymorphisms (SNPs), first author, publication date, country of origin, ethnicity, source of controls, genotyping method, total cases and controls, and P-value for Hardy–Weinberg equilibrium (HWE), as shown in Tables 1 and 2. Inconsistent results were settled generally through discussion.

TABLE 1.

Principle Characteristics of the Studies Included in the Meta-Analysis Based on Phenotypes of NAT2 Polymorphisms

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TABLE 2.

Principle Characteristics of the Studies Included in the Meta-Analysis Based on Genotypes of NAT2 Polymorphisms

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Statistical Analysis

Crude ORs with 95% CIs were calculated to assess the strength of association between NAT2 polymorphisms and lung cancer susceptibility. In terms of phenotypes, subgroup analyses were based on ethnicity and source of control. The Chi-square based Q-test was performed to evaluate heterogeneity. P < 0.05 indicates significant heterogeneity among studies, thus the pooled OR was calculated using random-effects model; otherwise, the fixed-effects model was used. Sensitivity analysis was performed to assess the stability of results. The potential publication bias was estimated by Egger test and Begg funnel plot. HWE was checked by χ2 test. Statistical analyses were conducted using the STATA software (version 12.0, Stata Corporation, College Station, TX).

RESULTS

Study Characteristics

As displayed in Figure 1, a total of 173 studies were selected through databases in which 7 articles were excluded for duplicates and 87 articles were excluded for obvious irrelevance and finally 79 full-text articles were assessed for eligibility. Among these 79 full-text articles, 53 articles were excluded for only meta-analysis and drug experiments on animals and without case-control and original genotype frequencies, finally 26 eligible studies on the association between NAT2 polymorphisms and lung cancer risk were included in our meta-analysis. Twenty-two studies involved phenotypes11,12,18–21,23–26,29–38,43,44 and 4 studies discussed about genotypes.39–42 Diverse genotyping methods were used, including polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism (PCR-RFLP), TaqManSNP (TaqMan), arrayed primer extension.

FIGURE 1.

FIGURE 1

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Flow diagram of included studies for the meta-analysis.

Meta-Analysis

The main results are shown in Tables 3 and 4. Overall, with respect to phenotypes, the pooled ORs showed no significant association of NAT2 polymorphisms with lung cancer susceptibility. In the subgroup analyses by ethnicity and source of control, there was still no significant association. In terms of genotypes, no obvious relationship was found between 5 SNPs in NAT2 gene and lung cancer susceptibility. But increased risk of lung cancer was found in association with NAT2 C282T polymorphism (TT vs. CC + TC: OR = 1.58, 95% CI = 1.11–2.25), as displayed in Figure 2.

TABLE 3.

NAT2 Polymorphisms With Phenotypes and Lung Cancer Risk

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TABLE 4.

NAT2 Polymorphisms With Genotypes and Lung Cancer Risk

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FIGURE 2.

FIGURE 2

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Forest plot of lung cancer susceptibility associated with NAT2 C282T polymorphism under TT versus CC + TC genetic model. For each study, the estimates of OR and its 95% CI are plotted with square and a horizontal line. The area of the squares reflects the weight (inverse of the variance). The diamond represents the summary OR and 95% CI.

Sensitivity Analysis

Sensitivity analysis was carried out to evaluate the influence of each individual study on the pooled ORs. The recalculated ORs were not materially altered, suggesting our results were statistically steady.

Publication Bias

Egger test and Begg funnel plot were performed to estimate the publication bias. The shape of the funnel plot did not indicate obvious asymmetry, as displayed in Figure 3. Additionally, result of Egger test did not show statistical evidence for bias (P = 0.805). Thus, there was no obvious publication bias and the results were credible.

FIGURE 3.

FIGURE 3

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Begg funnel plot of publication bias test. Each point represents a separate study for the indicated association. Log(OR), natural logarithm of OR. Horizontal line, mean effect size.

DISCUSSION

Both environmental and genetic factors are considered crucial in the etiology of lung cancer. The risk of lung cancer correlated with exposure to exogenous xenobiotics or endogenous substances may be modified by the genetic variation in metabolic detoxification activities. Thus, the relevance of the NAT2 polymorphisms to lung cancer risk is of particular importance.45

So far, the role of NAT2 acetylator status in lung cancer risk is unclear. Some epidemiological studies demonstrated that lung cancer susceptibility was not associated with NAT2 acetylator status.18,25,28,30,35 However, some investigators held the opinion that slow acetylator phenotype of NAT2 polymorphisms was associated with increased risk of lung cancer.20,24 In our meta-analysis, there was no significant association between slow acetylator phenotype of NAT2 polymorphisms and lung cancer risk. The disagreement may underlie differences in study population. Specifically, our study was based on Asians and Caucasians, whereas the studies of Sobti et al and Oyama et al were respectively performed in the North Indian population and Japanese population. With respect to rapid acetylator phenotype, Sorensen et al pointed out the NAT2 rapid acetylator phenotype seemed to be protective against lung cancer in light smokers but not among heavy smokers.34 Nevertheless, several research indicated rapid acetylator phenotype may contribute to increased risk of lung cancer.23,36,37

From the perspective of genotypes, to our knowledge, this is the second study definitely clarifying the association of NAT2 C282T polymorphism with increased risk of lung cancer, which is not in accordance with Nikishina et al.39 The inconsistency may be on account of study population and sample size. In detail, our study included 1988 cases and 2411 controls among Asians and Caucasians, while the study of Nikishina et al was performed in only 122 cases and 167 controls among Caucasians living in Novosibirsk.

Some limitations in our study should be pointed out. First, in the subgroup analysis by ethnicity, our study was based on Asians and Caucasians, not considering other ethnic groups. Second, our study was not stratified by smoking status which is an important cause of lung cancer. Finally, lacking some original data of genotypes, the comprehensiveness and precision of association between NAT2 polymorphisms and lung cancer may be influenced.

In conclusion, our meta-analysis demonstrated that TT genotype in C282T polymorphism among 5 SNPs in NAT2 gene was a susceptibility factor for lung cancer. Additionally, the acetylator status of NAT2 polymorphisms was not in association with lung cancer susceptibility. In the future, well-designed studies are required to give more comprehensive understanding of the association.

Footnotes

Abbreviations: CI = confidence intervals, HWE = Hardy–Weinberg equilibrium, NAT2 = N-acetyltransferase 2, OR = odds ratios, PCR = polymerase chain reaction, PCR-RFLP = PCR-restriction fragment length polymorphism, SNP = single nucleotide polymorphism, TaqMan = TaqManSNP.

The authors have no conflicts of interest to disclose.

REFERENCES

  • 1.Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55:74–108. [DOI] [PubMed] [Google Scholar]
  • 2.Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006; 24:2137–2150. [DOI] [PubMed] [Google Scholar]
  • 3.Gemignani F, Landi S, Szeszenia-Dabrowska N, et al. Development of lung cancer before the age of 50: the role of xenobiotic metabolizing genes. Carcinogenesis 2007; 28:1287–1293. [DOI] [PubMed] [Google Scholar]
  • 4.Nishikawa A, Mori Y, Lee IS, et al. Cigarette smoking, metabolic activation and carcinogenesis. Curr Drug Metab 2004; 5:363–373. [DOI] [PubMed] [Google Scholar]
  • 5.Lichtenstein P, Holm NV, Verkasalo PK, et al. Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000; 343:78–85. [DOI] [PubMed] [Google Scholar]
  • 6.Blum M, Grant DM, McBride W, et al. Human arylamine N-acetyltransferase genes: isolation, chromosomal localization, and functional expression. DNA Cell Biol 1990; 9:193–203. [DOI] [PubMed] [Google Scholar]
  • 7.Hickman D, Pope J, Patil SD, et al. Expression of arylamine N-acetyltransferase in human intestine. Gut 1998; 42:402–409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Hein DW, Doll MA, Gray K, et al. Metabolic activation of N-hydroxy-2-aminofluorene and N-hydroxy-2-acetylaminofluorene by monomorphic N-acetyltransferase (NAT1) and polymorphic N-acetyltransferase (NAT2) in colon cytosols of Syrian hamsters congenic at the NAT2 locus. Cancer Res 1993; 53:509–514. [PubMed] [Google Scholar]
  • 9.De Stefani E, Boffetta P, Mendilaharsu M, et al. Dietary nitrosamines, heterocyclic amines, and risk of gastric cancer: a case-control study in Uruguay. Nutr Cancer 1998; 30:158–162. [DOI] [PubMed] [Google Scholar]
  • 10.Hein DW, Ferguson RJ, Doll MA, et al. Molecular genetics of human polymorphic N-acetyltransferase: enzymatic analysis of 15 recombinant wild-type, mutant, and chimeric NAT2 allozymes. Hum Mol Genet 1994; 3:729–734. [DOI] [PubMed] [Google Scholar]
  • 11.Wikman H, Thiel S, Jager B, et al. Relevance of N-acetyltransferase 1 and 2 (NAT1, NAT2) genetic polymorphisms in non-small cell lung cancer susceptibility. Pharmacogenetics 2001; 11:157–168. [DOI] [PubMed] [Google Scholar]
  • 12.Seow A, Zhao B, Poh WT, et al. NAT2 slow acetylator genotype is associated with increased risk of lung cancer among non-smoking Chinese women in Singapore. Carcinogenesis 1999; 20:1877–1881. [DOI] [PubMed] [Google Scholar]
  • 13.Bell DA, Badawi AF, Lang NP, et al. Polymorphism in the N-acetyltransferase 1 (NAT1) polyadenylation signal: association of NAT1∗10 allele with higher N-acetylation activity in bladder and colon tissue. Cancer Res 1995; 55:5226–5229. [PubMed] [Google Scholar]
  • 14.Fukutome K, Watanabe M, Shiraishi T, et al. N-acetyltransferase 1 genetic polymorphism influences the risk of prostate cancer development. Cancer Lett 1999; 136:83–87. [DOI] [PubMed] [Google Scholar]
  • 15.Taylor JA, Umbach DM, Stephens E, et al. The role of N-acetylation polymorphisms in smoking-associated bladder cancer: evidence of a gene-gene-exposure three-way interaction. Cancer Res 1998; 58:3603–3610. [PubMed] [Google Scholar]
  • 16.Risch A, Wallace DM, Bathers S, et al. Slow N-acetylation genotype is a susceptibility factor in occupational and smoking related bladder cancer. Hum Mol Genet 1995; 4:231–236. [DOI] [PubMed] [Google Scholar]
  • 17.Kampman E, Slattery ML, Bigler J, et al. Meat consumption, genetic susceptibility, and colon cancer risk: a United States multicenter case-control study. Cancer Epidemiol Biomarkers Prev 1999; 8:15–24. [PubMed] [Google Scholar]
  • 18.Martinez C, Agundez JA, Olivera M, et al. Lung cancer and mutations at the polymorphic NAT2 gene locus. Pharmacogenetics 1995; 5:207–214. [PubMed] [Google Scholar]
  • 19.Osawa Y, Osawa KK, Miyaishi A, et al. NAT2 and CYP1A2 polymorphisms and lung cancer risk in relation to smoking status. Asian Pac J Cancer Prev 2007; 8:103–108. [PubMed] [Google Scholar]
  • 20.Sobti RC, Kaur P, Kaur S, et al. Impact of interaction of polymorphic forms of p53 codon 72 and N-acetylation gene (NAT2) on the risk of lung cancer in the North Indian population. DNA Cell Biol 2009; 28:443–449. [DOI] [PubMed] [Google Scholar]
  • 21.Mahasneh A, Jubaili A, El Bateiha A, et al. Polymorphisms of arylamine N-acetyltransferase2 and risk of lung and colorectal cancer. Genet Mol Biol 2012; 35:725–733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Mounetou E, Legault J, Lacroix J, et al. Antimitotic antitumor agents: synthesis, structure-activity relationships, and biological characterization of N-aryl-N′-(2-chloroethyl)ureas as new selective alkylating agents. J Med Chem 2001; 44:694–702. [DOI] [PubMed] [Google Scholar]
  • 23.Cascorbi I, Brockmoller J, Mrozikiewicz PM, et al. Homozygous rapid arylamine N-acetyltransferase (NAT2) genotype as a susceptibility factor for lung cancer. Cancer Res 1996; 56:3961–3966. [PubMed] [Google Scholar]
  • 24.Oyama T, Kawamoto T, Mizoue T, et al. N-acetylation polymorphism in patients with lung cancer and its association with p53 gene mutation. Anticancer Res 1997; 17:577–581. [PubMed] [Google Scholar]
  • 25.Bouchardy C, Mitrunen K, Wikman H, et al. N-acetyltransferase NAT1 and NAT2 genotypes and lung cancer risk. Pharmacogenetics 1998; 8:291–298. [DOI] [PubMed] [Google Scholar]
  • 26.Nyberg F, Hou SM, Hemminki K, et al. Glutathione S-transferase mu1 and N-acetyltransferase 2 genetic polymorphisms and exposure to tobacco smoke in nonsmoking and smoking lung cancer patients and population controls. Cancer Epidemiol Biomarkers Prev 1998; 7:875–883. [PubMed] [Google Scholar]
  • 27.Hayes RB, Zhang L, Yin S, et al. Genotoxic markers among butadiene polymer workers in China. Carcinogenesis 2000; 21:55–62. [DOI] [PubMed] [Google Scholar]
  • 28.Hansen JL, Schmeing TM, Klein DJ, et al. Progress toward an understanding of the structure and enzymatic mechanism of the large ribosomal subunit. Cold Spring Harbor Symp Quant Biol 2001; 66:33–42. [DOI] [PubMed] [Google Scholar]
  • 29.Zhou W, Liu G, Thurston SW, et al. Genetic polymorphisms in N-acetyltransferase-2 and microsomal epoxide hydrolase, cumulative cigarette smoking, and lung cancer. Cancer Epidemiol Biomarkers Prev 2002; 11:15–21. [PubMed] [Google Scholar]
  • 30.Belogubova EV, Kuligina E, Togo AV, et al. ‘Comparison of extremes’ approach provides evidence against the modifying role of NAT2 polymorphism in lung cancer susceptibility. Cancer Lett 2005; 221:177–183. [DOI] [PubMed] [Google Scholar]
  • 31.Chiou HL, Wu MF, Chien WP, et al. NAT2 fast acetylator genotype is associated with an increased risk of lung cancer among never-smoking women in Taiwan. Cancer Lett 2005; 223:93–101. [DOI] [PubMed] [Google Scholar]
  • 32.Habalova V, Salagovic J, Kalina I, et al. A pilot study testing the genetic polymorphism of N-acetyltransferase 2 as a risk factor in lung cancer. Neoplasma 2005; 52:364–368. [PubMed] [Google Scholar]
  • 33.Skuladottir H, Autrup H, Autrup J, et al. Polymorphisms in genes involved in xenobiotic metabolism and lung cancer risk under the age of 60 years. A pooled study of lung cancer patients in Denmark and Norway. Lung Cancer 2005; 48:187–199. [DOI] [PubMed] [Google Scholar]
  • 34.Sorensen M, Autrup H, Tjonneland A, et al. Genetic polymorphisms in CYP1B1, GSTA1, NQO1 and NAT2 and the risk of lung cancer. Cancer Letters 2005; 221:185–190. [DOI] [PubMed] [Google Scholar]
  • 35.Borlak J, Reamon-Buettner SM. N-acetyltransferase 2 (NAT2) gene polymorphisms in colon and lung cancer patients. BMC Med Genet 2006; 7:58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Chen HC, Cao YF, Hu WX, et al. Genetic polymorphisms of phase II metabolic enzymes and lung cancer susceptibility in a population of Central South China. Dis Markers 2006; 22:141–152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Lee CN, Yu MC, Bai KJ, et al. NAT2 fast acetylator genotypes are associated with an increased risk for lung cancer with wildtype epidermal growth factor receptors in Taiwan. Lung Cancer 2009; 64:9–12. [DOI] [PubMed] [Google Scholar]
  • 38.Zupa A, Sgambato A, Bianchino G, et al. GSTM1 and NAT2 polymorphisms and colon, lung and bladder cancer risk: a case-control study. Anticancer Res 2009; 29:1709–1714. [PubMed] [Google Scholar]
  • 39.Nikishina MV, Vavilin VA, Makarova SI, et al. Analysis of associations of NAT2 gene polymorphisms with the risk of lung cancer. Bull Exp Biol Med 2007; 143:83–86. [DOI] [PubMed] [Google Scholar]
  • 40.Zienolddiny S, Campa D, Lind H, et al. A comprehensive analysis of phase I and phase II metabolism gene polymorphisms and risk of non-small cell lung cancer in smokers. Carcinogenesis 2008; 29:1164–1169. [DOI] [PubMed] [Google Scholar]
  • 41.Tian F, Zhang Y, Ren Y, et al. N-acetyltransferase 2 (NAT2) gene polymorphism and exposure to smoking in lung cancer of Chinese males. Med Oncol 2014; 31:90. [DOI] [PubMed] [Google Scholar]
  • 42.Zheng DJ. Case Control Study of the Association Between CYP1A1 NAT2 GSTM1 Genetic Polymorphism and Lung Cancer Risk. China National Knowledge Infrastructure: Tianjin Medical University; 2010. [Google Scholar]
  • 43.Hou SM, Ryberg D, Falt S, et al. GSTM1 and NAT2 polymorphisms in operable and non-operable lung cancer patients. Carcinogenesis 2000; 21:49–54. [DOI] [PubMed] [Google Scholar]
  • 44.Saarikoski ST, Reinikainen M, Anttila S, et al. Role of NAT2 deficiency in susceptibility to lung cancer among asbestos-exposed individuals. Pharmacogenetics 2000; 10:183–185. [DOI] [PubMed] [Google Scholar]
  • 45.Windmill KF, Gaedigk A, Hall PM, et al. Localization of N-acetyltransferases NAT1 and NAT2 in human tissues. Toxicol Sci 2000; 54:19–29. [DOI] [PubMed] [Google Scholar]

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