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. 2011 Aug 30;137(11):1661–1667. doi: 10.1007/s00432-011-1045-6

Possible association of NAT2 polymorphism with laryngeal cancer risk: an evidence-based meta-analysis

Xin-Jiang Ying 1,✉, Pin Dong 1, Bin Shen 1, Jie Wang 1, Sang Wang 1, Guo Wang 1
PMCID: PMC11828131  PMID: 21877196

Abstract

Purpose

N-acetyltransferase 2 (NAT2) plays an important role in the metabolism of various potential carcinogens, which can be subdivided into rapid and slow acetylation phenotype according to the different genotypes. A number of studies have been devoted to the association of NAT2 polymorphism with susceptibility to laryngeal carcinoma; however, the results were inconsistent and inconclusive. The aim of the present study was to conduct a meta-analysis assessing the possible association of NAT2 polymorphism with laryngeal cancer risk.

Methods

The relevant studies were identified through a search of PubMed, Embase, ISI Web of Knowledge, and Chinese National Knowledge Infrastructure until February 2011 and selected on the basis of the established inclusion criteria for publications, and then a meta-analysis was performed to quantitatively summarize the association of NAT2 polymorphism with laryngeal cancer susceptibility.

Results

Seven studies were included in the present meta-analysis, which described a total of 980 laryngeal cancer cases and 1,487 controls. The overall odds ratio (OR) for NAT2 slow and rapid acetylators was 0.99 (95% CI = 0.71–1.38) and 1.01 (95% CI = 0.72–1.40), respectively. When stratifying for race, the pooled ORs for NAT2 slow acetylator were 1.99 (95% CI = 1.10–3.63) in Asians and 0.85 (95% CI = 0.62–1.15) in Caucasians, and the pooled ORs for NAT2 rapid acetylator were 0.50 (95% CI = 0.28–0.91) in Asians and 1.18 (95% CI = 0.87–1.60) in Caucasians.

Conclusions

This meta-analysis suggested that there was overall lack of association between NAT2 polymorphism and laryngeal cancer risk; however, NAT2 slow acetylation may contribute to a risk factor for laryngeal cancer in Asians but not in Caucasians.

Keywords: NAT2, Laryngeal carcinoma, Polymorphism, Meta-analysis, Risk, Susceptibility

Introduction

Laryngeal squamous cell carcinoma (SCC) is the most frequent malignancy in the head and neck region, the risk of which results from complex interactions between many genetic and environmental factors (Hashibe et al. 2007). A growing body of epidemiological studies shows that cigarette smoking and alcohol consumption play a critical role in the development of the disease (Koskinen et al. 2007). Additionally, it is well known that chemical pollutants are difficult to be degraded in the environment and thus may have a long-term effect on human health. Although many individuals have been exposed to these exogenous risk factors, laryngeal SCC develops in only a small group of them, which suggests that genetic host factors must contribute to the carcinogenic mechanisms (Frank 2004). Accumulating evidence indicates that genetic polymorphisms have also been extensively investigated to identify inherited genetic risk for laryngeal SCC (Boccia et al. 2008).

N-acetyltransferase 2 (NAT2) is a polymorphic gene located on chromosome 8p21.3-23.1 and encodes a 290-amino acid protein expressed in a wide range of human tissues (Blum et al. 1990). NAT2 polymorphisms have been reported to be associated with laryngeal cancer (Drozdz et al. 1987), bladder cancer (Garcia-Closas et al. 2005), colorectal cancer (Chen et al. 2005), breast cancer (Ambrosone et al. 2008), and other malignancies (Agundez 2008). A number of NAT2 alleles have been identified in various human populations (for NAT2 nomenclature, see http://www.louisville.edu/medschool/pharmacology/NAT.html), in which the NAT2*4 is the most common allele associated with rapid acetylation and the NAT2*11A, NAT2*12A-C, NAT2*13A, and NAT2*18 are also considered as rapid alleles, while the rest alleles are classified as slow ones. Concerning NAT2 phenotypes, individuals were classified as slow acetylators if homozygous for any of the slow alleles and as rapid acetylators if homozygous or heterozygous for rapid alleles (Hein et al. 2000). As one of the phase II enzymes, NAT2 plays a major role in the metabolism of heterocyclic arylamines, which are important ultimate carcinogens involved in the initiation process of carcinoma (Butcher et al. 2002).

Many studies have evaluated the potential role of NAT2 genotypes in the development of laryngeal SCC. Drózdz et al. firstly reported that the rapid acetylator NAT2 genotypes might be associated with a risk to develop laryngeal cancer (Drozdz et al. 1987). Conversely, Morita et al. reported that the risk of laryngeal SCC was associated with the slow acetylator NAT2 genotypes (Morita et al. 1999). A series of related studies were carried out later; however, results were generally inconsistent and inconclusive, and a single study may have been underpowered in clarifying the association of NAT2 polymorphism with laryngeal cancer susceptibility. Therefore, we conducted this meta-analysis that might increase statistical power to address the possible association of NAT2 polymorphism with laryngeal cancer risk.

Materials and methods

Search strategy

Relevant studies published up to February 2011 were identified by searching PubMed, Embase, ISI Web of Knowledge, and Chinese National Knowledge Infrastructure, with a combination of the following keywords: “N-acetyltransferase 2,” “NAT2,” “polymorphism,” “larynx,” and “cancer.” All searched papers were retrieved, and their references were checked as well for other relevant publications. Review articles were also searched to find additional eligible studies. For papers on the same population or with overlapping data, only the most recent or the ones with the largest group of subject data sets were included in this analysis. To identify potentially eligible papers, the title and abstract of each paper identified by the literature search were assessed independently by two authors. Disagreements were resolved by discussion.

Inclusion and exclusion criteria

All papers involving studies that investigated NAT2 and laryngeal cancer risk were included. The following criteria were used for the paper selection for further meta-analysis: (1) The papers should clearly evaluate the association of laryngeal cancer with NAT2 polymorphism; (2) Only the case–control or cohort studies were considered; (3) The laryngeal cancer diagnoses and the sources of cases and controls should be clearly described; (4) The polymorphism was determined by polymerase chain reaction (PCR)-based method; and (5) Enough information about the number of laryngeal cancer cases and controls studied with the different NAT2 genotypes should also be offered. Accordingly, the following exclusion criteria were also used: (1) The design and the definition of the experiments were obviously different from those of the selected papers; (2) Not offering the source of cases and controls or other essential information; (3) Reviews and repeated literature were also excluded.

Data extraction

From each of the eligible papers, the following data were extracted: first author’s surname, publication year, country of origin, ethnicity, numbers of cases and controls, and numbers of cases and controls of different genotypes, respectively. In some studies, the authors classified individuals into rapid acetylator (with 2 rapid alleles), intermediate acetylator (with 1 rapid and 1 slow allele), and slow acetylator (with 2 slow alleles). For data analysis in these studies, intermediate acetylators were reclassified as rapid acetylators. Data were extracted independently by the same authors previously mentioned, and consensuses were reached on all items. Discrepancies were resolved by discussion.

Statistical analysis

The strength of the association between laryngeal cancer and the NAT2 polymorphism was estimated by odds ratio (OR) and 95% confidence interval (CI), based on the genotype frequencies in cases and controls. A chi-square-based Q-statistic test was performed to assess heterogeneity. If the result of the heterogeneity test was P > 0.10, ORs were pooled according to the fixed-effect model (Mantel–Haenszel); otherwise, the random-effect model (Mantel–Haenszel) was used. Heterogeneity among studies was also tested by the I 2 statistic (Higgins et al. 2003). The fixed-effect model was performed when the test for heterogeneity was less than moderate (I 2 < 50%); otherwise, a random-effects model was considered. Galbraith plot was used to investigate heterogeneity. Visual inspection of asymmetry in funnel plots was conducted to estimate the potential publication bias (Bennett et al. 2004). In order to supplement the funnel plot, Begg’s funnel plots (Begg and Mazumdar 1994) and Egger’s regression method (Egger et al. 1997) were performed (P < 0.05 was considered representative of statistically significant publication bias). Statistical analysis was done using the program Review Manager 5.1 (2011, The Cochrane Collaboration) and the statistical software Stata10.0 (Stata Corporation, College Station, TX), and P < 0.05 was considered statistically significant.

Results

Study characteristics

The literature search identified 55 related articles through PubMed, Embase, ISI Web of Knowledge, and Chinese National Knowledge Infrastructure. With the step of screening the title or abstract, 11 eligible studies were selected (Boccia et al. 2008; Chatzimichalis et al. 2010; Drozdz et al. 1987; Gajecka et al. 2005; Henning et al. 1999; Jourenkova-Mironova et al. 1999; Lei et al. 2002; Morita et al. 1999; Rydzanicz et al. 2005; Unal et al. 2005; Varzim et al. 2002). Of the 11 articles selected, three studies by Boccia, Rydzanicz, and Unal (Boccia et al. 2008; Rydzanicz et al. 2005; Unal et al. 2005) were excluded because of the lack of data about acetylator status of laryngeal cancer and one study by Drozdz et al. (1987) was excluded because polymorphism was not determined by PCR-based method. Finally, seven studies including 980 laryngeal SCC cases and 1,487 controls were included in this meta-analysis based on inclusion and exclusion criteria (Table 1). There were 5 studies of Caucasians and 2 studies of Asians. Almost all of the cases were pathologically confirmed. Controls were mainly healthy populations and matched for age. Most of the included studies were hospital-based case–control studies.

Table 1.

Characteristics of all studies included in the meta-analysis

Year Author Cases Controls Country Ethnicity
Slow Rapid Slow Rapid
1999 Henning 138 117 286 224 German Caucasian
1999 Jourenkova 68 61 91 81 France Caucasian
1999 Morita 10 59 17 147 Japanese Asian
2002 Varzim 47 41 76 96 Portugal Caucasian
2002 Lei 50 12 34 22 China Asian
2005 Gajecka 127 162 165 146 Poland Caucasian
2010 Chatzimichalis 39 49 65 37 Greece Caucasian
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Test of heterogeneity

We analyzed the heterogeneity for all studies, and the test value of chi-square was 19.36 with 6 degree of freedom (df) and P < 0.10. Additionally, I-square value was another index for the heterogeneity test, which was 69% that was more than 50%, indicating a possible heterogeneity between studies. Considering the chi-square value and its P value, a random-effect model was used to pool the results. Analysis showed similar results when the heterogeneity was investigated by the Galbraith plot, which indicated that the heterogeneity resulted from 2 studies by Chatzimichalis and Lei (Fig. 1).

Fig. 1.

Fig. 1

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Galbraith plot of NAT2 genotype and laryngeal cancer susceptibility

Quantitative data synthesis

The overall ORs were calculated from the reported frequencies of genotype by disease status. The combined results based on all studies showed that there was no significant association in genotype distribution between laryngeal SCC and control (slow acetylator OR = 0.99, 95% CI = 0.71–1.38, Z = 0.04; rapid acetylator OR = 1.01, 95% CI = 0.72–1.40, Z = 0.04). Considering possible impacts of ethnic variations on the results, we utilized subgroup analysis concerning Asians and Caucasians, respectively. The pooled ORs for NAT2 slow acetylator were 1.99 (95% CI = 1.10–3.63) in Asians and 0.85 (95% CI = 0.62–1.15) in Caucasians, and the pooled ORs for NAT2 rapid acetylator were 0.50 (95% CI = 0.28–0.91) in Asians and 1.18 (95% CI = 0.87–1.60) in Caucasians, which indicated that there was significant association in Asians but not in Caucasians (Figs. 2, 3). It was not possible to perform some subgroup analyses (location, stage, and histological type) due to lack of data on these subtypes. In addition, interactions between smoking and NAT2 genotypes were not evaluated because of the fact that related data were not available in the articles.

Fig. 2.

Fig. 2

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Meta-analysis of slow acetylators and laryngeal cancer susceptibility

Fig. 3.

Fig. 3

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Meta-analysis of rapid acetylators and laryngeal cancer susceptibility

Sensitivity analysis

A single study involved in the meta-analysis was deleted each time to reflect the influence of the individual data set to the pooled ORs, and the corresponding pooled ORs were not materially altered (data not shown), indicating that our results were statistically robust. We also deleted the 2 studies investigated by the Galbraith plot, which showed no evidence of heterogeneity, and produced an OR not significantly different from the analysis of all studies (Fig. 4).

Fig. 4.

Fig. 4

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Meta-analysis of slow acetylators and laryngeal cancer susceptibility without heterogeneity

Publication bias

Funnel plot was created to assess the possible publication bias, the shape of which did not reveal any evidence of obvious asymmetry (Fig. 5). Begg’s funnel plot indicated no evidence for funnel plot asymmetry (P = 0.368, Fig. 6), and Egger’s test also suggested the absence of publication bias (P = 0.265, Fig. 7).

Fig. 5.

Fig. 5

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Funnel plot of association between NAT2 polymorphism and laryngeal cancer

Fig. 6.

Fig. 6

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Begg’s funnel plot with pseudo-95% confidence limits

Fig. 7.

Fig. 7

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Egger’s publication bias plot

Discussion

A series of studies have indicated that NAT2 genetic polymorphism may contribute to the risk of laryngeal SCC. However, the results of these studies assessing the association of laryngeal SCC susceptibility with acetylation status have been contradictory. Hence, we undertook this meta-analysis, which suggested that there was overall lack of association between NAT2 polymorphism and laryngeal cancer risk.

NAT2 plays an essential role in the metabolism of various potential carcinogens, and genotype polymorphisms of NAT2 have been reported to be associated with several cancers (Brockton et al. 2000; Ochs-Balcom et al. 2007; Rouissi et al. 2009; Zienolddiny et al. 2008). Previous meta-analyses indicate that NAT2 slow acetylation status is associated with a modest increase in bladder cancer risk (Johns and Houlston 2000; Marcus et al. 2000), and NAT2 rapid acetylator phenotype has a significantly increased risk for colorectal cancer (Chen et al. 2005; Ochs-Balcom et al. 2007). In contrast, a number of meta-analyses suggest no marked associations of NAT2 genotypes with either colon or lung cancer risk (Borlak and Reamon-Buettner 2006) and breast cancer risk (Ochs-Balcom et al. 2007). Similarly, our data failed to find a relationship between NAT2 acetylation status and laryngeal cancer risk. The present meta-analysis, which included 980 cases of laryngeal SCC and 1,487 controls, suggested that there was no association between NAT2 acetylation status and laryngeal SCC susceptibility. The combined OR for NAT2 slow and rapid acetylators was 0.99 (95% CI = 0.71–1.38) and 1.01 (95% CI = 0.72–1.40), respectively. However, NAT2 slow acetylation may contribute to a risk factor for laryngeal cancer in Asians but not in Caucasians, when the studies were stratified by ethnicity.

Several limitations of this study should be addressed. First, the sample size was still relatively small for the stratified analysis. Second, most of the included studies were hospital-based, which made results more prone to a degree of selection bias. Third, most of the included studies were conducted on Caucasians and a few on Asians, so that the results must be interpreted with caution. Further studies concerning populations in other areas are required to diminish the ethnic variation-produced bias. Fourth, we were unable to obtain information from most studies on the presence or absence of a history of smoking, because of the lack of investigation of gene-environment interactions. Finally, our meta-analysis was based on unadjusted estimates, whereas a more precise analysis could be performed if individual data were available and would allow for an adjustment estimate.

In conclusion, no association was found between NAT2 acetylation status and laryngeal cancer susceptibility in this meta-analysis based on current published data. It is of great essentiality to conduct large-sample studies regarding the relationship between NAT2 acetylation status and laryngeal SCC risk to investigate interaction with smoking in standardized exposure measures, which would greatly help summarize the results from published papers.

Acknowledgments

We are indebted to the authors of the primary studies.

Conflict of interest

We declare that we have no conflict of interest.

Abbreviations

NAT2

N-acetyltransferase 2

SCC

Squamous cell carcinoma

OR

Odds ratio

CI

Confidence interval

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