Association between Catechol-O-methyltransferase rs4680 (G > A) polymorphism and lung cancer risk

Lung cancer is the most frequently diagnosed cancer and is also considered as one of the most commonly lethal malignancies worldwide [1]. Despite the high morbidity and mortality of lung cancer, its etiology remains largely unknown. There are multiple factors and multistep processes contributing to lung cancer, among which environmental exposures, such as arsenic, asbestos, radon, and polycyclic aromatic hydrocarbons, specially tobacco smoking, are the major risk factor [2]. However, only a small proportion individual exposed to these carcinogens eventually develop lung cancer in the lifetime. Besides environmental risk, it has been believed that genetic factors also play a role in the development of lung cancer.

The catechol-O-methyl transferase (COMT) gene is located on the chromosome 22q11.2. The Val158Met (rs4680, G > A) single nucleotide polymorphism (SNP) in COMT gene have been identified in a protein coding region [3], which leads to a common substitution of methionine (Met) for valine (Val) at codon 158, This SNP has been reported to affect the activity of the COMT enzyme. For instance, individuals with the variant Met/Met genotype have a 3- to 4- fold lower COMT enzyme activity than those with wild-type Val/Val genotype [4]. COMT enzyme is involved in methylation of catechol estrogens, especially catechol estrogens formed from the 2- and 4-hydroxylations of estradiol. Reduced the activity of this enzyme may lead to increasing the accumulation of catecholestrogens, which may cause oxidative DNA damage through participating in redox cycling processes or quinones metabolism [4]-[7]. The DNA adducts can generate apurinic sites that may lead to cancer-initiating mutations [8] cause cellular transformation [9],[10], and thereby initiate cancer development.

Up to date, a number of molecular epidemiologic case-control studies have shown the potential role of COMT Val158Met polymorphism in the risk of lung cancer. However, the results remain inconclusive and controversial. For example, Zhang et al. [7] had shown that COMT Val158Met was significantly associated with a reduced risk of NSCLC, whereas Lim et al. [11] had suggested that the variant A allele of COMT Val158Met polymorphism was positively associated with lung cancer in never-smokers. So far, no meta-analysis had been conducted to investigate the association between COMT Val158Met polymorphism and Lung cancer. With this in mind, we performed this meta-analysis with large samples to reevaluate this association.

Lung cancer is the leading cause of cancer-related mortality worldwide. Lung carcinogenesis is a complicated long multi stage process, involving the interplay of cancer susceptibility genes and specific environmental exposures [21]. For example, a personal history of cigarette smoking probably is the most important contributor to the imitation and development of tobacco-related lung cancer. Apart from smoke exposure, genome-wide association studies (GWAS) has provided a strong evidence that tobacco-dependent lung cancer patients had a susceptibility region in chromosome 15q25.1, including some genes (CHRNB4, CHRNA3, and CHRNA5) that encode for nicotinic acetylcholine receptors [22]. These results suggest that genetic and environmental risk factors may collaboratively contribute lung cancer carcinogenesis.

Numerous studies have adopted a candidate gene approach to explore the effects of genetic variations on the genetic susceptibility to lung cancer. A large proportion of relevant studies has been focused on SNPs in the genes coding for enzymes involved in tobacco carcinogen metabolism (e.g. CYP1A1 and NQO1) and genes involved in DNA repair (e.g. XRCC1) [23],[24]. Moreover, so many meta-analysis had investigated the association between the gene polymorphisms and the risk of lung cancer. The meta-analysis of Tan et al. [25] had reported a correlation between (ERCC2) Lys751Gln polymorphism and an increased risk of lung cancer based on 23,370 subjects. Wang et al. [26] performed a meta-analysis showed that there was no association between IL-6 rs1800796 polymorphism and lung cancer, etc. Therefore, Meta-analysis can provide a quantitative summary of the available data that will be stronger evidence for identifying the association between gene variations and cancer risk.

COMT polymorphism has also gained more and more attentions in this field. In addition, COMT is a rate-limiting enzyme that played a role in the detoxification of catechol estrogens. Reduced activity of this enzyme might cause the accumulation of catechol estrogens, which may sequentially lead to oxidative DNA damage [18],[27]. Estrogen receptor β is expressed in lung tissue, and estrogen receptor antagonists could significantly inhibit growth in non-small-cell lung cancer cell lines [28],[29]. There might be the oxidative metabolism of 17-estradiol and estrone to catechol estrogens that plays a key role in carcinogenesis [30].

Several epidemiologic studies have reported the role of COMT Val158Met polymorphism in the risk of lung cancer. Zienolddiny et al. [20] suggested that the exonic SNP (Val158Met) of the COMT gene was associated with an increased risk of lung cancer. Intriguingly, Zhang et al. [7] reported an opposite results in his research. Therefore, the previous results were conflicting and inconclusive. Although only limited studies were included, our meta-analysis provided a new evidence of the null association between COMT Val158Met polymorphism and overall lung cancer risk. To the best of our knowledge, this is the first meta-analysis that has evaluated the relationship between the COMT Vall58Met polymorphism and the risk of lung cancer.

We used the methods of the Newcastle-Ottawa Scale (NOS) to assess the quality of the studies included in our meta-analysis. As a result, three studies [7],[18],[20] were rewarded eight stars, while two studies [11],[19] were rewarded seven stars according to the NOS assessment system. Zhang et al. [7] and Lim et al. [11] had identified the association of COMT Val158Met polymorphism with the risk of lung cancer in Chinese non-smokers. The limitations of study by Zhang et al. [7] was that the sample size was small, and they did not analyze the effects of second-hand smoke and exposure to cooking smoke on the risk of NSCLC. The strengths of study by Lim et al. [11] included homogeneity with regard to gender and ethnicity and the large number of never-smokers. However, this study might be subjected to biases that exist in the hospital-based case-control studies. The individual data about environmental factors in the study by the Cote et al. [18] were relatively were detailed, including information on past medical and reproductive histories, occupational exposures, BMI, etc. Therefore, this study was able to explore the gene-gene and gene-environment interactions that influence an individual lung cancer risk. Nevertheless, the majority of the subjects in the study were lung adenocarcinomas. Thus, the findings might not be representative of lung cancer. Zienolddiny et al. [20] and Gemignani et al. [19] performed the genotyping of more than one hundred polymorphisms in genes involved in carcinogen and xenobiotic metabolism. However,the sample sizes of both studies were moderate. Therefore, there probably existed potential confounding false positives.

Although we took considerable efforts to collect all available data to investigate the association of COMT Vall58Met polymorphism and its correlation with lung cancer risk, there were also some limitations to be addressed. Firstly, there were only a few studies investigating relationship between COMT polymorphisms and lung cancer risk, therefore, the sample size of our meta-analysis was relatively small. Moreover, this meta-analysis might be also subjected from population stratification, a systematic difference in allele frequencies between subpopulations. In some cases, positive finding of an association study could result from population stratification, instead of a true association between studies SNP and disease. Secondly, our meta-analysis was based on unadjusted estimates, while a more precise analysis should be performed if individual data such as age, smoking status, lifestyle and environmental factors were available. These factors may be sources of the heterogeneity. Thirdly, only five studies were retrieved from Pubmed, Embase, China National Knowledge Infrastructure, and Medline data base. And unpublished studies and conference abstracts were excluded from the current study. Although Begg's funnel plot, Begg's test, and Egger's test were conducted to estimate the publication bias. Lack of publication bias in this study might be due to the fact that Egger's test was not very powerful with only a few studies in the meta-analyses, the results must be considered cautious. In spite of these limitations, our research was more powerful than each of single study.

In conclusion, no significant association was found between COMT Vall58Met polymorphism and lung cancer risk in the overall analysis. However, a borderline significant association indicated that COMT Vall58Met polymorphism might increase lung cancer susceptibility. Finally, high-quality case-control studies with large sample sizes will be required to confirm these findings.

TX and MC carried out the meta-analysis study, drafted the manuscript and involved in revising the manuscript critically for important intellectual content. Both authors read and approved the final manuscript.