Association between the hOGG1 Ser326Cys polymorphism and lung cancer susceptibility: a meta-analysis based on 22,475 subjects

Lung cancer has become one of the most common malignancies all over the world with an extremely low survival rate is one of the leading causes to contribut to cancer mortality [1]. A number of environmental and genetic risk factors for lung cancer have been identified, and it is caused primarily by tobacco smoke, as manifested by the fact that 80% to 90% of lung cancer patients are smokers, while “only” 10% to 15% of heavy smokers develop lung cancer, suggesting the existence of personal risk factors of genetic origin, which predispose a fraction of smokers to the disease [2‐5]. DNA damage may lead to carcinogenesis through inactivation of tumor suppressor genes or activation of oncogenes [6, 7], and recent studies have focused on the association between genetic polymorphisms in different genes and risk of lung cancer [8‐10], and they were certified by different techniques [11].

The 8-oxoguanine lesion is one of themajor forms of oxidative DNA damage [12, 13], and it can be removed from DNA by human 8-oxoguanine DNA N-glycosylase 1 (hOGG1) [14]. This glycosylase has been suggested as a possible suppressor of lung carcinogenesis in OGG1-knockout mice [15], and in a bacterial complementation assay system the hOGG1 Cys326 allele was postulated to reduce the activity of 8-oxoguanine lesion removal [16]. 8-Oxodeoxyguanosine, the most abundant lesion generated by oxidative stress from the environment and normal cellular metabolism, is highly mutagenic resulting in GC to TA transversion [17, 18]. hOGG1 gene located on chromosome 3 encodes a DNA glycosylase/apurinic-apyrimidinic lyase that catalyzes the excision and removal of 8-hydroy-2-deoxyguanine adducts [19]. An approximately 2-fold increased risk of lung cancer associated with the Cys/Cys or Ser/Cys genotype of hOGG1 has been observed in many different ethnicity populations [20‐22]. In the past years, the hOGG1 Ser326Cys polymorphism has attracted widespread attention. Previous epithio studies were performed to identify the association of Ser326Cys polymorphism with lung cancer risk [16, 20‐46]. However, the results remain inconclusive and inconsistent. Therefore, a meta-analysis was performed in our present study to further evaluate the association between hOGG1 Ser326Cys polymorphism and lung cancer risk, by which can facilitate this disease prevention and diagnosis.

It is well recognized that there is a range of individual susceptibility to the same kind of cancer even with identical environmental exposure. Host factors, including polymorphisms of genes involved in carcinogenesis, may have accounted for this difference. Therefore, genetic susceptibility to cancer has been a research focus in scientific community. Among the common single nucleotide polymorphisms (SNPs) of the hOGG1 gene, one located in exon 7, resulting in an amino acid substitution of serine (Ser) with cysteine (Cys) at codon 326 (Ser326Cys, rs1052133), has been demonstrated to affect hOGG1 function [53]. The protein resulting from this substitution exhibits reduced DNA repair activity [53], and this SNP has been reported to be associated with the risk of many types of cancer [54]. Epidemiological studies of the OGG1 Ser326Cys polymorphism in relation to cancer have yielded mixed results with a weak association between the OGG1 Ser326Cys genotype and the risk of lung cancer. Wikman et al. carried out a case–control study which suggested that the hOGG1 polymorphisms were probably not major contributors to individual lung cancer susceptibility in Caucasians [33]. Hung et al. also observed that there were no such associations between them [36]. The same results were found in other studies [23]. Sugimura et al. found that the Ser326Cys polymorphism was not associated with an increased risk of lung cancer in any subtypes; however, when homozygous Cys326Cys were compared with other genotypes in combination, an increased risk was observed for the squamous cell carcinoma and nonadenocarcinoma after adjustment for age and smoking [32]. Ito et al. found no any effects of the OGG1 Ser326Cys polymorphism on the development of either adenocarcinomas or small cell carcinoma [34]. De Ruyck et al. found a reduced cancer risk associated with the OGG1 Ser326Cys polymorphism [40]. Individual studies on the relationships between SNPs of genes and cancer risk always yield inconsistent and controversial results partly because of a rather small sample size and low precision. Meta-analysis could solve the problem caused by the low statistical power of single studies and enable drawing of a more robust conclusion. Since there have been contradictory findings so far, we conducted a meta-analysis of 10,327 lung cancer cases and 12,148 controls to investigate its association with lung cancer risk.

The meta-analysis of Hung et al. showed that the summary OR was 1.37 (95% CI = 1.02–1.82) for the Cys/Cys genotype in various ethnic populations combined [55]. Li et al. performed another meta-analysis showed that individuals carrying the Cys/Cys genotype did not have significantly increased risk of lung cancer in all populations combined but, in the stratified analysis by ethnicity, a significantly increased risk was found among Asians (OR = 1.18, 95% CI = 1.01–1.38) [56]. Our work, including 22,475 subjects from 30 published case–control studies, explored the association between a potentially functional polymorphism, hOGG1 Ser326Cys and lung cancer susceptibility. We found that the variant genotypes of the hOGG1 were associated with a significant increased overall risk of lung cancer. When stratified according to ethnicity, Asians with the Ser/Ser showed a higher risk of lung cancer compared with those with the Cys/Cys genotype. However, Caucasians did not show the same risk. Ethnic difference in the association between lung cancer risk and the hOGG1 Ser326Cys polymorphism was suggested. Large studies including different ethnic groups with a careful matching between cases and controls should be considered in future association studies to confirm results from the meta-analyses.

Heterogeneity is a potential problem when interpreting the results of all meta-analyses. As looked through our study carefully, we found that the three studies [27, 37, 45] were noted to be a major source of heterogeneity. The reason may be that the study was only among non-smokers, and the controls were found to be out of HWE. Although this study was a major source of heterogeneity, the corresponding pooled ORs were not materially altered with or without including it almost in all genetic models, suggesting that the results of this meta-analysis are stable.

Some limitations of this meta-analysis should be addressed. Firstly, lung cancer is a multi-factorial disease that results from complex interactions between many genetic and environmental factors. This means that there will not be single gene or single environmental factor that has large effects on lung cancer susceptibility. Our results were based on unadjusted estimates, while a more precise analysis should be conducted if individual data were available, which would allow for the adjustment by other covariates including age, sex, family history, environmental factors and lifestyle. Secondly, in the subgroup analyses by ethnicity, control sources, the number of subjects was relatively small, not having enough statistical power to explore the real association. Thirdly, the controls were not uniformly defined. Although most of the controls were selected mainly from healthy populations, some had respiratory disease. Therefore, non-differential misclassification bias was possible because these studies may have included the control groups who had different risks of developing lung cancer.

Despite some limitations listed above, this work suggests that the hOGG1 Ser326Cys variant is a risk factor for developing lung cancer. Additionally, we found that this phenomenon was more prominent in subgroups such as in Asians. However, it is necessary to conduct large studies using standardized unbiased methods, homogeneous lung cancer patients and well matched controls, with the assessors blinded to the data. Moreover, gene–gene and gene–environment interactions should also be considered in future analysis. Such studies taking these factors into account may eventually lead to our better, comprehensive understanding of the association between the hOGG1 Ser326Cys polymorphism and lung cancer risk.