XRCC3 Thr241Met gene polymorphisms and lung cancer risk: a meta-analysis

Lung cancer remains the most lethal cancer worldwide, despite improvements in diagnostic and therapeutic techniques[1]. Its incidence has not peaked in many parts of world, particularly in China, which has become a major public health challenge all the world[2]. The mechanism of lung carcinogenesis is not understood. Although smoking status is the single most important factor that causes lung cancer, host factors including genetic polymorphism, had garnered interest with regard to the study of the tumorigenesis of lung cancer[3]. Otherwise, accumulating studies have suggested that lung cancers occurring in never smokers have different molecular profiles. In this way, host genetic susceptibility is a very important factor in the development of lung cancer, contributing to the variation in individual cancer risk. DNA repair gene system plays a crucial role in protecting against gene mutation caused by tobacco smoke. Recent studies have revealed that single nucleotide polymorphisms (SNPs) in DNA repair genes may be the underlying molecular mechanism of the individual variation of DNA repair capacity[4, 5]. Increasing molecular epidemiologic evidence has shown that polymorphisms in various DNA repair genes are associated with an increased risk of lung cancer[6, 7].

The X-ray repair cross-complementing group 3 (XRCC3) belongs to a family of genes responsible for repairing DNA double strand breaks caused by normal metabolic processes and/or exposure to ionizing radiation[8].The XRCC3 gene codes for a protein involved in homologous recombinational repair (HRR) for double strand breaks of DNA (DBSs) and cross-link repair in mammalian cells[9]. During HRR, the XRCC3 protein interacts with Rad51 protein and likely contributes to maintain chromosome stability. A common polymorphism in exon 7 of the XRCC3 gene results in an amino acid substitution at codon 241 (Thr241Met) that may affect the enzyme function and/or its interaction with other proteins involved in DNA damage and repair[10]. The predominant homozygous allele, the heterozygous allele and the homozygous rare allele of the XRCC3 Thr241Met gene polymorphism are named the homozygous wild-type genotype (C/C), the heterozygote (C/T) and the homozygote (T/T), respectively.

Recently, many studies have investigated the role of the XRCC3 Thr241Met gene polymorphism in lung cancer. However, the results of these studies remain inconclusive. A single study might not be powered sufficiently to detect a small effect of the polymorphisms on lung cancer, particularly in relatively small sample sizes. Further, past studies have not controlled for the potential confounding effect of smoking properly-the main risk determinant for lung cancer. Various types of study populations and study designs might also have contributed to these disparate findings. To clarify the effect of the XRCC3 Thr241Met gene polymorphism on the risk for lung cancer, we performed a meta-analysis of all eligible case–control studies that have been published and conducted the subgroup analysis by stratification according to the ethnicity source, histological types of lung caner and smoking status of case and control population.

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. Recently, genetic variants of the DNA repair genes in the etiology of several cancers have drawn increasing attention. As it is known that individual studies with a small sample size may have not enough statistical power to detect a small risk factor, in this meta-analysis, we involved a total of 4123 lung cancer cases and 5597 controls and explored the association between the XRCC3 Thr241Met polymorphisms and lung cancer risk. Our results indicated that XRCC3 Thr241Met polymorphism was not significantly associated with the susceptibility to lung cancer. Additionally, no significant associations were also found in the stratified analysis by ethnicity, histological types or smoking status.

Population stratification is a troubling issue and can lead to spurious evidence on the association between markers and a disease, implicating the disparate effects of environment and ethnic differences on genetic background[32]. In this meta-analysis, ethnicity stratification of differences between Asians and Caucasians was not found. Tobacco smoke contains many known carcinogens and pro-carcinogens, such as benzopyrene and nitrosamine. Our meta-analysis results showed no significantly risks were found to be associated with the XRCC3 Thr241Met polymorphisms and lung cancer risk in smokers or non-smokers. There were only small number of studies examined the association between the XRCC3 Thr241Met gene polymorphism and lung cancer risk in smokers or non-smokers; moreover, the p value of Q test for heterogeneity test was significant. Considering the limited studies and P value of Q-test for heterogeneity test included in this meta-analysis, our results should be interpreted with caution.

When subgroup analyses by pathological type were considered, no significant associations were also found in lung AC subgroup or SCC subgroup. There are growing biological and epidemiological data to suggest that different lung cancer pathological subtypes, particularly the two most common, were distinct etiological entities that should be analyzed separately[33]. In the process of histological differentiation of lung cancer, XRCC3 Thr241Met polymorphisms may be not independent factor.

In our study, the three studies[17, 19, 25] accounted for 32.7% weight of all 17 studies. Popanda et al.[19] study accounted for 12.2% weight and included 921 cases, Lopez-Cima et al.[25] study accounted for 11.4% and included 837 cases, Misra et al.[17] study accounted for 9% and included 619 cases. The results of these three studies were consistent, with no significant association between the XRCC3Thr241 Met polymorphism and lung cancer risk. Moreover, the pooled OR of our meta-analysis was coincident with these three studies.

Improta G et al.[27] conducted a case–control study to examine the role of XRCC3 and XRCC1 genetic polymorphisms in the context of lung and colorectal cancer risk for Southern Italian population. As a result, the significant association was found between the XRCC3 Thr241Met polymorphisms and colorectal and lung cancer, more importantly, the risk of lung cancer of XRCC3 Thr241Met polymorphisms was relatively high (OR = 2.52, 95%: 1.44-4.41). In Wang et al. study[18], they found that no significant association between the XRCC3Thr241 Met polymorphism (OR = 1.04; 95% CI = 0.65–1.56) and lung cancer risk was shown. However, a significantly increased risk for lung cancer (OR = 4.77; 95% CI = 1.52 –14.97) was evident in smokers with the variant T-allele genotypes. Furthermore, a joint effect of the T-allele and heavy smoking was observed (OR = 37.31; 95% CI = 11.43–121.72). In our meta-analysis, for all studies the pooled OR was 0.95 (95% CI = 0.87-1.04), however the OR of the above-two studies was relative higher, thus they shown on the outlier of the Figures1 and3.

Some limitations of this meta-analysis should be acknowledged. First, heterogeneity can interfere with the interpretation of the results of a meta-analysis. Although we minimized this likelihood by performing a careful search of published studies, using explicit criteria for a study's inclusion and performing strict data extraction and analysis, significant interstudy heterogeneity nevertheless existed in nearly every comparison. The presence of heterogeneity can result from differences in the selection of controls, age distribution, and prevalence of lifestyle factors. Although most controls were selected from healthy populations, some studies had selected controls among friends or family members of lung cancer patients or patients with other diseases. Further, only published studies were included in this meta-analysis. The presence of publication bias indicates that non-significant or negative findings might be unpublished. Finally, our results were based on unadjusted estimates; a more precise analysis should have been conducted if individual data were available, which would have allowed us to adjust using other covariates, including age, ethnicity, family history, environmental factors, and lifestyle[34].

Despite these limitations, this meta-analysis suggests that the XRCC3 Thr241Met polymorphisms are not associated with lung cancer risk stratified analysis by ethnicity, histology and smoking status. However, it is necessary to conduct large sample studies using standardized unbiased genotyping methods and well-matched controls.