|Year : 2018 | Volume
| Issue : 12 | Page : 1173-1177
Meta-analysis on the association between xeroderma pigmentosum Group A A23G polymorphism and esophageal cancer in a Chinese population
Jiang-Lan Xu1, Jing Bai2, Jian-Feng Jiao2, Li Ding2, Li Lei2, Xiao-Ping Bai2, Yu-Feng Cheng3
1 Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan 250012; Department of Radiation Oncology, Baotou Tumor Hospital, Baotou 014030, China
2 Department of Radiation Oncology, Baotou Tumor Hospital, Baotou 014030, China
3 Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan 250012, China
|Date of Web Publication||11-Dec-2018|
Department of Radiation Oncology, Qilu Hospital of Shandong University, No. 107, Wenhua West Road, Jinan 250012
Source of Support: None, Conflict of Interest: None
Aim of the Study: Several studies have evaluated the correlation between xeroderma pigmentosum Group A (XPA) A23G polymorphism (rs 1800975) and esophageal cancer in Chinese people. However, the results are inconsistent. To assess the effects of XPA A23G variants on the risk for development of esophageal cancer in the Chinese population, a meta-analysis was performed.
Materials and Methods: Studies were identified using PubMed and Chinese databases through December 2015. The associations were assessed with pooled odds ratios (ORs) and 95% confidence intervals (95% CIs).
Results: This meta-analysis identified seven studies including 1514 esophageal cancer cases and 2120 controls. In the overall analysis, no significant association between XPA A23G polymorphism and esophageal cancer was found in the Chinese population. In the subgroup analyses by geographic area(s) and source of controls, significant results were only found in studies with hospital-based controls (GG vs. AA: OR = 0.42, 95% CI = 0.28–0.62; GG vs. AA + AG: OR = 0.55, 95% CI = 0.39–0.78; GG + AG vs. AA: OR = 0.54, 95% CI = 0.40–0.72; G vs. A: OR = 0.61, 95% CI = 0.50–0.75).
Conclusions: This meta-analysis suggested that XPA A23G gene polymorphism may be one low-penetrant risk factor for esophageal cancer in Chinese individuals.
Keywords: Esophageal cancer, meta-analysis, polymorphism, xeroderma pigmentosum Group A
|How to cite this article:|
Xu JL, Bai J, Jiao JF, Ding L, Lei L, Bai XP, Cheng YF. Meta-analysis on the association between xeroderma pigmentosum Group A A23G polymorphism and esophageal cancer in a Chinese population. J Can Res Ther 2018;14, Suppl S5:1173-7
|How to cite this URL:|
Xu JL, Bai J, Jiao JF, Ding L, Lei L, Bai XP, Cheng YF. Meta-analysis on the association between xeroderma pigmentosum Group A A23G polymorphism and esophageal cancer in a Chinese population. J Can Res Ther [serial online] 2018 [cited 2019 Sep 15];14:1173-7. Available from: http://www.cancerjournal.net/text.asp?2018/14/12/1173/184517
| > Introduction|| |
Despite considerable medical advances, esophageal cancer with high incidence and mortality is still an intractable disease. Moreover, there are regional and racial differences in the prevalence of esophageal cancer. Its incidence rates vary internationally, and the highest rates found in Southern and Eastern Africa and Eastern Asia were nearly 16-fold higher than the lowest rates observed in Western and Middle Africa and Central America in both men and women. It is well-known that the carcinogenesis of various cancers is associated with interaction between environmental carcinogens and individuals' genetic background. Polymorphisms in cancer-related genes have been suggested to be the genetic basis of individuals' susceptibility to esophageal cancer.
In recent years, many candidate genes have been identified as potential esophageal cancer susceptibility loci. Of these genes, an important one is xeroderma pigmentosum Group A (XPA) gene, which is a vital component of the DNA repair machinery. The XPA gene is located on chromosome 9q22.3 and encodes a zinc finger DNA-binding protein participating in DNA excision repair to maintain genomic integrity. In the XPA gene, a polymorphic site has been identified in the 5' untranslated region and consists of an A to G substitution in the fourth nucleotide before the ATG start codon (XPA A23G, rs 1800975). It has been shown that the polymorphism could affect protein levels in the cell., To date, the XPA A23G substitution is the most widely studied polymorphism in XPA. In 2002, Park et al. conducted the first ever study investigating the relationship between XPA A23G polymorphism and lung cancer in Korea. Many studies have thereafter attempted to clarify its association with other cancers such as esophageal cancer; however, no clear consensus has been made. Differences in findings may be due to race and clinical heterogeneity in patients who have been studied, as well as a limited number of patients in each study.
Meta-analysis is one-way to overcome the problems of small sample size and inadequate statistical power. To lessen the influence of differing genetic backgrounds, we performed this meta-analysis to assess the relationship between the XPA A23G polymorphism and the risk for esophageal cancer in the Chinese population. We also performed a subgroup analysis, to explore the possible effects of gene-environment interaction on the risk of esophageal cancer.
| > Materials and Methods|| |
Search strategy and selection criteria
Eligible studies were identified by searching the PubMed and Chinese databases for relevant reports published before December 2015 using the following search terms: (Esophageal cancer or esophageal neoplasms) and (XPA) and (China or Chinese or Taiwan). The search was restricted to humans without language restrictions. Additional studies were identified by a hand search of references of original or review articles on this topic.
Studies included in this meta-analysis had to meet the following criteria: (1) They were case–control or cohort studies describing the association of XPA A23G polymorphism and esophageal cancer, (2) they provided the gene types in cases and controls, (3) participants were Chinese population. We excluded case-only studies, case reports, review articles, studies without raw data for the XPA A23G genotype, and repetitive publications.
We conducted a systematic review and meta-analysis in accordance with the guidelines provided by the preferred reporting items for systematic reviews and meta-analyses statement. Two authors independently extracted information from all included publications disagreements were resolved by discussion. Titles and abstracts of all identified studies were screened first. Full articles were scrutinized if the title and abstract were ambiguous. Data extracted from identified studies included first author's name, year of publication, source of controls, geographic area(s), and a number of cases and controls (total and genotypes). Hardy–Weinberg equilibrium (HWE) in controls was calculated from corresponding genotype distributions.
Statistical analysis was conducted using the Stata package version 12.0 (Stata Corporation, College Station, TX, USA). The χ2-test was used for determining the HWE of genotypes and the heterogeneity of rare allele frequencies in the control groups of each study reviewed. The association of XPA A23G polymorphism and esophageal cancer risk was estimated by odds ratios (ORs) with 95% confidence intervals (95% CIs). Depending on the results of the heterogeneity test among individual studies, the fixed-effect model (Mantel–Haenszel) or random-effect model (DerSimonian and Laird) was selected to summarize the pooled ORs and their 95% CIs. The significance of the pooled OR was determined by a Z-test. Sensitivity analysis was evaluated by comparing the results of fixed-effects model and random-effects model. We also performed stratification analyses by geographic area(s) and source of controls. P <0.05 was considered to be statistically significant.
| > Results|| |
Description of included studies
[Figure 1] illustrates the literature search process in the form of a flow chart. We identified 27 articles that examined the association between XPA polymorphism and risk of esophageal cancer in various databases. After screening the titles and abstracts, 14 articles were excluded according to the exclusion criteria described. Then, we reviewed all of the remaining full-articles,,,,,,,,,,,,, five,,,, were excluded due to duplicate studies, one was excluded due to lack of raw data. Finally, seven articles for the association between XPA A23G polymorphism and esophageal cancer,,,,,, were included in this meta-analysis. The publication year of involved studies ranged from 2006 to 2012. In total, 1514 esophageal cancer cases and 2120 controls were included in this meta-analysis. The source of controls in five studies was population-based. Characteristics of included studies are summarized in [Table 1].
[Table 2] lists the primary results of our meta-analysis. In the total analyses, the combined results showed that XPA A23G variants were not significantly associated with esophageal cancer in the Chinese population (for GG vs. AA: OR = 0.92, 95% CI = 0.50–1.70; for GG vs. AA + AG: OR = 1.07, 95% CI = 0.67–1.72; for GG + AG vs. AA: OR = 0.81, 95% CI = 0.55–1.19; for G vs. A: OR = 0.92, 95% CI = 0.66–1.27) [Figure 2]. In the subgroup analyses by geographic area(s) and source of controls, significant results of the association between the XPA A23G variants and esophageal cancer were only found in studies with hospital-based controls (for GG vs. AA: OR = 0.42, 95% CI = 0.28–0.62; for GG vs. AA + AG: OR = 0.55, 95% CI = 0.39–0.78; for GG + AG vs. AA: OR = 0.54, 95% CI = 0.40-0.72; for G vs. A: OR = 0.61, 95% CI = 0.50–0.75).
|Table 2: Association of the XPA A23G polymorphism on esophageal cancer susceptibility|
Click here to view
|Figure 2: The forest plots of all selected studies on the association between xeroderma pigmentosum Group A A23G polymorphism and esophageal cancer risk in Chinese (for allele model)|
Click here to view
To compare the difference and evaluate the sensitivity of the analyses, we used both models (the fixed-effects model and random-effects model) to evaluate the stability of this meta-analysis. All the significant pooled ORs did not materially alter, suggesting that the results of this meta-analysis are stable [Table 2].
| > Discussion|| |
The evidence suggests that reduced DNA repair capacity may lead to genetic instability and carcinogenesis, genes involved in DNA repair have been proposed as candidate cancer susceptibility genes. The relationship between XPA A23G polymorphism and esophageal cancer risk attracted the attention of both doctors and researchers. Since the first association between XPA A23G and esophageal cancer was reported in Korea, many studies have been undertaken to replicate the association. However, results of individual studies were inconclusive. Two meta-analyses, have evaluated the association between XPA A23G polymorphism and cancer risk and reported that this polymorphism is associated with an increased lung cancer risk and may be a low-penetrant risk factor for the development of esophageal cancer in people of Asian ethnicity. Subsequently, He et al. conducted another meta-analysis to assess the association between XPA A23G polymorphism and risk of digestive system cancers and suggested that the XPA A23G polymorphism is not associated with a risk of digestive system cancers. Regional and racial differences are one likely reason for the conflict results. Therefore, we performed this meta-analysis to assess the effect of the XPA A23G polymorphism on risk for esophageal cancer in the Chinese population, specifically, to reduce the impact of genetic background.
A total of seven studies with 1514 esophageal cancer cases and 2120 controls were included to systematically explore the association between XPA A23G polymorphism and esophageal cancer risk in this meta-analysis. From the combined statistical results, we did not find a significant association between XPA A23G polymorphism and the risk of esophageal cancer in the overall analysis. To further explain environmental factors can modulate the risk, subgroup analyses stratified by geographical areas, and source of controls was performed. We found that XPA A23G G allele, GG genotype carries might have a decreased risk of esophageal cancer only in studies with hospital-based controls. This result suggested that the same gene polymorphism may have different roles in esophageal cancer susceptibility among different controls. Therefore, further studies of esophageal cancer-related genes should be on the basis of region, nationality, and the control subjects should be comparable with the cases in all relevant aspects. Because of insufficient data, we were unable to perform subgroup analysis for other environment factors.
Heterogeneity is a potential problem in the understanding the results of meta-analyses. In this study, significant heterogeneity between different studies was observed in the overall population. To clarify the source of heterogeneity, geographic areas, and controls source were used to stratify the studies, finding part of this heterogeneity can be effectively attenuated or removed when stratification by the source of controls. It can be assumed that the heterogeneity partly results from the difference of source of controls. That may be because potential confounding factors in many epidemiologic studies may result from the difference in control types. Furthermore, other factors also should be explored to identify the source of heterogeneity if more data were available.
Although our study has obvious strengths, such as we investigated the influence of geographic areas and source of controls on the risk of esophageal cancer and XPA A23G. Several limitations should be considered in our meta-analysis. First, our meta-analysis only included Chinese population, and the results may not be applicable to other ethnic groups. Second, since this meta-analysis was based primarily on unadjusted effect estimates and CIs, confounding factors were not controlled. Third, the number of eligible studies in the subgroup analysis was very small. Therefore, some subgroup analysis may not have enough statistical power to detect the association of the XPA A23G polymorphism with esophageal cancer susceptibility. Finally, due to the limitations of funnel plotting, which requires a range of studies, we did not evaluate publication bias in this meta-analysis.
| > Conclusion|| |
This meta-analysis suggested that the XPA A23G polymorphism might be associated with a decreased risk of developing esophageal cancer in the Chinese population. Due to the limited number of available studies, a further study conducted in larger populations with multiple adjusted variables is required to obtain robust findings.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90.
Asahina H, Kuraoka I, Shirakawa M, Morita EH, Miura N, Miyamoto I, et al.
The XPA protein is a zinc metalloprotein with an ability to recognize various kinds of DNA damage. Mutat Res 1994;315:229-37.
Butkiewicz D, Rusin M, Harris CC, Chorazy M. Identification of four single nucleotide polymorphisms in DNA repair genes: XPA and XPB (ERCC3) in Polish population. Hum Mutat 2000;15:577-8.
Kozak M. Interpreting cDNA sequences: Some insights from studies on translation. Mamm Genome 1996;7:563-74.
Wu X, Zhao H, Wei Q, Amos CI, Zhang K, Guo Z, et al.
XPA polymorphism associated with reduced lung cancer risk and a modulating effect on nucleotide excision repair capacity. Carcinogenesis 2003;24:505-9.
Park JY, Park SH, Choi JE, Lee SY, Jeon HS, Cha SI, et al.
Polymorphisms of the DNA repair gene xeroderma pigmentosum group A and risk of primary lung cancer. Cancer Epidemiol Biomarkers Prev 2002;11 (10 Pt 1):993-7.
Duan PF. A Case-control Study on Polymorphisms of XPA, XPC and Esophageal Carcinoma. Master Thesis of Shanxi Medical University, China; 2007.
Wan LL. Trends in Mortality of Upper Gastrointestinal Cancer in the Risk-region of Esophageal Cancer and Study on Molecular Mechanisms. Master Thesis of Hebei Medical University, China; 2007.
Liu R, Yin LH, Pu YP, Wang Y, Pan EC. The mRVA expression profile of metabolism genes and DNA repair genes in esophageal tissues and PBMC. Prog Mod Biomed 2009;9:62-5.
Wan LL, Zhou RM, Wang N, Li Y, Guo W. Corrdation of XPA polymorphisms to risk of squamous cell carcinoma and gastric cardia adenocarcinoma. Cancer Res Prev Treat 2007;34:63-6.
Zhang WC, Yin LH, Pu YP, Liu R, Hu X, Liu YZ, et al
. Relationship between polymorphisms of DNA repair genes and esoph ageal cancer susceptibility. Chin J Public Health 2006;22:557-8.
Ma WJ, Lv GD, Zheng ST, Huang CG, Liu Q, Wang X, et al.
DNA polymorphism and risk of esophageal squamous cell carcinoma in a population of North Xinjiang, China. World J Gastroenterol 2010;16:641-7.
Zhang WC. Effects of Genetic and Environmental Risk Factors to Esophageal Cancer in Huaian Population. Master Thesis of Southeast University, China; 2006.
Huang XX. Polymorphisms of XPA and XRCC3, Environmental Agent and Susceptibilities to Esophageal, Cardia and Non-cardia Gastric Cancer. Master Thesis of Fujian Medical University, China; 2007.
Liu R. Study on Expression Characteristics of Susceptibility Genes and Genetic Susceptibility Markers for Esophageal Carcinomas. Doctor Thesis of Southeast University, China; 2007.
Feng XX, Duan PF, Wang LB, Zhang JB, Lu ZX. Study on the relationship between polymorphisms of XPA gene and susceptibility of esophageal cancer. Zhonghua Liu Xing Bing Xue Za Zhi 2008;29:930-3.
Guo W, Zhou RM, Wan LL, Wang N, Li Y, Zhang XJ, et al.
Polymorphisms of the DNA repair gene xeroderma pigmentosum groups A and C and risk of esophageal squamous cell carcinoma in a population of high incidence region of North China. J Cancer Res Clin Oncol 2008;134:263-70.
Zhu XL. Study on Relationship Between DNA Repair Genes Polymorphism of hOGG1, XPC, XPA and Esophageal Squamous Cell Carcinoma Susceptibility. Master Thesis of Huazhong University of Science and Technology, China; 2008.
Zhen Q. XPA Gene Polymorphisms and Susceptibility to Developing Esophageal Cancer in Chinese Han Population. Master Thesis of Zhengzhou University, China; 2012.
Wood RD, Mitchell M, Sgouros J, Lindahl T. Human DNA repair genes. Science 2001;291:1284-9.
Zou JH, An L, Chen S, Ren LQ. XPA A23G polymorphism and lung cancer risk: A meta-analysis. Mol Biol Rep 2012;39:1435-40.
Liu J, Zhang Z, Cao XL, Lei DP, Wang ZQ, Jin T, et al.
XPA A23G polymorphism and susceptibility to cancer: A meta-analysis. Mol Biol Rep 2012;39:6791-9.
He L, Deng T, Luo H. XPA A23G polymorphism and risk of digestive system cancers: A meta-analysis. Onco Targets Ther 2015;8:385-94.
Li L, Zhang M, Holman D. Population versus hospital controls for case-control studies on cancers in Chinese hospitals. BMC Med Res Methodol 2011;11:167.
[Figure 1], [Figure 2]
[Table 1], [Table 2]