GENETIC TESTING AND MOLECULAR BIOMARKERS Volume 17, Number 10, 2013 ª Mary Ann Liebert, Inc. Pp. 780–785 DOI: 10.1089/gtmb.2013.0224
The OGG1 Ser326Cys Polymorphism and the Risk of Esophageal Cancer: A Meta-Analysis Zhan Wang,1,* Lu Gan,2,* Wei Nie,3,* and Yan Geng 4
Background: The oxoguanine DNA glycosylase (OGG1) Ser326Cys polymorphism has been implicated in susceptibility to esophageal cancer. Several studies investigated the association of this polymorphism with esophageal cancer in different populations. However, the results were contradictory. A meta-analysis was conducted to assess the association between the OGG1 Ser326Cys polymorphism and esophageal cancer susceptibility. Methods: Databases, including PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), and Weipu Database were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. A random-effects model was used. Results: Twelve studies involving 2363 cases and 3621 controls were included. Overall, a significant association between the OGG1 Ser326Cys polymorphism and esophageal cancer was observed for Cys/Cys versus Cys/Ser + Ser/Ser (OR = 1.40; 95% CI 1.12–1.74; p = 0.003; Pheterogeneity = 0.18). In the subgroup analysis by ethnicity, a significant association was found among Asians (OR = 1.51; 95% CI 1.15–1.96; p = 0.002; Pheterogeneity = 0.22), but not among Caucasians (OR = 1.21; 95% CI 0.81–1.81; p = 0.35; Pheterogeneity = 0.21). In the subgroup analysis by pathologic type, we found that the Cys/Cys genotype was associated with increased esophageal squamous cell carcinoma risk (OR = 1.86; 95% CI 1.36–2.53; p < 0.0001; Pheterogeneity = 0.73). Conclusions: This meta-analysis suggested that the OGG1 Ser326Cys polymorphism was a risk factor of esophageal cancer.
Introduction
E
sophageal cancer is the eighth most common cancer in the world, with approximately 462,000 cases and 386,000 deaths worldwide in 2002, making it the sixth most common cause of cancer-related deaths (Parkin et al., 2005). The estimated age-adjusted 5-year survival rate in developed countries is 15% for males and 8% for females, while it is 17% and 16%, respectively, in developing countries (Parkin et al., 2005). Oxidative DNA damage induced by reactive oxidative species contributes to the generation and development of cancer (Marnett, 2000). Of such damage, the formation of 8hydroxyl-2¢-deoxyguanosine (8-OHdG), a marker of oxidative damage on guanine (G), is the most common type and is highly mutagenic. If not repaired and accumulated in the affected tissues, 8-OHdG will mispair with adenine (A) instead of cytosine (C), which may cause a G:C to T:A transversion and further initiate subsequent carcinogenesis (Kasai et al., 1991; Shibutani et al., 1991; Cheng et al., 1992). The human
oxoguanine DNA glycosylase (OGG1) gene encodes a DNA glycosylase/apuriniclyase, which catalyzes the excision and removal of 8-OHdG adducts (Boiteux and Radicella, 2000; Sunaga et al., 2001). OGG1 maps on chromosome 3p26.2. Codon 326 at position 1245 in exon 7 of OGG1 holds a singlenucleotide polymorphism (SNP) with a C > G variation, thereby the amino acid translation of codon 326 can be changed from serine (Ser) to cysteine (Cys). Functionally, homozygous Ser/Ser (wild type) has the highest repair activity followed by the heterozygous Ser/Cys variant and then the homozygous Cys/Cys variant (Kohno et al., 1998). In a rat esophageal cancer model, Chen et al. (2000) found that 8OHdG in the esophagus was significantly higher compared with the control. Therefore, it is possible that the OGG1 Ser326Cys polymorphism, which affects enzyme activities, could influence the risk of esophageal cancer. So far, some studies investigated the association between the OGG1 Ser326Cys polymorphism and esophageal cancer risk (Xing et al., 2001; Gao et al., 2001; Liu et al., 2005; Hall et al., 2007;
1
Department of Oncology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. 3 Department of Respiratory Disease, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China. 4 Department of Oncology, Zhabei District Central Hospital, Shanghai, China. *These authors contributed equally to this work. 2
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Ferguson et al., 2008; Tse et al., 2008; Akbari et al., 2009; Zhu et al., 2009; Lagadu et al., 2010; Upadhyay et al., 2010; Hu et al., 2010). However, the results were conflicting and inconclusive. For instance, Xing and coworkers found that the OGG1 326Cys allele might play a role in the carcinogenesis of the esophageal cancer (Xing et al., 2001). However, Tse et al. (2008) did not observe this association. Thus, we carried out a meta-analysis to ascertain whether there was a genetic effect of OGG1 Ser326Cys on esophageal cancer susceptibility. Materials and Methods Publication search PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), and Weipu Database were searched (last search was updated on April, 2013). The search terms were used as follows: (‘‘esophagus cancer’’ or ‘‘esophageal carcinoma’’ or ‘‘esophageal neoplasm’’) and (human 8-oxoguanine DNA glycosylase or hOGG1 or OGG1 or OGG) and (polymorphism or mutation or variant). The following MeSH terms were used in PubMed: ‘‘esophageal neoplasms’’ and ‘‘polymorphism, genetic’’ and ‘‘8-oxoguanine DNA glycosylase.’’ All the searched studies were retrieved, and their references were checked as well for other relevant publications. Review articles were also searched to find additional eligible studies. Inclusion and exclusion criteria Studies fulfilling the following selection criteria were included in this meta-analysis: (1) the studies evaluated the association between the OGG1 Ser326Cys polymorphism and esophageal cancer risk, (2) the design had to be a case–control study, and (3) sufficient data (genotype distributions for cases and controls) were available for estimating an odds ratio (OR) and 95% confidence interval (CI). Studies were excluded if one of the following criteria existed: (1) the studies were not relevant to the OGG1 Ser326Cys polymorphism or esophageal cancer, (2) nonclinical studies or the design based on family or sibling pairs, (3) genotype frequencies or numbers were not reported, and (4) reviews, abstracts, or comments. For overlapping studies, only the one with the largest sample size was included. There was no language restriction.
Data extraction Two authors (Wang and Gan) independently reviewed full manuscripts of eligible studies. The following variables were extracted from each study, if available: first author’s surname, year of publication, original country, ethnicity, pathologic type, sample size, genotyping method, and genotype numbers in cases and controls. Statistical analysis The strength of association between the OGG1 Ser326Cys polymorphism and esophageal cancer risk was measured by OR and 95% CI. OR1, OR2, and OR3 were calculated for the genotypes: Cys/Cys versus Ser/Ser (OR1), Cys/Ser versus Ser/Ser (OR2), and Cys/Cys versus Cys/Ser (OR3) for OGG1 Ser326Cys polymorphisms. These pairwise differences were used to indicate the most appropriate genetic model as follows: if OR1 = OR3s1 and OR2 = 1, then a recessive model was suggested; if OR1 = OR2s1 and OR3 = 1, then a dominant model was suggested; if OR2 = 1/OR3s1 and OR1 = 1, then a complete overdominant model was suggested; if OR1 > OR2 > 1 and OR1 > OR3 > 1 (or OR1 < OR2 < 1 and OR1 < OR3 < 1), then a codominant model was suggested (Thakkinstian et al., 2005; Nie et al., 2012a, 2012b, 2013a, 2013b). Once the best genetic model was identified, this model was used to collapse the three genotypes into two groups (except in the case of a codominant model) and to pool the results again. A random-effects model, using the MantelHaenszel method, was used to calculate the pooled ORs. The statistical significance of OR was determined with the Z test. Hardy–Weinberg equilibrium (HWE) was tested using the chi-square test and it was considered statistically significant when p < 0.05. Heterogeneity was evaluated by a Q statistic and was considered statistical significant at p value < 0.10. Subgroup analyses were performed by ethnicity and pathologic type. Sensitivity analysis was performed through sequentially excluded individual studies to assess the stability of the results. In addition, sensitivity analysis was also conducted by omitting the studies not in HWE. Publication bias was analyzed by several methods. Visual inspection of asymmetry in funnel plots was carried out. The Egger’s test was also used to statistically assess publication bias (Egger et al., 1997).
Table 1. Characteristics of the Case–Control Studies Included in Meta-Analysis First author
Year
Country
Ethnicity
Pathologic type
Case (n)
Control (n)
Genotyping method
Xing Gao Liu Hall
2001 2001 2005 2007
Asian Asian Asian Caucasian
NA NA NA NA
201 93 106 173
196 200 106 969
PCR-SSCP PCR-SSCP diASA-AMP TaqMan
Ferguson Tse Akbari Zhu Lagadu Liu Upadhyay Hu
2008 2008 2009 2009 2010 2010 2010 2010
China China China European countries Ireland Canada Iran China France USA India China
Caucasian Caucasian Caucasian Asian Caucasian Caucasian Asian Asian
Adenocarcinoma Adenocarcinoma Squamous Cell Squamous Cell Mixed Adenocarcinoma Mixeda Squamous Cell
209 312 197 188 17 335 335 235
248 454 254 203 43 319 402 228
TaqMan TaqMan MassARRAY PCR-SSCP PCR-RFLP Illumina GoldenGate PCR-RFLP PCR-RFLP
a Data for adenocarcinoma or squamous cell carcinoma patients could be separately extracted. PCR, polymerase chain reaction; SSCP, single-strand conformation polymorphism; diASA-AMP, diallele-specific amplification with artificially modified primer; RFLP, restriction fragment length polymorphism; NA, not available.
Studies Xing Gao Liu Hall Ferguson Tse Akbari Zhu Lagadu Liu Upadhyay Hu
Controls
Cys/ Cys
Cys/ Ser
Ser/ Ser
Cys/ Cys
Cys/ Ser
Ser/ Ser
HWE (p-value)
42 24 33 10 4 17 29 36 0 15 29 54
76 55 57 56 67 95 76 85 3 114 163 93
78 14 16 107 138 198 91 37 14 206 143 88
27 49 35 27 11 26 25 28 2 12 23 28
106 120 50 320 96 133 102 95 19 101 189 120
68 29 21 622 141 294 124 80 22 206 190 80
0.154 0.001 0.682 0.061 0.288 0.040 0.552 0.981 0.402 0.931 0.006 0.096
HWE, Hardy–Weinberg equilibrium.
0.19 0.01 0.13 0.18 0.22 0.21 0.23 0.73 0.15 14.74 23.59 16.30 15.15 7.07 7.16 4.35 0.63 11.94 R R R R R R R R R 0.003 0.81 0.008 0.003 0.002 0.35 0.74 < 0.0001 0.005 2.94 0.24 2.67 2.99 3.02 0.93 0.33 3.93 2.83 (1.13–1.83) (0.81–1.18) (1.09–1.77) (1.12–1.74) (1.15–1.96) (0.81–1.81) (0.69–1.67) (1.36–2.53) (1.13–1.97) 1.44 0.98 1.39 1.40 1.51 1.21 1.08 1.86 1.49 12 12 12 12 6 6 4 3 9
p-Value Model
w2
Heterogeneity
p-Value Z OR (95% CI) Control
2170 3328 1744 3621 1338 2283 1422 682 2568 1423 2070 1233 2363 1123 1240 1189 589 1625
Bonferroni correction was applied ( p < 0.017). R, random-effects model; OR, odds ratios; CI, confidence intervals.
Patients
Overall Overall Overall Overall Asian Caucasian Adenocarcinoma Squamous cell HWE
Table 2. Distribution of OGG1 Ser326Cys Genotype Among Patients and Controls
Cys/Cys vs. Ser/Ser Cys/Ser vs. Ser/Ser Cys/Cys vs. Cys/Ser Cys/Cys vs. Cys/Ser + Ser/Ser Cys/Cys vs. Cys/Ser + Ser/Ser Cys/Cys vs. Cys/Ser + Ser/Ser Cys/Cys vs. Cys/Ser + Ser/Ser Cys/Cys vs. Cys/Ser + Ser/Ser Cys/Cys vs. Cys/Ser + Ser/Ser
In the subgroup analysis by ethnicity, a significant association was found among Asians (OR = 1.51; 95% CI 1.15–1.96;
Case
Subgroup analyses
Study
All studies. The association between the OGG1 Ser326Cys polymorphism and esophageal cancer was examined in 11 case–control studies with a total of 2028 cases and 3302 controls. The estimated OR1, OR2, and OR3 were 1.44 (95% CI 1.11–1.88), 0.96 (95% CI 0.78–1.18), and 1.41 (95% CI 1.09– 1.82), respectively (Table 3). These estimates suggested a recessive genetic model, and therefore Cys/Ser and Ser/Ser were combined and compared with Cys/Cys. The pooled OR was 1.41 (95% CI 1.11–1.78) and the Z test for the overall effect was 2.83 ( p = 0.005) (Fig. 1). There was moderate heterogeneity (I2 = 33% and Pheterogeneity = 0.13).
Comparisons
Quantitative data synthesis
Test of association
There were 20 records relevant to our searching strategy. After reading the abstracts and full-texts, 9 were excluded for being not relevant to esophageal cancer risk or OGG1 Ser326Cys. Finally, a total of 11 case–control studies met our inclusion criteria (Xing et al., 2001; Gao et al., 2001; Liu et al., 2005; Hall et al., 2007; Ferguson et al., 2008; Tse et al., 2008; Akbari et al., 2009; Zhu et al., 2009; Lagadu et al., 2010; Upadhyay et al., 2010; Hu et al., 2010; Li et al., 2011). There were six studies of Asians and five studies of Caucasians. Two studies were performed in adenocarcinoma patients, three in squamous cell carcinoma patients, and two included both adenocarcinoma and squamous cell carcinoma patients. The characteristics of each study are presented in Table 1. Genotype numbers and HWE examination results are listed in Table 2.
No. of studies
Study inclusion and characteristics
Sample size
Results
Table 3. Determination of the Genetic Effect of OGG1 Ser326Cys Polymorphism on Esophageal Cancer and Subgroup Analyses
All statistical tests were performed by using the STATA 11.0 software (Stata Corporation, College Station, TX). The Bonferroni correction of critical p values was applied when performing a high number of comparisons.
25.0 53.0 33.0 27.0 29.0 30.0 31.0 0 33.0
WANG ET AL. I2 (%)
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FIG. 1. Meta-analysis with a random-effects model for the association between the OGG1 Ser326Cys polymorphism and esophageal cancer risk.
p = 0.002; Pheterogeneity = 0.22), but not among Caucasians (OR = 1.18; 95% CI 0.71–1.98; p = 0.52; Pheterogeneity = 0.13) in the recessive genetic model (Table 3). In the subgroup analysis by pathologic type, no significant association was found among adenocarcinoma patients (OR = 0.99; 95% CI 0.53–1.86; p = 0.99; Pheterogeneity = 0.12). However, there was a significant association between the OGG1 Ser326Cys polymorphism and esophageal squamous cell carcinoma (OR = 1.86; 95% CI 1.36– 2.53; p < 0.0001; Pheterogeneity = 0.73). Summary results of comparisons are listed in Table 3.
Publication bias The funnel plot was performed to assess the publication bias in this meta-analysis and showed a symmetrical inverse funnel shape (Fig. 3). The Egger’s test also indicated no significant publication bias ( p = 0.140). Discussion
To assess the stability of the results of the meta-analysis, we performed a sensitivity analysis through sequentially excluded individual studies. Statistically similar results were obtained after sequentially excluding each study (Fig. 2). Furthermore, omitting the studies deviating from HWE also did not change the result (Table 3).
This meta-analysis of 11 articles, including 2028 cases and 3302 controls systematically evaluated the association between the OGG1 Ser326Cys polymorphism and esophageal cancer risk. The results indicated that OGG1 Ser326Cys polymorphisms may be a risk factor for developing esophageal cancer. Our results suggested that individuals who carried the Cys/Cys genotype may have a 41% increased esophageal cancer risk compared with Cys/Ser or Ser/Ser carriers. In the subgroup analysis by ethnicity, no significant association was found in Caucasians. Nonetheless, increased esophageal cancer risk was observed in Asians. This result
FIG. 2. Sensitivity analysis for the association between the OGG1 Ser326Cys polymorphism and esophageal cancer risk.
FIG. 3. The funnel plot for the OGG1 Ser326Cys polymorphism and esophageal cancer risk.
Sensitivity analysis
784 suggested a possible role of ethnic differences in genetic backgrounds and the environment they lived in. However, our meta-analysis included only five studies using Caucasians. The positive association between Caucasians and esophageal cancer could not be ruled out, because studies with small sample size may have insufficient statistical power to detect a slight effect. More studies should be performed focusing on Caucasians with esophageal cancer. Subgroup analysis was also done according to pathologic type. A significant association was detected in esophageal squamous cell carcinoma, but not in esophageal adenocarcinoma. Tobacco smoke contains multiple carcinogens that are known to chemically modify genomic DNA and further lead to genetic mutations (Hecht, 1999). Shen et al. (1997) reported that the sperm DNA of smokers contained a significantly higher amount of 8-OHdG compared with nonsmokers. Elevated levels of 8-OHdG have been found in human tissues, including lungs and peripheral leukocytes of smokers (Kiyosawa et al., 1990; Asami et al., 1996). In addition, increased levels of 8-OHdG have been found in passive smokers in the workplace exposed to environmental tobacco smoke (Howard et al., 1998). Esophageal squamous cell carcinoma has been reported to be epidemiologically associated with tobacco consumption (Vaughan et al., 1995; Nasrollahzadeh et al., 2008). Therefore, it is biologically plausible that the Cys/Cys genotype could increase the risk of esophageal squamous cell carcinoma. Esophageal cancer is a complex disease. Not only genetic factors, but also the life style and environmental factors play important roles in the pathogenesis of esophageal cancer. Smoking is a risk factor for esophageal cancer. Gao et al. (2001) reported that smoking increased the esophageal cancer risk among Cys/Ser or Ser/Ser carriers. However, other investigators did not find a significant association between OGG1– smoking interactions and esophageal cancer risk (Xing et al., 2001; Liu et al., 2005; Upadhyay et al., 2010). Thus, it was necessary to address this association by meta-analysis. Nevertheless, the results from previous studies were not presented in a uniform standard. Therefore, future studies are still needed to resolve this problem. We should mention the importance of heterogeneity. Heterogeneity is an important issue when interpreting the results of meta-analysis. In our meta-analysis, there was no significant heterogeneity in most of the comparisons. Furthermore, no publication bias was found. Therefore, heterogeneity and publication bias did not influence the results. We also conducted sensitivity analyses. No individual study was found to affect the overall result. Excluding the studies not in HWE also did not influence the overall result. These results indicated that our result was stable and robust. Several limitations of this meta-analysis should be considered. First, lack of original data limited our further evaluation of potential gene–gene and gene–environment interactions. Second, all of the case–control studies were conducted in Asians and Caucasians; thus, our results may be applicable only to these ethnic groups. Third, the overall outcome was based on individual unadjusted data, while a more precise evaluation should be adjusted by other potentially suspected factors, such as age, sex, body mass index, and lifestyle factors. Fourthly, the number of included studies was small. Finally, because of the complex nature of esophageal cancer, it is unlikely that a SNP in one single gene would be obviously
WANG ET AL. associated with an increased esophageal cancer risk. Because there were insufficient data that could be extracted from primary studies, we did not perform analysis of other SNPs in OGG1 and a haplotype analysis. To the best of our knowledge, this was the most comprehensive genetic meta-analysis of the association between the OGG1 Ser326Cys polymorphism and esophageal cancer risk. Our results suggested that the OGG1 Ser326Cys polymorphism represented a risk factor for esophageal cancer. Future large-scale studies are needed to validate our findings. Author Disclosure Statement The authors have declared that no competing interests exist. References Akbari MR, Malekzadeh R, Shakeri R, et al. (2009) Candidate gene association study of esophageal squamous cell carcinoma in a high-risk region in Iran. Cancer Res 69:7994– 8000. Asami S, Hirano T, Yamaguchi R, et al. (1996) Increase of a type of oxidative DNA damage, 8-hydroxyguanine, and its repair activity in human leukocytes by cigarette smoking. Cancer Res 56:2546–2549. Boiteux S, Radicella JP (2000) The human OGG1 gene: structure, functions, and its implication in the process of carcinogenesis. Arch Biochem Biophys 377:1–8. Chen X, Ding YW, Yang G-y, et al. (2000) Oxidative damage in an esophageal adenocarcinoma model with rats. Carcinogenesis 21:257–263. Cheng K, Cahill DS, Kasai H, et al. (1992) 8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G——T and A——C substitutions. J Biol Chem 267:166–172. Egger M, Smith GD, Schneider M, et al. (1997) Bias in metaanalysis detected by a simple, graphical test. BMJ 315: 629–634. Ferguson HR, Wild CP, Anderson LA, et al. (2008) No association between hOGG1, XRCC1, and XPD polymorphisms and risk of reflux esophagitis, Barrett’s esophagus, or esophageal adenocarcinoma: results from the factors influencing the Barrett’s adenocarcinoma relationship case-control study. Cancer Epidemiol Biomarkers Prev 17:736–739. Gao C, Haruhiko S, Toshiro T (2001) hOGG1 genotypes, life style and the risk of esophageal and stomach cancers. Bull Chin Cancer 10:500–502. Hall J, Hashibe M, Boffetta P, et al. (2007) The association of sequence variants in DNA repair and cell cycle genes with cancers of the upper aerodigestive tract. Carcinogenesis 28:665–671. Hecht SS (1999) Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 91:1194–1210. Howard DJ, Ota RB, Briggs LA, et al. (1998) Environmental tobacco smoke in the workplace induces oxidative stress in employees, including increased production of 8-hydroxy-2¢deoxyguanosine. Cancer Epidemiol Biomarkers Prev 7: 141–146. Hu H, Wu J, Jin Y, et al. (2010) OGG1 Ser326Cys polymorphism and susceptibility to esophageal cancer in YuBei. Shandong Yi Yao 50:49–50. Kasai H, Chung M, Jones D, et al. (1991) 8-Hydroxyguanine, a DNA adduct formed by oxygen radicals: its implication on oxygen radical-involved mutagenesis/carcinogenesis. J Toxicol Sci 16:95–105.
OGG1 AND ESOPHAGEAL CANCER Kiyosawa H, Suko M, Okudaira H, et al. (1990) Cigarette smoking induces formation of 8-hydroxydeoxyguanosine, one of the oxidative DNA damages in human peripheral leukocytes. Free Radic Res 11:23–27. Kohno T, Shinmura K, Tosaka M, et al. (1998) Genetic polymorphisms and alternative splicing of the hOGG1 gene, that is involved in the repair of 8-hydroxyguanine in damaged DNA. Oncogene 16:3219–3225. Lagadu S, Lechevrel M, Sichel F, et al. (2010) 8-oxo-7,8-dihydro2¢-deoxyguanosine as a biomarker of oxidative damage in oesophageal cancer patients: lack of association with antioxidant vitamins and polymorphism of hOGG1 and GST. J Exp Clin Cancer Res 29:157. Liu CY, Wu MC, Chen F, et al. (2010) A large-scale genetic association study of esophageal adenocarcinoma risk. Carcinogenesis 31:1259–1263. Liu R, Ying L, Pu Y, et al. (2005) Relationship between human 8-hydroxyguanine glycosylase Ser32Cys gene polymorphism and esophageal cancer. Chin J Public Health 21:1430-1432. Marnett LJ (2000) Oxyradicals and DNA damage. Carcinogenesis 21:361–370. Nasrollahzadeh D, Kamangar F, Aghcheli K, et al. (2008) Opium, tobacco, and alcohol use in relation to oesophageal squamous cell carcinoma in a high-risk area of Iran. Br J Cancer 98:1857–1863. Nie W, Chen J, Xiu Q (2012a) Cytotoxic T-lymphocyte associated antigen 4 polymorphisms and asthma risk: a meta-analysis. PLoS One 7:e42062. Nie W, Fang Z, Li B, et al. (2012b) Interleukin-10 promoter polymorphisms and asthma risk: a meta-analysis. Cytokine 60:849–855. Nie W, Liu Y, Bian J, et al. (2013a) Effects of polymorphisms1112C/T and + 2044A/G in interleukin-13 gene on asthma risk: a meta-analysis. PLoS One 8:e56065. Nie W, Zhu Z, Pan X, et al. (2013b) The interleukin-4-589C/T polymorphism and the risk of asthma: A meta-analysis including 7345 cases and 7819 controls. Gene 520:22–29. Parkin DM, Bray F, Ferlay J, et al. (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108. Shen H-M, Chia S-E, Ni Z-Y, et al. (1997) Detection of oxidative DNA damage in human sperm and the association with cigarette smoking. Reprod Toxicol 11:675–680.
785 Shibutani S, Takeshita M, Grollman AP (1991) Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature 349:431–434. Sunaga N, Kohno T, Shinmura K, et al. (2001) OGG1 protein suppresses G: C/T: A mutation in a shuttle vector containing 8-hydroxyguanine in human cells. Carcinogenesis 22:1355– 1362. Thakkinstian A, McElduff P, D’Este C, et al. (2005) A method for meta-analysis of molecular association studies. Stat Med 24:1291–1306. Tse D, Zhai R, Zhou W, et al. (2008) Polymorphisms of the NER pathway genes, ERCC1 and XPD are associated with esophageal adenocarcinoma risk. Cancer Causes Control 19:1077– 1083. Upadhyay R, Malik MA, Zargar SA, et al. (2010) OGG1 Ser326Cys polymorphism and susceptibility to esophageal cancer in low and high at-risk populations of northern India. J Gastrointest Cancer 41:110–115. Vaughan TL, Davis S, Kristal A, et al. (1995) Obesity, alcohol, and tobacco as risk factors for cancers of the esophagus and gastric cardia: adenocarcinoma versus squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 4:85–92. Xing DY, Tan W, Song N, et al. (2001) Ser326Cys polymorphism in hOGG1 gene and risk of esophageal cancer in a Chinese population. Int J Cancer 95:140–143. Zhu X, Zhang H, Du H, et al. (2009) Association of hOGG1 polymorphism Ser326Cys between the susceptibility of esophageal cancer and its clinicopathological characteristics. J Environ Occup Med 126:25–28.
Address correspondence to: Zhan Wang, MD Department of Oncology Shanghai Changzheng Hospital Second Military Medical University 415 Fengyang Road Shanghai 200003 China E-mail: [email protected]
The OGG1 Ser326Cys Polymorphism and the Risk of Esophageal Cancer: A Meta-Analysis Zhan Wang,1,* Lu Gan,2,* Wei Nie,3,* and Yan Geng 4
Background: The oxoguanine DNA glycosylase (OGG1) Ser326Cys polymorphism has been implicated in susceptibility to esophageal cancer. Several studies investigated the association of this polymorphism with esophageal cancer in different populations. However, the results were contradictory. A meta-analysis was conducted to assess the association between the OGG1 Ser326Cys polymorphism and esophageal cancer susceptibility. Methods: Databases, including PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), and Weipu Database were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. A random-effects model was used. Results: Twelve studies involving 2363 cases and 3621 controls were included. Overall, a significant association between the OGG1 Ser326Cys polymorphism and esophageal cancer was observed for Cys/Cys versus Cys/Ser + Ser/Ser (OR = 1.40; 95% CI 1.12–1.74; p = 0.003; Pheterogeneity = 0.18). In the subgroup analysis by ethnicity, a significant association was found among Asians (OR = 1.51; 95% CI 1.15–1.96; p = 0.002; Pheterogeneity = 0.22), but not among Caucasians (OR = 1.21; 95% CI 0.81–1.81; p = 0.35; Pheterogeneity = 0.21). In the subgroup analysis by pathologic type, we found that the Cys/Cys genotype was associated with increased esophageal squamous cell carcinoma risk (OR = 1.86; 95% CI 1.36–2.53; p < 0.0001; Pheterogeneity = 0.73). Conclusions: This meta-analysis suggested that the OGG1 Ser326Cys polymorphism was a risk factor of esophageal cancer.
Introduction
E
sophageal cancer is the eighth most common cancer in the world, with approximately 462,000 cases and 386,000 deaths worldwide in 2002, making it the sixth most common cause of cancer-related deaths (Parkin et al., 2005). The estimated age-adjusted 5-year survival rate in developed countries is 15% for males and 8% for females, while it is 17% and 16%, respectively, in developing countries (Parkin et al., 2005). Oxidative DNA damage induced by reactive oxidative species contributes to the generation and development of cancer (Marnett, 2000). Of such damage, the formation of 8hydroxyl-2¢-deoxyguanosine (8-OHdG), a marker of oxidative damage on guanine (G), is the most common type and is highly mutagenic. If not repaired and accumulated in the affected tissues, 8-OHdG will mispair with adenine (A) instead of cytosine (C), which may cause a G:C to T:A transversion and further initiate subsequent carcinogenesis (Kasai et al., 1991; Shibutani et al., 1991; Cheng et al., 1992). The human
oxoguanine DNA glycosylase (OGG1) gene encodes a DNA glycosylase/apuriniclyase, which catalyzes the excision and removal of 8-OHdG adducts (Boiteux and Radicella, 2000; Sunaga et al., 2001). OGG1 maps on chromosome 3p26.2. Codon 326 at position 1245 in exon 7 of OGG1 holds a singlenucleotide polymorphism (SNP) with a C > G variation, thereby the amino acid translation of codon 326 can be changed from serine (Ser) to cysteine (Cys). Functionally, homozygous Ser/Ser (wild type) has the highest repair activity followed by the heterozygous Ser/Cys variant and then the homozygous Cys/Cys variant (Kohno et al., 1998). In a rat esophageal cancer model, Chen et al. (2000) found that 8OHdG in the esophagus was significantly higher compared with the control. Therefore, it is possible that the OGG1 Ser326Cys polymorphism, which affects enzyme activities, could influence the risk of esophageal cancer. So far, some studies investigated the association between the OGG1 Ser326Cys polymorphism and esophageal cancer risk (Xing et al., 2001; Gao et al., 2001; Liu et al., 2005; Hall et al., 2007;
1
Department of Oncology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. 3 Department of Respiratory Disease, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China. 4 Department of Oncology, Zhabei District Central Hospital, Shanghai, China. *These authors contributed equally to this work. 2
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Ferguson et al., 2008; Tse et al., 2008; Akbari et al., 2009; Zhu et al., 2009; Lagadu et al., 2010; Upadhyay et al., 2010; Hu et al., 2010). However, the results were conflicting and inconclusive. For instance, Xing and coworkers found that the OGG1 326Cys allele might play a role in the carcinogenesis of the esophageal cancer (Xing et al., 2001). However, Tse et al. (2008) did not observe this association. Thus, we carried out a meta-analysis to ascertain whether there was a genetic effect of OGG1 Ser326Cys on esophageal cancer susceptibility. Materials and Methods Publication search PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), and Weipu Database were searched (last search was updated on April, 2013). The search terms were used as follows: (‘‘esophagus cancer’’ or ‘‘esophageal carcinoma’’ or ‘‘esophageal neoplasm’’) and (human 8-oxoguanine DNA glycosylase or hOGG1 or OGG1 or OGG) and (polymorphism or mutation or variant). The following MeSH terms were used in PubMed: ‘‘esophageal neoplasms’’ and ‘‘polymorphism, genetic’’ and ‘‘8-oxoguanine DNA glycosylase.’’ All the searched studies were retrieved, and their references were checked as well for other relevant publications. Review articles were also searched to find additional eligible studies. Inclusion and exclusion criteria Studies fulfilling the following selection criteria were included in this meta-analysis: (1) the studies evaluated the association between the OGG1 Ser326Cys polymorphism and esophageal cancer risk, (2) the design had to be a case–control study, and (3) sufficient data (genotype distributions for cases and controls) were available for estimating an odds ratio (OR) and 95% confidence interval (CI). Studies were excluded if one of the following criteria existed: (1) the studies were not relevant to the OGG1 Ser326Cys polymorphism or esophageal cancer, (2) nonclinical studies or the design based on family or sibling pairs, (3) genotype frequencies or numbers were not reported, and (4) reviews, abstracts, or comments. For overlapping studies, only the one with the largest sample size was included. There was no language restriction.
Data extraction Two authors (Wang and Gan) independently reviewed full manuscripts of eligible studies. The following variables were extracted from each study, if available: first author’s surname, year of publication, original country, ethnicity, pathologic type, sample size, genotyping method, and genotype numbers in cases and controls. Statistical analysis The strength of association between the OGG1 Ser326Cys polymorphism and esophageal cancer risk was measured by OR and 95% CI. OR1, OR2, and OR3 were calculated for the genotypes: Cys/Cys versus Ser/Ser (OR1), Cys/Ser versus Ser/Ser (OR2), and Cys/Cys versus Cys/Ser (OR3) for OGG1 Ser326Cys polymorphisms. These pairwise differences were used to indicate the most appropriate genetic model as follows: if OR1 = OR3s1 and OR2 = 1, then a recessive model was suggested; if OR1 = OR2s1 and OR3 = 1, then a dominant model was suggested; if OR2 = 1/OR3s1 and OR1 = 1, then a complete overdominant model was suggested; if OR1 > OR2 > 1 and OR1 > OR3 > 1 (or OR1 < OR2 < 1 and OR1 < OR3 < 1), then a codominant model was suggested (Thakkinstian et al., 2005; Nie et al., 2012a, 2012b, 2013a, 2013b). Once the best genetic model was identified, this model was used to collapse the three genotypes into two groups (except in the case of a codominant model) and to pool the results again. A random-effects model, using the MantelHaenszel method, was used to calculate the pooled ORs. The statistical significance of OR was determined with the Z test. Hardy–Weinberg equilibrium (HWE) was tested using the chi-square test and it was considered statistically significant when p < 0.05. Heterogeneity was evaluated by a Q statistic and was considered statistical significant at p value < 0.10. Subgroup analyses were performed by ethnicity and pathologic type. Sensitivity analysis was performed through sequentially excluded individual studies to assess the stability of the results. In addition, sensitivity analysis was also conducted by omitting the studies not in HWE. Publication bias was analyzed by several methods. Visual inspection of asymmetry in funnel plots was carried out. The Egger’s test was also used to statistically assess publication bias (Egger et al., 1997).
Table 1. Characteristics of the Case–Control Studies Included in Meta-Analysis First author
Year
Country
Ethnicity
Pathologic type
Case (n)
Control (n)
Genotyping method
Xing Gao Liu Hall
2001 2001 2005 2007
Asian Asian Asian Caucasian
NA NA NA NA
201 93 106 173
196 200 106 969
PCR-SSCP PCR-SSCP diASA-AMP TaqMan
Ferguson Tse Akbari Zhu Lagadu Liu Upadhyay Hu
2008 2008 2009 2009 2010 2010 2010 2010
China China China European countries Ireland Canada Iran China France USA India China
Caucasian Caucasian Caucasian Asian Caucasian Caucasian Asian Asian
Adenocarcinoma Adenocarcinoma Squamous Cell Squamous Cell Mixed Adenocarcinoma Mixeda Squamous Cell
209 312 197 188 17 335 335 235
248 454 254 203 43 319 402 228
TaqMan TaqMan MassARRAY PCR-SSCP PCR-RFLP Illumina GoldenGate PCR-RFLP PCR-RFLP
a Data for adenocarcinoma or squamous cell carcinoma patients could be separately extracted. PCR, polymerase chain reaction; SSCP, single-strand conformation polymorphism; diASA-AMP, diallele-specific amplification with artificially modified primer; RFLP, restriction fragment length polymorphism; NA, not available.
Studies Xing Gao Liu Hall Ferguson Tse Akbari Zhu Lagadu Liu Upadhyay Hu
Controls
Cys/ Cys
Cys/ Ser
Ser/ Ser
Cys/ Cys
Cys/ Ser
Ser/ Ser
HWE (p-value)
42 24 33 10 4 17 29 36 0 15 29 54
76 55 57 56 67 95 76 85 3 114 163 93
78 14 16 107 138 198 91 37 14 206 143 88
27 49 35 27 11 26 25 28 2 12 23 28
106 120 50 320 96 133 102 95 19 101 189 120
68 29 21 622 141 294 124 80 22 206 190 80
0.154 0.001 0.682 0.061 0.288 0.040 0.552 0.981 0.402 0.931 0.006 0.096
HWE, Hardy–Weinberg equilibrium.
0.19 0.01 0.13 0.18 0.22 0.21 0.23 0.73 0.15 14.74 23.59 16.30 15.15 7.07 7.16 4.35 0.63 11.94 R R R R R R R R R 0.003 0.81 0.008 0.003 0.002 0.35 0.74 < 0.0001 0.005 2.94 0.24 2.67 2.99 3.02 0.93 0.33 3.93 2.83 (1.13–1.83) (0.81–1.18) (1.09–1.77) (1.12–1.74) (1.15–1.96) (0.81–1.81) (0.69–1.67) (1.36–2.53) (1.13–1.97) 1.44 0.98 1.39 1.40 1.51 1.21 1.08 1.86 1.49 12 12 12 12 6 6 4 3 9
p-Value Model
w2
Heterogeneity
p-Value Z OR (95% CI) Control
2170 3328 1744 3621 1338 2283 1422 682 2568 1423 2070 1233 2363 1123 1240 1189 589 1625
Bonferroni correction was applied ( p < 0.017). R, random-effects model; OR, odds ratios; CI, confidence intervals.
Patients
Overall Overall Overall Overall Asian Caucasian Adenocarcinoma Squamous cell HWE
Table 2. Distribution of OGG1 Ser326Cys Genotype Among Patients and Controls
Cys/Cys vs. Ser/Ser Cys/Ser vs. Ser/Ser Cys/Cys vs. Cys/Ser Cys/Cys vs. Cys/Ser + Ser/Ser Cys/Cys vs. Cys/Ser + Ser/Ser Cys/Cys vs. Cys/Ser + Ser/Ser Cys/Cys vs. Cys/Ser + Ser/Ser Cys/Cys vs. Cys/Ser + Ser/Ser Cys/Cys vs. Cys/Ser + Ser/Ser
In the subgroup analysis by ethnicity, a significant association was found among Asians (OR = 1.51; 95% CI 1.15–1.96;
Case
Subgroup analyses
Study
All studies. The association between the OGG1 Ser326Cys polymorphism and esophageal cancer was examined in 11 case–control studies with a total of 2028 cases and 3302 controls. The estimated OR1, OR2, and OR3 were 1.44 (95% CI 1.11–1.88), 0.96 (95% CI 0.78–1.18), and 1.41 (95% CI 1.09– 1.82), respectively (Table 3). These estimates suggested a recessive genetic model, and therefore Cys/Ser and Ser/Ser were combined and compared with Cys/Cys. The pooled OR was 1.41 (95% CI 1.11–1.78) and the Z test for the overall effect was 2.83 ( p = 0.005) (Fig. 1). There was moderate heterogeneity (I2 = 33% and Pheterogeneity = 0.13).
Comparisons
Quantitative data synthesis
Test of association
There were 20 records relevant to our searching strategy. After reading the abstracts and full-texts, 9 were excluded for being not relevant to esophageal cancer risk or OGG1 Ser326Cys. Finally, a total of 11 case–control studies met our inclusion criteria (Xing et al., 2001; Gao et al., 2001; Liu et al., 2005; Hall et al., 2007; Ferguson et al., 2008; Tse et al., 2008; Akbari et al., 2009; Zhu et al., 2009; Lagadu et al., 2010; Upadhyay et al., 2010; Hu et al., 2010; Li et al., 2011). There were six studies of Asians and five studies of Caucasians. Two studies were performed in adenocarcinoma patients, three in squamous cell carcinoma patients, and two included both adenocarcinoma and squamous cell carcinoma patients. The characteristics of each study are presented in Table 1. Genotype numbers and HWE examination results are listed in Table 2.
No. of studies
Study inclusion and characteristics
Sample size
Results
Table 3. Determination of the Genetic Effect of OGG1 Ser326Cys Polymorphism on Esophageal Cancer and Subgroup Analyses
All statistical tests were performed by using the STATA 11.0 software (Stata Corporation, College Station, TX). The Bonferroni correction of critical p values was applied when performing a high number of comparisons.
25.0 53.0 33.0 27.0 29.0 30.0 31.0 0 33.0
WANG ET AL. I2 (%)
782
OGG1 AND ESOPHAGEAL CANCER
783
FIG. 1. Meta-analysis with a random-effects model for the association between the OGG1 Ser326Cys polymorphism and esophageal cancer risk.
p = 0.002; Pheterogeneity = 0.22), but not among Caucasians (OR = 1.18; 95% CI 0.71–1.98; p = 0.52; Pheterogeneity = 0.13) in the recessive genetic model (Table 3). In the subgroup analysis by pathologic type, no significant association was found among adenocarcinoma patients (OR = 0.99; 95% CI 0.53–1.86; p = 0.99; Pheterogeneity = 0.12). However, there was a significant association between the OGG1 Ser326Cys polymorphism and esophageal squamous cell carcinoma (OR = 1.86; 95% CI 1.36– 2.53; p < 0.0001; Pheterogeneity = 0.73). Summary results of comparisons are listed in Table 3.
Publication bias The funnel plot was performed to assess the publication bias in this meta-analysis and showed a symmetrical inverse funnel shape (Fig. 3). The Egger’s test also indicated no significant publication bias ( p = 0.140). Discussion
To assess the stability of the results of the meta-analysis, we performed a sensitivity analysis through sequentially excluded individual studies. Statistically similar results were obtained after sequentially excluding each study (Fig. 2). Furthermore, omitting the studies deviating from HWE also did not change the result (Table 3).
This meta-analysis of 11 articles, including 2028 cases and 3302 controls systematically evaluated the association between the OGG1 Ser326Cys polymorphism and esophageal cancer risk. The results indicated that OGG1 Ser326Cys polymorphisms may be a risk factor for developing esophageal cancer. Our results suggested that individuals who carried the Cys/Cys genotype may have a 41% increased esophageal cancer risk compared with Cys/Ser or Ser/Ser carriers. In the subgroup analysis by ethnicity, no significant association was found in Caucasians. Nonetheless, increased esophageal cancer risk was observed in Asians. This result
FIG. 2. Sensitivity analysis for the association between the OGG1 Ser326Cys polymorphism and esophageal cancer risk.
FIG. 3. The funnel plot for the OGG1 Ser326Cys polymorphism and esophageal cancer risk.
Sensitivity analysis
784 suggested a possible role of ethnic differences in genetic backgrounds and the environment they lived in. However, our meta-analysis included only five studies using Caucasians. The positive association between Caucasians and esophageal cancer could not be ruled out, because studies with small sample size may have insufficient statistical power to detect a slight effect. More studies should be performed focusing on Caucasians with esophageal cancer. Subgroup analysis was also done according to pathologic type. A significant association was detected in esophageal squamous cell carcinoma, but not in esophageal adenocarcinoma. Tobacco smoke contains multiple carcinogens that are known to chemically modify genomic DNA and further lead to genetic mutations (Hecht, 1999). Shen et al. (1997) reported that the sperm DNA of smokers contained a significantly higher amount of 8-OHdG compared with nonsmokers. Elevated levels of 8-OHdG have been found in human tissues, including lungs and peripheral leukocytes of smokers (Kiyosawa et al., 1990; Asami et al., 1996). In addition, increased levels of 8-OHdG have been found in passive smokers in the workplace exposed to environmental tobacco smoke (Howard et al., 1998). Esophageal squamous cell carcinoma has been reported to be epidemiologically associated with tobacco consumption (Vaughan et al., 1995; Nasrollahzadeh et al., 2008). Therefore, it is biologically plausible that the Cys/Cys genotype could increase the risk of esophageal squamous cell carcinoma. Esophageal cancer is a complex disease. Not only genetic factors, but also the life style and environmental factors play important roles in the pathogenesis of esophageal cancer. Smoking is a risk factor for esophageal cancer. Gao et al. (2001) reported that smoking increased the esophageal cancer risk among Cys/Ser or Ser/Ser carriers. However, other investigators did not find a significant association between OGG1– smoking interactions and esophageal cancer risk (Xing et al., 2001; Liu et al., 2005; Upadhyay et al., 2010). Thus, it was necessary to address this association by meta-analysis. Nevertheless, the results from previous studies were not presented in a uniform standard. Therefore, future studies are still needed to resolve this problem. We should mention the importance of heterogeneity. Heterogeneity is an important issue when interpreting the results of meta-analysis. In our meta-analysis, there was no significant heterogeneity in most of the comparisons. Furthermore, no publication bias was found. Therefore, heterogeneity and publication bias did not influence the results. We also conducted sensitivity analyses. No individual study was found to affect the overall result. Excluding the studies not in HWE also did not influence the overall result. These results indicated that our result was stable and robust. Several limitations of this meta-analysis should be considered. First, lack of original data limited our further evaluation of potential gene–gene and gene–environment interactions. Second, all of the case–control studies were conducted in Asians and Caucasians; thus, our results may be applicable only to these ethnic groups. Third, the overall outcome was based on individual unadjusted data, while a more precise evaluation should be adjusted by other potentially suspected factors, such as age, sex, body mass index, and lifestyle factors. Fourthly, the number of included studies was small. Finally, because of the complex nature of esophageal cancer, it is unlikely that a SNP in one single gene would be obviously
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Address correspondence to: Zhan Wang, MD Department of Oncology Shanghai Changzheng Hospital Second Military Medical University 415 Fengyang Road Shanghai 200003 China E-mail: [email protected]
