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. 2013 Nov 7;8(11):e81403. doi: 10.1371/journal.pone.0081403

The GSTM1 Null Genotype Increased Risk of Gastric Cancer: A Meta-Analysis Based on 46 Studies

Yi Zhao 1,*, Xin Deng 1, Guoqing Song 1, Shibo Qin 1, Zhanzhan Liu 1
Editor: Rupesh Chaturvedi2
PMCID: PMC3820558  PMID: 24244742

Abstract

Background

Glutathione S-transferases M1 (GSTM1) is an important phase II metabolizing enzyme. The null genotype of GSTM1 causes total loss of GSTM1 enzyme activity and numerous studies have investigated the association between GSTM1 null genotype and gastric cancer risk.

Methods

This meta-analysis was designed to investigate the relationship between GSTM1 null genotype and susceptibility to gastric cancer and assess the influence of Helicobacter pylori infection, smoking, Lauren’s classification, and other factors. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the association strength.

Results

A total of 46 eligible studies were indentified and analyzed in this meta-analysis, including 8138 cases of gastric cancer and 13867 controls. Pooled results showed that the GSTM1 null genotype was associated with a significantly increased risk of gastric cancer (OR=1.217, 95% CI: 1.113-1.331, Pheterogeneity<0.001). Sub-group analysis suggested that the significant association was only observed in Asians (OR=1.273, 95%: 1.137-1.426, Pheterogeneity = 0.002), but not in Caucasians. The increased risk was found among H. pylori positive population (OR=1.928, 95% CI: 1.028-3.615, Pheterogeneity=0.065), while no association was found among H. pylori negative population (OR=0.969, 95% CI: 0.618-1.521, Pheterogeneity=0.168). For smoking status, the GSTM1 null genotype increased risk of gastric cancer in both ever-smokers and non-smokers. Source of control, sample size, location of tumor and Lauren’s classification did not modify the association.

Conclusions

In this meta-analysis based on 46 epidemiological studies, we show that the GSTM1 null genotype is associated with an increased risk of gastric cancer among Asians but not among Caucasians. H. pylori infection but not smoking status could modify the association.

Introduction

It has been well demonstrated that gastric cancer is the second leading cause of cancer related death and the fourth most common malignancy, which accounts for 9.7% of total cancer deaths worldwide [1]. As a major public health challenge, it is reported that about one million new cases of gastric cancer were diagnosed in 2008. However, the mechanism of gastric carcinogenesis is still not fully understood. Current evidence suggests that, in combination with environmental factors, low-pentrance susceptibility genes play an important role in the development of cancer [2].

Human glutathione S-transferases (GSTs) are phase II metabolizing enzymes that are critical for protection from cancer by detoxifying numerous potentially cytotoxic or genotoxic compounds [3]. According to their amino acid sequence, immunological cross-reactivity, and substrate specificity, human cytosolic GSTs have been classified into seven families, namely GST alpha, mu, pi, sigma, omega, theta, and zeta [4,5]. Glutathione S-transferase M1 (GSTM1), belonging to the GST mu gene family, is polymorphic and the common deletion polymorphism of GSTM1 has been extensively studied. The homozygous deletion of GSTM1 gene lead to total absence of GSTM1 enzyme activity. It was reported that the deleted GSTM1 genotype was in high percentage of human population, about 40-60% in Europeans [6] and about 50% in Asians [7].

A lot of epidemiological studies have investigated the association of GSTM1 depletion with risk of gastric cancer and several meta-analyses have been performed to clarify this issue [5,8,9]. The most recent meta-analysis was conducted in 2010 [1,6], as well as several other similar meta-analyses and a lot of studies with larger sample size have been published [10-12]. However, limited by number of studies, previous studies failed to assess the influence of some important factors, like Helicobacter pylori infection, the well established risk factor of gastric cancer, smoking status, location of tumor, and sample size [5,8].

Thus, we conducted an updated meta-analysis to comprehensively assess the relationship between GSTM1 deletion polymorphism and risk of gastric cancer and evaluate the influence of confounding factors

Materials and Methods

Identification of eligible studies

This study was carried out and reported in agreement with the PRISMA guidelines for systematic reviews and meta-analyses [13] (supplementary information: Checklist S1. PRISMA checklist). Eligible case-control studies were extracted by searching databases and manual search of references of relative articles and reviews. A comprehensive literature search was carried out using electronic databases of PubMed and EMBASE. To avoid selection bias, Chinese databases like China National Knowledge Infrastructure (CNKI) was not searched. The following medical subheadings (MeSH) and key words were utilized during database searching: “glutathione S-transferase M1” or “GSTM1”, “polymorphisms, single nucleotide” or “polymorphism”, and “stomach neoplasms” or “gastric cancer”. Alternative spellings of these key words were also considered. There was no limitation of research and the last research was performed on August 12, 2013. References of related studies and reviews were manually searched for additional studies.

Inclusion and exclusion criteria

Studies were selected according to the following inclusion criteria: (1) case-control studies; (2) investigating the association between GSTM1 deletion polymorphism and gastric cancer risk; (3) with available genotype distribution data to calculate combined odds ratios (ORs) and 95% confidence intervals (95% CIs). Studies without detail genotype distribution data were excluded. Titles and abstracts of searching records were primarily screened and full text papers were further retrieved to confirm eligibility. Two reviewers (ZY and DX) extracted eligible studies independently according to the inclusion criteria. Disagreement between two reviewers was discussed with another reviewer (SGQ) till consensus was achieved.

Data extraction

Data of eligible studies was extracted by two reviewers (ZY and DX) independently with a pre-designed data-collection form. The following data was collected: name of first author, year of publication, country where the study was conducted, ethnicity, source of control, number of cases and controls, genotype frequency in cases and controls, H. pylori infection (positive and negative), smoking status (ever-smoker and non-smoker), tumor location (cardia and non-cardia), and Lauren’s classification (diffuse and intestinal). Different ethnicity descents were categorized as Asian, Caucasian, and Latin American. For H. pylori infection and smoking status, we collected data according the original definition of eligible studies and no modification or adjustment was performed. Eligible studies were defined as hospital-based (HB) and population-based (PB) according to the control source. Two reviewers reached consensus on each item.

Statistical analysis

The association strength between GSTM1 null genotype and gastric cancer risk was measured by OR with 95% CI. The estimated ORs were achieved by pooling genotype distribution data from each eligible study. A 95% CI was used for statistical significance test and a 95% CI without 1 for OR indicating a significant increased or reduced cancer risk. The pooled ORs were calculated for the comparison of null genotype versus present genotype. Subgroup analyses were also conducted to explore the effects of confounding factors: ethnicities, sources of control, sample size, H. pylori infection, smoking status, location, and Lauren’s classification.

Chi-square based Q test was used to check the statistical heterogeneity between studies, and the heterogeneity was considered significant when p<0.10[14]. Given the significant heterogeneity and to achieve a conservative estimate, random-effects model (based on DerSimonian-Laird method) were used to pool the data from different studies [15]. Meta-regression was performed to detect the source of heterogeneity and a p<0.05 was considered significant[16].

Publication bias was detected with Begg’s funnel plot and the Egger’ linear regression test, and a p < 0.05 was considered significant[17]. To test the influence of publication bias, fail-safe number for p=0.05 (Nfs0.05) and p=0.01 (Nfs0.01) was also calculated[18].All statistical analyses were calculated with STATA software (version 10.0; StataCorp, College Station, Texas USA). And all P values were two-side.

Results

The detailed process of study selection was shown in Figure 1. After comprehensive search and rigid selection, 46 eligible studies were identified[10-12,19-61]. The genotype distribution data was available for 8138 patients of gastric cancer and 13867 controls. The baseline characteristics of eligible studies were shown in Table 1. 28 studies were carried out in Asian, 16 studies were in Caucasian, and 2 studies were in Latin American. Notably, 32 of 46 studies were of a small sample size and only 14 studies included more than 500 participants.

Figure 1. Flow chart of study selection.

Figure 1

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Table 1. Baseline characteristics of eligible studies.

Author Year Country Ethnicity Source Cases Controls Case
 Control
Null Present Null Present
Kato S 1996 Japan Asian HB 81 151 30 34 61 59
Katoh T 1996 Japan Asian HB 139 126 79 60 55 71
Alves GM 1998 Portugal Caucasian HB 148 84 71 77 44 40
Oda Y 1999 Japan Asian HB 147 112 91 56 55 57
Cai L 2001 China Asian PB 95 94 60 35 43 51
Saadat I 2001 Iran Asian PB 42 131 26 16 53 78
Setiawan VWa 2001 China Asian PB 133 433 40 39 202 205
Shen J 2001 China Asian PB 112 675 71 41 361 314
Gao CM 2002 China Asian PB 153 223 95 63 133 90
Sgambato A 2002 Italy Caucasian HB 8 100 5 3 53 47
Wu MS 2002 China Asian HB 356 278 173 183 136 142
Colombo Ja 2004 Brazil Latin America HB 100 150 47 53 62 88
Roth MJ 2004 China Asian PB 90 454 24 66 145 309
Suzuki S 2004 Japan Asian HB 146 177 87 58 84 93
Torres MM 2004 Colombia Latin America HB 46 96 30 16 36 60
Lai KC 2005 China Asian HB 123 121 73 50 55 66
Li H 2005 Chian Asian HB 102 62 67 33 26 36
Nan HM 2005 Korea Asian HB 110 220 73 34 130 90
Palli D 2005 Italy Caucasian PB 175 546 90 85 275 271
Shen J 2005 China Asian PB 114 693 71 41 361 314
Tamer L 2005 Turkey Caucasian HB 70 204 40 30 88 116
Agudo A 2006 UK Caucasian PB 243 946 122 120 498 434
Hong SH 2006 Korea Asian HB 108 238 60 48 134 104
Lee K 2006 Chile Caucasian HB 73 263 13 60 56 207
Martínez C 2006 Spain Caucasian PB 98 329 33 54 149 180
Boccia S 2007 Italy Caucasian HB 102 254 59 43 135 119
Ruzzo A 2007 Italy Caucasian HB 126 144 35 44 61 51
Wideroff L 2007 USA Caucasian PB 116 209 61 55 121 87
Tripathi Sa 2008 India Asian HB 76 100 31 45 39 61
Al-Moundhri MS 2009 Oman Caucasian HB 107 107 42 65 32 75
Malik MA 2009 India Asian HB 108 195 64 44 79 116
Masoudi M 2009 Iran Caucasian PB 67 134 37 30 60 74
Moy KA 2009 China Asian PB 307 911 98 72 415 320
Piao JM 2009 Korea Asian PB 2213 1699 1225 988 923 776
Zendehdel K 2009 Sweden Caucasian PB 126 471 70 54 239 230
Nguyen TV 2010 Vietnam Asian HB 59 109 43 16 75 34
Palli D 2010 Italy Caucasian PB 314 548 166 130 275 271
Yadav DS 2010 India Asian HB 133 270 49 84 120 150
Darazy M 2011 Lebanese Caucasian PB 13 70 6 7 12 58
Luo YP 2011 China Asian PB 123 129 93 50 71 58
Yadav D 2011 India Asian PBb 41 130 11 30 38 92
Zhang AP 2011 China Asian PB 194 412 105 89 194 218
García-González MA 2012 Spain Caucasian PB 557 557 284 273 267 290
Jing C 2012 China Asian HB 410 410 240 170 207 203
Kim HJ 2012 Korea Asian HB 102 200 61 41 124 76
Malakar M 2012 India Asian PB 102 204 57 45 97 107
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PB: population-based; HB: hospital-based; a: only genotype data of healthy controls were extracted; b: source of controls were not described and the study was assumed as PB

Overall analysis

All meta-analysis results were shown in Table 2. By pooling all 46 eligible studies, we found the GSTM1 null genotype was associated with a significantly increased risk of gastric cancer (OR=1.217, 95% CI: 1.113-1.331, Pheterogeneity<0.001; Figure 2). Since significant heterogeneity existed, meta-regression was performed to detect the source of heterogeneity and the results suggested that ethnicities (p<0.001), source of control(p<0.001), and sample size (p<0.001) contributed to the heterogeneity. Egger’s test (p=0.02) and Begg’s test (p=0.003) found the evidence of publication bias (Figure 3). However, the fail-safe-number was large (Nfs0.05=1299.9, Nfs0.01=602.8), which suggested that the publication bias was feeble and our result is solid.

Table 2. Meta-analysis results of GSTM1 polymorphism and gastric cancer risk.

comparison No. of Studies OR (95% CI) Heterogeneity
Overall 46 1.217 (1.113-1.331)* p<0.001
Source of Control
Hospital-Based 24 1.283 (1.104-1.490) * 0.002
Population-Based 22 1.156 (1.041-1.284) * 0.041
Enthnicity
Asian 28 1.273 (1.137-1.426) * 0.002
Caucasian 16 1.081 (0.941-1.243) 0.094
Latin American 2 1.906 (0.784-4.630) 0.046
Sample Size
Small 32 1.296 (1.125-1.494) * p<0.001
Large 14 1.120 (1.029-1.220) * 0.311
Smoking Status
Non-smoker 12 1.777 (1.301-2.426) * p<0.001
Ever-smoker 11 1.459 (1.024-2.077) * 0.014
H. pylori Infection
Positive 3 1.928 (1.028-3.615) * 0.065
Negative 4 0.969 (0.618-1.521) 0.168
Location of Tumor
Cardia 3 0.904 (0.648-1.261) 0.338
Non-Cardia 2 1.051 (0.831-1.331) 0.394
Lauren’s Classification
Diffuse Type 5 1.162 (0.776-1.741) 0.066
Intestinal Type 5 1.524 (0.998-2.327) 0.017
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OR: odds ratio, 95% CI: 95% confidence intervals; p<0.1 indicates significant heterogeneity; * significant association

Figure 2. Overall analysis of GSTM1 null genotype and gastric cancer risk.

Figure 2

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A number of 46 studies were included.

Figure 3. Funnel plot for the overall analysis of GSTM1 null genotype and gastric cancer risk.

Figure 3

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Circles represent the weight of each study.

Sub-group analysis

Ethnicities

Sub-group analysis for ethnicities was performed and the increased risk of gastric cancer was only observed in Asians (OR=1.273, 95%: 1.137-1.426, Pheterogeneity=0.002), while no significant association was found in Caucasians or Latin Americans (Figure S1).

Source of control

The results showed that source of controls did not affect the pooled results and we observed a significantly increased risk of gastric cancer both in PB and HB studies.

Sample size

As shown in Table 1, most eligible studies about GSTM1 polymorphism and gastric cancer were small-sized (less than 500 participants). The mean number of participants for “small studies” was 252 and the mean for “large studies” was 964. Sub-group analysis revealed that the pooled results did not differ between large studies and small studies, since increased susceptibility was observed in both sub-groups (Table 2).

Helicobacter pylori infection

HP infection is a well known risk factor of gastric cancer and 4 studies provided data about HP infection status and GSTM1 genotype distribution. As shown in Table 2, the null genotype of GSTM1 was associated with an elevated risk of gastric cancer in the HP positive sub-group (OR=1.928, 95% CI: 1.028-3.615, Pheterogeneity=0.065), while no significant association was found in the HP negative sub-group (OR=0.969, 95% CI: 0.618-1.521, Pheterogeneity=0.168).

Smoking status

Smoking is a risk factor of various kinds of cancer, including gastric cancer, and GST family is also involved in the metabolism of various carcinogens in cigarette smoke. As shown in Table 2, data of smoking status and GSTM1 genotype distribution were available in 12 studies. Sub-group analysis results suggested that there was no difference of gastric cancer risk between ever-smokers and non-smokers, because significantly increased risk was found in both sub-groups (Figure 4).

Figure 4. Sub-group analysis of smoking status (ever-smoker and non-smoker).

Figure 4

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Location and Lauren’s classification

We also performed stratified analyses according to location of tumor (cardia and non-cardia) and Lauren’s classification (diffuse and intestinal). The number of studies available for the sub-group analysis of location was quite small (3 studies), and no significant association of GSTM1 null genotype with gastric cancer risk was observed in neither sub-group (Table 2). As for sub-groups of Lauren’s classification, we did not found any significant association for diffuse type cancer or intestinal type cancer.

Discussion

Genetic polymorphisms are natural DNA sequence variations and the expected frequency is about 1% among healthy population [62]. Functional genetic polymorphism in the gene regulation region or coding sequences could change gene expression or function. Additionally, genetic polymorphism may, to some degree, explain the inter-individual variation and diversity, and has been recently considered as principal genetic elements involved in the development of cancer [63]. The GST gene family encoding phase II detoxification enzymes is critical for the protection against various chemical carcinogenesis [3]. The GSTM1 enzyme is responsible for the metabolism of reactive electrophilic intermediates, including environmental pollutants and other polycyclic aromatic hydrocarbons, which are potent carcinogenic agents. Thus, impaired GSTM1 function may lead to serious DNA damage and carcinogenesis. Considering that the GSTM1 null genotype caused a complete loss of GSTM1 enzyme activity, it is biologically plausible that the GSTM1 null genotype may increase risk of gastric cancer.

Since the first study in 1991 by Strange and colleagues [64] which reported the association between the GSTM1 null genotype and increased risk of gastric cancer, a lot of epidemiological studies about the relationship between GSTM1 and gastric cancer have been conducted[23,48,55]. Limited by number of studies, the conclusion about GSTM1 null genotype and gastric cancer was still unclear, as well as influence of some important factors like H. pylori infection and smoking status. Since a large number of studies have been published [10-12], it is necessary to perform an update meta-analysis to assess the association between GSTM1 and gastric cancer and explore the effect of H. pylori infection, smoking, location and Lauren’s classification.

In this study, we identified 46 eligible studies, including 8138 gastric cancer cases and 13867 controls, which could provide sufficient statistic power. By pooling all available data, we found the null genotype was associated with a statistically elevated risk of gastric cancer (OR=1.217, 95% CI: 1.113-1.331), which was consistent with previous meta-analyses [8,65]. By stratifying studies according to ethnicities, increased risk of gastric cancer was only observed in Asians and no significant association was found in Caucasians or Latin Americans, which was also in agreement with previous studies. The ethnic difference was common for genetic association studies, which may be due to different genetic background and environmental differences. Additionally, the incidence of gastric cancer is quite heterogeneous in Asia population, and the findings should be explained with caution when applied to a specific area. Notably, heterogeneity was significant in this meta-analysis (Table 2). Meta-regression analysis indicated that ethnicities (p<0.001), source of control (p<0.001), and sample size (p<0.001) were the source of heterogeneity. For source of control, participants from hospital may have different genetic background compared with those from general population. To achieve an acute estimation of the relationship between GSTM1 null genotype and gastric cancer risk, future studies should take these factors into consideration.

Helicobacter pylori, the group I carcinogen classified by World Health Organization, is one of the most important risk factors for gastric cancer[66]. By performing sub-group analysis, we only found the increased risk of gastric cancer in the H. pylori positive group (OR=1.928, 95% CI: 1.028-3.615), while there was no significant association in the H. pylori negative group (OR=0.969, 95% CI: 0.618-1.521). This finding suggested that H. pylori infection could modify the association between GSTM1 polymorphism and susceptibility to gastric cancer [67-69]. Tobacco smoke contains various carcinogens like N-nitrosamines, polycylic aromatic hydrocarbons, and heterocyclic amines, which require detoxification by different pathways, including GSTs. To assess the influence of smoking, we extracted data from 12 eligible studies and found that smoking status did not alter the relationship between GSTM1 null genotype and risk of gastric cancer. This may be explained by that GSTM1 is just a member of GST family and the null genotype will not significantly impair the overall GST enzyme activity. For location of tumor and Lauren’s classification, we did not found any significant association. Given that studies included in these sub-groups were few (Table 2), further studies are warranted.

Compared with previous meta-analysis, we included more studies and performed sub-group analyses to assess the influence of ethnicities, source of controls, sample size, H. pylori infection, smoking, tumor location, and Lauren’s classification. Notably, we searched databases of PubMed and EMBASE but not China National Knowledge Infrastructure (CNKI), because CNKI Chinese-language database, which is usually not accessible for non-Chinese researchers. However, limitations of this meta-analysis should be highlighted. First, Egger’s test and Begg’s test suggested the evidence of publication bias. We calculated the fail-safe number and the number was large enough (Nfs0.05=1299.9, Nfs0.01=602.8) to provide credence to our results. Secondly, heterogeneity was significant in this study. To achieve a precise and conservative estimation, we used random-effects model to pool eligible studies and meta-regression found that ethnicities, source of control, and sample size were the source of heterogeneity. Thirdly, in the sub-group analysis of location, number of studies was relatively small and the results should be interpreted with caution.

To summary, in this meta-analysis based on 46 epidemiological studies, we show that the GSTM1 null genotype is associated with increased risk of gastric cancer among Asians but not among Caucasians. The null genotype increased susceptibility to gastric cancer both in ever-smokers and non-smokers, while the significant association was only observed in H. pylori positive population.

Supporting Information

Checklist S1

PRISMA checklist.

(DOC)

Click here for additional data file. (59KB, doc)
Figure S1

Sub-group analysis of ethnicities.

(TIF)

Click here for additional data file. (1.1MB, tif)

Funding Statement

The authors have no support or funding to report.

References

  • 1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C et al. (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127: 2893-2917. doi: 10.1002/ijc.25516. PubMed: 21351269. [DOI] [PubMed] [Google Scholar]
  • 2. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J et al. (2000) Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343: 78-85. doi: 10.1056/NEJM200007133430201. PubMed: 10891514. [DOI] [PubMed] [Google Scholar]
  • 3. Hayes JD, Pulford DJ (1995) The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol 30: 445-600. doi: 10.3109/10409239509083491. PubMed: 8770536. [DOI] [PubMed] [Google Scholar]
  • 4. Board PG, Coggan M, Chelvanayagam G, Easteal S, Jermiin LS et al. (2000) Identification, characterization, and crystal structure of the Omega class glutathione transferases. J Biol Chem 275: 24798-24806. doi: 10.1074/jbc.M001706200. PubMed: 10783391. [DOI] [PubMed] [Google Scholar]
  • 5. Saadat M (2006) Genetic polymorphisms of glutathione S-transferase T1 (GSTT1) and susceptibility to gastric cancer: a meta-analysis. Cancer Sci 97: 505-509. doi: 10.1111/j.1349-7006.2006.00207.x. PubMed: 16734729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. Garte S, Gaspari L, Alexandrie AK, Ambrosone C, Autrup H et al. (2001) Metabolic gene polymorphism frequencies in control populations. Cancer Epidemiol Biomarkers Prev 10: 1239-1248. PubMed: 11751440. [PubMed] [Google Scholar]
  • 7. Benhamou S, Lee WJ, Alexandrie AK, Boffetta P, Bouchardy C et al. (2002) Meta- and pooled analyses of the effects of glutathione S-transferase M1 polymorphisms and smoking on lung cancer risk. Carcinogenesis 23: 1343-1350. doi: 10.1093/carcin/23.8.1343. PubMed: 12151353. [DOI] [PubMed] [Google Scholar]
  • 8. Qiu LX, Wang K, Lv FF, Chen ZY, Liu X et al. (2011) GSTM1 null allele is a risk factor for gastric cancer development in Asians. Cytokine 55: 122-125. doi: 10.1016/j.cyto.2011.03.004. PubMed: 21474334. [DOI] [PubMed] [Google Scholar]
  • 9. Zhu Y, He Q, Wang J, Pan HF (2012) The association between GSTM1 polymorphism and gastric cancer risk: a meta-analysis. Mol Biol Rep 39: 685-691. doi: 10.1007/s11033-011-0786-2. PubMed: 21553222. [DOI] [PubMed] [Google Scholar]
  • 10. Jing C, Huang ZJ, Duan YQ, Wang PH, Zhang R et al. (2012) Glulathione-S-transferases gene polymorphism in prediction of gastric cancer risk by smoking and Helicobacter pylori infection status. Asian Pac J Cancer Prev 13: 3325-3328. doi: 10.7314/APJCP.2012.13.7.3325. PubMed: 22994755. [DOI] [PubMed] [Google Scholar]
  • 11. García-González MA, Quintero E, Bujanda L, Nicolás D, Benito R et al. (2012) Relevance of GSTM1, GSTT1, and GSTP1 gene polymorphisms to gastric cancer susceptibility and phenotype. Mutagenesis 27: 771-777. doi: 10.1093/mutage/ges049. PubMed: 22952149. [DOI] [PubMed] [Google Scholar]
  • 12. Zhang AP, Liu BH, Wang L, Gao Y, Li F et al. (2011) Glutathione S-transferase gene polymorphisms and risk of gastric cancer in a Chinese population. Asian Pac J Cancer Prev 12: 3421-3425. PubMed: 22471491. [PubMed] [Google Scholar]
  • 13. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC et al. (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLOS Med 6: e1000100 PubMed: 196315071962251219621070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Lau J, Ioannidis JP, Schmid CH (1997) Quantitative synthesis in systematic reviews. Ann Intern Med 127: 820-826. doi: 10.7326/0003-4819-127-9-199711010-00008. PubMed: 9382404. [DOI] [PubMed] [Google Scholar]
  • 15. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7: 177-188. doi: 10.1016/0197-2456(86)90046-2. PubMed: 3802833. [DOI] [PubMed] [Google Scholar]
  • 16. Whitehead A, Whitehead J (1991) A general parametric approach to the meta-analysis of randomized clinical trials. Stat Med 10: 1665-1677. doi: 10.1002/sim.4780101105. PubMed: 1792461. [DOI] [PubMed] [Google Scholar]
  • 17. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315: 629-634. doi: 10.1136/bmj.315.7109.629. PubMed: 9310563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Zhuo WL, Zhang YS, Wang Y, Zhuo XL, Zhu B et al. (2009) Association studies of CYP1A1 and GSTM1 polymorphisms with esophageal cancer risk: evidence-based meta-analyses. Arch Med Res 40: 169-179. doi: 10.1016/j.arcmed.2009.01.003. PubMed: 19427967. [DOI] [PubMed] [Google Scholar]
  • 19. Palli D, Polidoro S, D'Errico M, Saieva C, Guarrera S et al. (2010) Polymorphic DNA repair and metabolic genes: a multigenic study on gastric cancer. Mutagenesis 25: 569-575. doi: 10.1093/mutage/geq042. PubMed: 20817763. [DOI] [PubMed] [Google Scholar]
  • 20. Zendehdel K, Bahmanyar S, McCarthy S, Nyren O, Andersson B et al. (2009) Genetic polymorphisms of glutathione S-transferase genes GSTP1, GSTM1, and GSTT1 and risk of esophageal and gastric cardia cancers. Cancer Causes Control 20: 2031-2038. doi: 10.1007/s10552-009-9399-7. PubMed: 19618282. [DOI] [PubMed] [Google Scholar]
  • 21. Moy KA, Yuan JM, Chung FL, Wang XL, Van Den Berg D et al. (2009) Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms and gastric cancer risk: a prospective study of men in Shanghai, China. Int J Cancer 125: 2652-2659. doi: 10.1002/ijc.24583. PubMed: 19610060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Agudo A, Sala N, Pera G, Capellá G, Berenguer A et al. (2006) No association between polymorphisms in CYP2E1, GSTM1, NAT1, NAT2 and the risk of gastric adenocarcinoma in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev 15: 1043-1045. doi: 10.1158/1055-9965.EPI-06-0073. PubMed: 16702391. [DOI] [PubMed] [Google Scholar]
  • 23. Shen J, Wang RT, Xu YC, Wang LW, Wang XR (2005) Interaction models of CYP1A1, GSTM1 polymorphisms and tobacco smoking in intestinal gastric cancer. World J Gastroenterol 11: 6056-6060. PubMed: 16273625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Roth MJ, Abnet CC, Johnson LL, Mark SD, Dong ZW et al. (2004) Polymorphic variation of Cyp1A1 is associated with the risk of gastric cardia cancer: a prospective case-cohort study of cytochrome P-450 1A1 and GST enzymes. Cancer Causes Control 15: 1077-1083. doi: 10.1007/s10552-004-2233-3. PubMed: 15801491. [DOI] [PubMed] [Google Scholar]
  • 25. Palli D, Saieva C, Gemma S, Masala G, Gomez-Miguel MJ et al. (2005) GSTT1 and GSTM1 gene polymorphisms and gastric cancer in a high-risk italian population. Int J Cancer 115: 284-289. doi: 10.1002/ijc.20864. PubMed: 15688399. [DOI] [PubMed] [Google Scholar]
  • 26. Wu MS, Chen CJ, Lin MT, Wang HP, Shun CT et al. (2002) Genetic polymorphisms of cytochrome p450 2E1, glutathione S-transferase M1 and T1, and susceptibility to gastric carcinoma in Taiwan. Int J Colorectal Dis 17: 338-343. doi: 10.1007/s00384-001-0383-2. PubMed: 12172927. [DOI] [PubMed] [Google Scholar]
  • 27. Shen J, Wang R, Xu X (2001) [Application of the interaction models between the polymorphism(s) of metabolic gene(s) and environmental exposure]. Zhonghua Liu Xing Bing Xue Za Zhi 22: 61-64. PubMed: 11860849. [PubMed] [Google Scholar]
  • 28. Setiawan VW, Zhang ZF, Yu GP, Lu QY, Li YL et al. (2001) GSTP1 polymorphisms and gastric cancer in a high-risk Chinese population. Cancer Causes Control 12: 673-681. doi: 10.1023/A:1011261602940. PubMed: 11562107. [DOI] [PubMed] [Google Scholar]
  • 29. Malakar M, Devi KR, Phukan RK, Kaur T, Deka M et al. (2012) Genetic polymorphism of glutathione S-transferases M1 and T1, tobacco habits and risk of stomach cancer in Mizoram, India. Asian Pac J Cancer Prev 13: 4725-4732. doi: 10.7314/APJCP.2012.13.9.4725. PubMed: 23167410. [DOI] [PubMed] [Google Scholar]
  • 30. Darazy M, Balbaa M, Mugharbil A, Saeed H, Sidani H et al. (2011) CYP1A1, CYP2E1, and GSTM1 gene polymorphisms and susceptibility to colorectal and gastric cancer among Lebanese. Genet Test Mol Biomarkers 15: 423-429. doi: 10.1089/gtmb.2010.0206. PubMed: 21385088. [DOI] [PubMed] [Google Scholar]
  • 31. Luo YP, Chen HC, Khan MA, Chen FZ, Wan XX et al. (2011) Genetic polymorphisms of metabolic enzymes-CYP1A1, CYP2D6, GSTM1, and GSTT1, and gastric carcinoma susceptibility. Tumour Biol 32: 215-222. doi: 10.1007/s13277-010-0115-8. PubMed: 20878561. [DOI] [PubMed] [Google Scholar]
  • 32. Yadav DS, Devi TR, Ihsan R, Mishra AK, Kaushal M et al. (2010) Polymorphisms of glutathione-S-transferase genes and the risk of aerodigestive tract cancers in the Northeast Indian population. Genet Test Mol Biomarkers 14: 715-723. doi: 10.1089/gtmb.2010.0087. PubMed: 20854097. [DOI] [PubMed] [Google Scholar]
  • 33. Nguyen TV, Janssen MJ, van Oijen MG, Bergevoet SM, te Morsche RH et al. (2010) Genetic polymorphisms in GSTA1, GSTP1, GSTT1, and GSTM1 and gastric cancer risk in a Vietnamese population. Oncol Res 18: 349-355. PubMed: 20377137. [DOI] [PubMed] [Google Scholar]
  • 34. Malik MA, Upadhyay R, Mittal RD, Zargar SA, Modi DR et al. (2009) Role of xenobiotic-metabolizing enzyme gene polymorphisms and interactions with environmental factors in susceptibility to gastric cancer in Kashmir Valley. J Gastrointest Cancer 40: 26-32. doi: 10.1007/s12029-009-9072-0. PubMed: 19521675. [DOI] [PubMed] [Google Scholar]
  • 35. Al-Moundhri MS, Alkindy M, Al-Nabhani M, Al-Bahrani B, Burney IA et al. (2009) Combined polymorphism analysis of glutathione S-transferase M1/G1 and interleukin-1B (IL-1B)/interleukin 1-receptor antagonist (IL-1RN) and gastric cancer risk in an Omani Arab Population. J Clin Gastroenterol 43: 152-156. doi: 10.1097/MCG.0b013e31815853fa. PubMed: 18779738. [DOI] [PubMed] [Google Scholar]
  • 36. Masoudi M, Saadat I, Omidvari S, Saadat M (2009) Genetic polymorphisms of GSTO2, GSTM1, and GSTT1 and risk of gastric cancer. Mol Biol Rep 36: 781-784. doi: 10.1007/s11033-008-9245-0. PubMed: 18398695. [DOI] [PubMed] [Google Scholar]
  • 37. Tripathi S, Ghoshal U, Ghoshal UC, Mittal B, Krishnani N et al. (2008) Gastric carcinogenesis: Possible role of polymorphisms of GSTM1, GSTT1, and GSTP1 genes. Scand J Gastroenterol 43: 431-439. doi: 10.1080/00365520701742930. PubMed: 18365908. [DOI] [PubMed] [Google Scholar]
  • 38. Boccia S, Sayed-Tabatabaei FA, Persiani R, Gianfagna F, Rausei S et al. (2007) Polymorphisms in metabolic genes, their combination and interaction with tobacco smoke and alcohol consumption and risk of gastric cancer: a case-control study in an Italian population. BMC Cancer 7: 206. doi: 10.1186/1471-2407-7-206. PubMed: 17996038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Wideroff L, Vaughan TL, Farin FM, Gammon MD, Risch H et al. (2007) GST, NAT1, CYP1A1 polymorphisms and risk of esophageal and gastric adenocarcinomas. Cancer Detect Prev 31: 233-236. doi: 10.1016/j.cdp.2007.03.004. PubMed: 17646057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Ruzzo A, Canestrari E, Maltese P, Pizzagalli F, Graziano F et al. (2007) Polymorphisms in genes involved in DNA repair and metabolism of xenobiotics in individual susceptibility to sporadic diffuse gastric cancer. Clin Chem Lab Med 45: 822-828. PubMed: 17617021. [DOI] [PubMed] [Google Scholar]
  • 41. Lee K, Cáceres D, Varela N, Csendes DA, Rios RH et al. (2006) [Allelic variants of cytochrome P4501A1 (CYP1A1), glutathione S transferase M1 (GSTM1) polymorphisms and their association with smoking and alcohol consumption as gastric cancer susceptibility biomarkers]. Rev Med Chil 134: 1107-1115. PubMed: 17171211. [DOI] [PubMed] [Google Scholar]
  • 42. Martínez C, Martín F, Fernández JM, García-Martín E, Sastre J et al. (2006) Glutathione S-transferases mu 1, theta 1, pi 1, alpha 1 and mu 3 genetic polymorphisms and the risk of colorectal and gastric cancers in humans. Pharmacogenomics 7: 711-718. doi: 10.2217/14622416.7.5.711. PubMed: 16886896. [DOI] [PubMed] [Google Scholar]
  • 43. Hong SH, Kim JW, Kim HG, Park IK, Ryoo JW et al. (2006) [Glutathione S-transferases (GSTM1, GSTT1 and GSTP1) and N-acetyltransferase 2 polymorphisms and the risk of gastric cancer]. J Prev Med Public Health 39: 135-140. PubMed: 16615268. [PubMed] [Google Scholar]
  • 44. Lai KC, Chen WC, Tsai FJ, Li SY, Chou MC et al. (2005) Glutathione S-transferase M1 gene null genotype and gastric cancer risk in Taiwan. Hepatogastroenterology 52: 1916-1919. PubMed: 16334806. [PubMed] [Google Scholar]
  • 45. Li H, Chen XL, Li HQ (2005) Polymorphism of CYPIA1 and GSTM1 genes associated with susceptibility of gastric cancer in Shandong Province of China. World J Gastroenterol 11: 5757-5762. PubMed: 16270381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. Nan HM, Song YJ, Yun HY, Park JS, Kim H (2005) Effects of dietary intake and genetic factors on hypermethylation of the hMLH1 gene promoter in gastric cancer. World J Gastroenterol 11: 3834-3841. PubMed: 15991278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47. Torres MM, Acosta CP, Sicard DM, Groot de Restrepo H (2004) [Genetic susceptibility and risk of gastric cancer in a human population of Cauca, Colombia]. Biomedica 24: 153-162. PubMed: 15495595. [PubMed] [Google Scholar]
  • 48. Tamer L, Ateş NA, Ateş C, Ercan B, Elipek T et al. (2005) Glutathione S-transferase M1, T1 and P1 genetic polymorphisms, cigarette smoking and gastric cancer risk. Cell Biochem Funct 23: 267-272. doi: 10.1002/cbf.1148. PubMed: 15473001. [DOI] [PubMed] [Google Scholar]
  • 49. Colombo J, Rossit AR, Caetano A, Borim AA, Wornrath D et al. (2004) GSTT1, GSTM1 and CYP2E1 genetic polymorphisms in gastric cancer and chronic gastritis in a Brazilian population. World J Gastroenterol 10: 1240-1245. PubMed: 15112335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Suzuki S, Muroishi Y, Nakanishi I, Oda Y (2004) Relationship between genetic polymorphisms of drug-metabolizing enzymes (CYP1A1, CYP2E1, GSTM1, and NAT2), drinking habits, histological subtypes, and p53 gene point mutations in Japanese patients with gastric cancer. J Gastroenterol 39: 220-230. doi: 10.1007/s00535-003-1281-x. PubMed: 15064998. [DOI] [PubMed] [Google Scholar]
  • 51. Sgambato A, Campisi B, Zupa A, Bochicchio A, Romano G et al. (2002) Glutathione S-transferase (GST) polymorphisms as risk factors for cancer in a highly homogeneous population from southern Italy. Anticancer Res 22: 3647-3652. PubMed: 12552971. [PubMed] [Google Scholar]
  • 52. Gao CM, Takezaki T, Wu JZ, Li ZY, Liu YT et al. (2002) Glutathione-S-transferases M1 (GSTM1) and GSTT1 genotype, smoking, consumption of alcohol and tea and risk of esophageal and stomach cancers: a case-control study of a high-incidence area in Jiangsu Province, China. Cancer Lett 188: 95-102. doi: 10.1016/S0304-3835(02)00115-5. PubMed: 12406553. [DOI] [PubMed] [Google Scholar]
  • 53. Oda Y, Kobayashi M, Ooi A, Muroishi Y, Nakanishi I (1999) Genotypes of glutathione S-transferase M1 and N-acetyltransferase 2 in Japanese patients with gastric cancer. Gastric Cancer 2: 158-164. doi: 10.1007/s101200050040. PubMed: 11957090. [DOI] [PubMed] [Google Scholar]
  • 54. Cai L, Yu SZ, Zhang ZF (2001) Glutathione S-transferases M1, T1 genotypes and the risk of gastric cancer: a case-control study. World J Gastroenterol 7: 506-509. PubMed: 11819818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55. Saadat I, Saadat M (2001) Glutathione S-transferase M1 and T1 null genotypes and the risk of gastric and colorectal cancers. Cancer Lett 169: 21-26. doi: 10.1016/S0304-3835(01)00550-X. PubMed: 11410321. [DOI] [PubMed] [Google Scholar]
  • 56. Alves GM (1998) Glutathione S transferase mu polymorphism and gastric cancer in the Portuguese population. Biomarkers 3: 441-447. doi: 10.1080/135475098231084. PubMed: 23899396. [DOI] [PubMed] [Google Scholar]
  • 57. Katoh T, Nagata N, Kuroda Y, Itoh H, Kawahara A et al. (1996) Glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) genetic polymorphism and susceptibility to gastric and colorectal adenocarcinoma. Carcinogenesis 17: 1855-1859. doi: 10.1093/carcin/17.9.1855. PubMed: 8824506. [DOI] [PubMed] [Google Scholar]
  • 58. Kato S, Onda M, Matsukura N, Tokunaga A, Matsuda N et al. (1996) Genetic polymorphisms of the cancer related gene and Helicobacter pylori infection in Japanese gastric cancer patients. An age and gender matched case-control study. Cancer 77: 1654-1661. doi: 10.1002/(SICI)1097-0142(19960415)77:8 + PubMed; : 8608558 [DOI] [PubMed] [Google Scholar]
  • 59. Kim H, Um J, Kim Y (2012) Glutathione S-transferase gene polymorphism in Korean subjects with gastric and colorectal cancer. Oriental Pharmacy and Experimental Medicine 12: 307-312. doi: 10.1007/s13596-012-0091-1. [DOI] [Google Scholar]
  • 60. Yadav D, Chandra R, Saxena R, Agarwal D, Agarwal M et al. (2011) Glutathione-S-transferase M1 and T1 genes and gastric cancer: a case control study in North Indian population. Gene 487: 166-169. doi: 10.1016/j.gene.2011.07.010. PubMed: 21839153. [DOI] [PubMed] [Google Scholar]
  • 61. Piao JM, Shin MH, Kweon SS, Kim HN, Choi JS et al. (2009) Glutathione-S-transferase (GSTM1, GSTT1) and the risk of gastrointestinal cancer in a Korean population. World J Gastroenterol 15: 5716-5721. doi: 10.3748/wjg.15.5716. PubMed: 19960570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62. Balasubramanian SP, Brown NJ, Reed MW (2002) Role of genetic polymorphisms in tumour angiogenesis. Br J Cancer 87: 1057-1065. doi: 10.1038/sj.bjc.6600625. PubMed: 12402142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Rannala B (2001) Finding genes influencing susceptibility to complex diseases in the post-genome era. Am J Pharmacogenomics 1: 203-221. doi: 10.2165/00129785-200101030-00005. PubMed: 12083968. [DOI] [PubMed] [Google Scholar]
  • 64. Strange RC, Matharoo B, Faulder GC, Jones P, Cotton W et al. (1991) The human glutathione S-transferases: a case-control study of the incidence of the GST1 0 phenotype in patients with adenocarcinoma. Carcinogenesis 12: 25-28. doi: 10.1093/carcin/12.1.25. PubMed: 1988177. [DOI] [PubMed] [Google Scholar]
  • 65. La Torre G, Boccia S, Ricciardi G (2005) Glutathione S-transferase M1 status and gastric cancer risk: a meta-analysis. Cancer Lett 217: 53-60. doi: 10.1016/j.canlet.2004.08.020. PubMed: 15596296. [DOI] [PubMed] [Google Scholar]
  • 66. Correa P (1992) Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 52: 6735-6740. PubMed: 1458460. [PubMed] [Google Scholar]
  • 67. Tripathi S, Ghoshal U, Mittal B, Chourasia D, Kumar S et al. (2011) Association between gastric mucosal glutathione-S-transferase activity, glutathione-S-transferase gene polymorphisms and Helicobacter pylori infection in gastric cancer. Indian J Gastroenterol 30: 257-263. doi: 10.1007/s12664-011-0144-2. PubMed: 22139978. [DOI] [PubMed] [Google Scholar]
  • 68. Beil W, Obst B, Sewing KF, Wagner S (2000) Helicobacter pylori reduces intracellular glutathione in gastric epithelial cells. Dig Dis Sci 45: 1769-1773. doi: 10.1023/A:1005530227603. PubMed: 11052318. [DOI] [PubMed] [Google Scholar]
  • 69. Verhulst ML, van Oijen AH, Roelofs HM, Peters WH, Jansen JB (2000) Antral glutathione concentration and glutathione S-transferase activity in patients with and without Helicobacter pylori. Dig Dis Sci 45: 629-632. doi: 10.1023/A:1005426130826. PubMed: 10749343. [DOI] [PubMed] [Google Scholar]

Associated Data

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Supplementary Materials

Checklist S1

PRISMA checklist.

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Figure S1

Sub-group analysis of ethnicities.

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