Mutagenesis Advance Access originally published online on March 3, 2006
Mutagenesis 2006 21(2):115-123; doi:10.1093/mutage/gel005
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Glutathione S-transferase T1 status and gastric cancer risk: a meta-analysis of the literature
Institute of Hygiene, Catholic University of Sacred Heart, L.go F.Vito, 1-00168 Rome, Italy
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Abstract |
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To clarify the risk of gastric cancer associated with glutathione S-transferase T1 (GSTT1) status, a meta-analysis of published studies was performed. Eligible studies included all reports investigating an association between GSTT1 status and gastric cancer published before October 31, 2005. A qualitative scoring of papers was applied to evaluate the quality of the published data. The principal outcome measure was the odds ratio (OR) for the risk of gastric cancer associated with GSTT1 deletion status using a random effects model. Eighteen case–control studies detailing a possible association between the GSTT1 null genotype and gastric cancer were selected. Combining data from these studies, totalling 2508 cases and 4634 controls, a non-statistically significant OR for gastric cancer risk associated with GSTT1 deficiency emerged [OR = 1.09; 95% confidence interval (CI): 0.97–1.21; I2 = 0%]. When only high-quality scored studies were considered, a statistically significant increased risk appeared (OR = 1.23; 95% CI: 1.04–1.45; I2 = 0%), as well as considering only Caucasians (OR = 1.23; 95% CI: 1.03–1.56; I2 = 0%). By pooling data from seven studies (319 cases and 656 controls) that considered combinations of GSTT1 and GSTM1 genotypes, a statistically significant increased risk for gastric cancer (OR = 1.95, 95% CI: 1.42–2.67; I2 = 0%) was detected for individuals with deletion mutations in both genes compared with wild-types. In conclusion, this meta-analysis suggests that the GSTT1 null genotype may slightly increase the risk of gastric cancer and that interaction between unfavourable GST genotypes may exist. Greater attention should, therefore, be paid to the design of future studies; the investigation of interactions among multiple genotypes and environmental exposures are justified to clarify GSTT1 null status influence on gastric cancer risk.
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Introduction |
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Sequence variations in genes coding for phase II enzymes, such as the glutathione S-transferase (GST) family, may potentially alter individual susceptibility to cancer (1
). GST are a family of genes with a critical function in protecting against electrophiles and the products of oxidative stress. The GST enzymes are involved in the detoxification of many xenobiotics, including several environmental carcinogens and endogenously derived reactive oxygen species (2). Four major GST families are widely expressed in mammalian tissue: GSTA (
), GSTM (µ), GSTT (
) and GSTP (
). Certain genes within the GSTM and GSTT (GSTM1 and GSTT1) subfamilies exhibit homozygous deletion (null genotype) polymorphisms that are considered important modifiers of individual risk for environmentally induced cancers (1). Individuals who have the homozygous deletion in one of these genes have no GSTM1 and GSTT1 enzyme activity, and thus are more susceptible to carcinogens such as benzo[]pyrene-7,8-diol epoxide, the activated form of benzo[]pyrene, and smaller reactive hydrocarbons, such as ethylene oxide and diepoxybutane (2,3). The prevalence of GSTM1 and GSTT1 null genotypes was found to vary among ethnic groups. In human populations, GSTM1 and GSTT1 are absent in 10–60 and 13–55% of individuals, respectively (4).
The common expression of GST, GSTT1-1 and GSTP1-1 in many cell types along the human gastrointestinal tract suggests an important role in the protection against carcinogens and other xenobiotics (5). The deletion mutations in the GSTT1 and GSTM1 genes and their association with gastric cancer have been investigated in a large number of studies. In our recent meta-analysis, which identified 15 studies investigating an association between GSTM1 null genotype and the risk of gastric cancer, we reported a slight increase in gastric cancer risk associated with GSTM1 deficiency [odds ratio (OR) of 1.24; 95% confidence interval (CI): 1.00–1.54] (6). A recent review of genetic susceptibility and gastric cancer risk reported that the results of case–control studies detailing associations between the GSTT1 gene and gastric cancer risk are inconclusive (7). Since Deakin et al. (8) first investigated the relationship between GSTT1 deficiency and gastric cancer in 1996, 17 studies have appeared in the literature, and most of them have refuted an association between GSTT1 deficiency and gastric cancer risk (3,9–24). One of the major problems with the published studies is that most of them were based on small numbers of cases and controls. Furthermore, because the GSTT1 genotype is presumed to affect gastric cancer risk by influencing detoxification of activated environmental carcinogens and by interaction with other unfavourable GST polymorphisms, the potential modifying effect of GSTT1 status on the relationship between tobacco smoking, other GST and gastric cancer is of particular interest, even though not often investigated.
To clarify the effect of GSTT1 status on the risk of developing gastric cancer, we carried out a quantitative meta-analysis of research published through October 31, 2005. In addition, we combined data available from published papers to explore the possible effects of the interactions between the GSTT1 genotype and smoking habits and between GSTT1 and GSTM1 genotypes with respect to gastric cancer risk.
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Materials and methods |
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Identification of relevant studies
The digital medical databases used for the search were MEDLINE and EMBASE. The key words used for the research were glutathione S-transferase T1 or GSTT1, gastric or stomach, cancer, without restriction on language. The time period includes research articles published up to October 31, 2005.
For the meta-analysis, the following inclusion criteria were considered:
- Presence of a quantitative assessment of the relationship between GSTT1 status and gastric cancer.
- An appropriate description of GSTT1 status in cases and controls.
- Results expressed as relative risk (RR) or OR.
- Studies with a 95% CI for RR or OR, or with the possibility to calculate these measures if standard deviation (SD) values were present.
Quality assessment and data extraction
Each article was blinded with respect to the authors, institutions and journals. The articles were read and scored for quality by two independent researchers using a system that incorporates elements of the methods developed by Angelillo et al. (25) and Chalmers et al. (26). We also followed suggestions useful to evaluate a molecular epidemiological study from Thakkinstian et al. (27) and Bogardus et al. (28). The criteria employed are shown in the results section below. A quality score was then calculated for each paper as the percentage of applicable criteria that were met in each study. Items concerned with efforts to minimize potential bias (nine points, items A–I, results section) were given twice the weight of those evaluating data analysis (nine points, items J–R). Lastly, even though reported in the quality score scale, the item related to Hardy–Weinberg equilibrium (item R) was not applicable because it could not have been checked in the included studies because of the analytical method used for GSTT1 genotyping, which does not provide the frequency of heterozygous individuals. Therefore, high-quality scored studies were considered as the ones with at least 70% of the total score (19 out of 26).
The same two researchers extracted the data from each article using a structured sheet and entered into a database. The following data were considered: year and location of study; ethnicity, source, sex ratio and mean age (or range whenever possible) of cases and controls; the number of cases and controls with GSTT1 deficiency; OR values with their 95% CI and covariates investigated in the study.
Statistical analysis
The OR for gastric cancer associated with GSTT1 deficiency was estimated for each study. In carrying out the meta-analysis, the random effect model was used, taking into account the possibility of heterogeneity between studies, which was tested with I2 test and a standard 
2-test (29). The resulting P-value of the 2-test for heterogeneity is reported in the result section after the result of the I2 test. The Mantel–Haenszel method (fixed effect model) was also used to assess the effect of the model's assumptions on our conclusions (30,31). Statistical analysis was undertaken using the RevMan program, release 4.2 (32). In order to detect potential publication bias, ORs and 95% CI were plotted against standard errors in each study. We also computed the power of the selected studies, in order to assess the probability of detecting an association between GSTT1 deficiency and gastric cancer at the 0.05 level of significance, assuming a genotypic risk of 2.0 and 1.5, using the method described by Schlesselmann (33). On the basis of previous literature findings, we planned to perform several subgroup meta-analyses based on the ethnicity, study design, power of the study and quality score of the papers. Lastly, we performed two additional sensitivity analyses in an attempt to evaluate whether the interaction between GSTT1 and cigarette smoking, as well as between GSTT1 and GSTM1 null genotypes, can modify the risk of gastric cancer. The z statistic was used to formally assess if any statistically significant difference among the results of each subgroup meta-analyses exists, as reported by Deeks et al. (34). In order to collect the most complete data concerning those interactions, when not extensively published in the results section of a paper, the corresponding author of the individual studies were contacted by e-mail and fax. We thus invited those authors to provide data useful for us in performing the two subgroup meta-analyses.
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Results |
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Identification of relevant studies
Eighteen articles were retrieved by our bibliographic search, with three papers written in non-English language (10
,17,20). In order to collect data from the last three papers, the corresponding authors were contacted by e-mail and fax and invited to fill in an empty table with the results of their studies. All the authors answered and their data were included in the analysis. Eighteen case–control studies were therefore considered for the present meta-analysis (3,8–24). In Table I the ORs are reported with their corresponding 95% CI, including all the data that were extracted from each study. In each report, GSTT1 status was determined by analysis of the gene via polymerase chain reaction. Ten case–control studies were population-based (C-C pb), with six of them enrolling sex- and age-matched controls, and eight were hospital-based case–control studies (C-C hb), of which only three had sex- and age-matched controls (Table I). History of smoking was verified for cases and controls in 12 of 18 studies, with 4 reporting results of the interaction between GSTT1 status and gastric cancer risk in relation to cigarette smoking habits (11,12,15,21). Lastly, though 17 of 18 studies collected data on GSTM1 status, only 5 reported data concerning the combination of those genotypes with respect to gastric cancer risk in a form suitable for a subgroup meta-analysis (3,12,19,21,22). Authors were contacted to obtain data on the interactions between GSTT1 status and smoking habits, and GSTT1 status and GSTM1 status; two authors answered (10,20) and their data were included in the two subgroup meta-analyses.
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Quality assessment
Table II shows the quality scoring items with the relative percentages of the studies complying with those criteria. The quality scoring procedure was performed for all the studies included in the meta-analysis, with the exception of the articles written in a non-English language. The potential for selection bias may be a concern in all of the individual studies considered. Cases and controls were chosen in most of the reports in the appropriate manner: 5 of 15 studies used cancer registries to identify cases and 7 identified randomly selected cases. Most of the studies stated that cancer diagnosis was validated by histology and all the studies specified disease criteria (Table II). Furthermore, in all of the studies the controls were drawn from the same population as the cases; 10 reports selected population controls. However, the response rates for cases and controls were frequently <75%, which may have led to a selection bias. Misclassification bias should be considered as a concern: only 2 of 15 studies clearly stated that the analyst was unaware of the clinical status of the subjects when genotyping their samples, so exposure misclassification may exist (Table II). One other issue is that almost all the studies did not report the reproducibility of the laboratory method used. Age, sex and other potential confounders/effect modifiers were considered in almost all of the studies, while demographic data were reported in only seven reports. Statistical analysis was judged appropriate in all of the studies, and P-values and/or 95% CI were always listed, while no study provided power calculations. Quality scores for the individual studies ranged from 0.46 to 0.81, and 5 of 15 resulted as high-quality scored studies (11
,12,14,22,23).
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Statistical analysis
Figure 1 shows the results of the combined data, depicting a plot of ORs (95% CI) for the risk of developing gastric cancer associated with GSTT1 deficiency in the 18 case–control studies, involving a total of 7142 subjects (2508 cases and 4634 controls). The meta-analysis resulted in a statistically non-significant association between GSTT1 deficiency and gastric cancer risk (OR = 1.09; 95% CI: 0.97–1.21; I2 = 0%, P for heterogeneity = 0.48). This analysis is based on combining data from studies based on a number of different ethnic groups. Separate meta-analyses were therefore conducted stratified by ethnicity. For Asians (10 studies) we found an OR = 1.02 (95% CI: 0.89–1.18; I2 = 12.1%, P for heterogeneity = 0.33), whereas for Caucasians (8 studies) the OR value was 1.27 (95% CI: 1.03–1.56; I2 = 0%, P for heterogeneity = 0.87; P-value of z statistic among the two groups = 0.08) (Fig. 1). By considering separately C-C hb and C-C pb studies, similar OR values were found [C-C hb: OR of 1.08 (95% CI : 0.92–1.27; I2 = 0%, P for heterogeneity = 0.56); C-C pb: OR of 1.09 (95% CI: 0.92–1.29; I2 = 16.7%, P for heterogeneity = 0.29)]. When combining data from the studies with a power of at least 80% for a RR = 2.0 (Table I), we found an OR of 1.08 (95% CI: 0.95–1.24; I2 = 17.9%, P for heterogeneity = 0.27). In addition, when only high-quality papers were considered, a statistically significant increase in risk for gastric cancer appeared (OR = 1.23, 95% CI: 1.04–1.45; I2 = 0%, P for heterogeneity = 0.41), while an OR of 0.99 (95% CI: 0.85–1.15; I2 = 0%, P for heterogeneity = 0.75; P-value of z statistic among the two groups = 0.07) resulted by pooling data from low-quality papers (Fig. 1).
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The funnel plot (Figure 2) shows no evidence of publication bias, with the exception of one outlier (16
). As far as the interaction between GSTT1 status and smoking habits is concerned, in relation to gastric cancer risk, we obtained data from 6 of the 12 studies in a form suitable for a subgroup meta-analysis. After stratification by smoking status, an overall OR of 1.54 (95% CI: 0.95–2.48; I2 = 59.2%, P for heterogeneity = 0.03) for the risk of gastric cancer appears in ever-smokers with GSTT1 deficiency compared with ever-smokers with a normal GSTT1 genotype. On the other hand, an overall estimate of OR = 0.86 (95% CI: 0.59–1.27; I2 = 26.3%, P for heterogeneity = 0.24; P-value of z statistic among the two groups = 0.006) appears when comparing the effect of GSTT1 status (null versus normal genotype) in never-smokers with respect to gastric cancer risk (Fig. 1). Furthermore, pooling data concerning the combination of GSTT1 and GSTM1 genotypes from seven studies demonstrated that individuals with combined deletion mutations in those genes have an OR of 1.95 for gastric cancer (95% CI: 1.42–2.67; I2 = 0%, P for heterogeneity = 0.58) in comparison with individuals with wild-type genotypes.
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Discussion |
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Most of the cancer susceptibility genes identified to date are rare and highly penetrant. While the individuals with rare alterations of these genes (e.g. tumor suppressor genes) have a dramatically higher risk of cancer, more common differences in low penetrant susceptibility genes (e.g. xenobiotic metabolism genes) could be responsible for a relatively small, but observable increase of gastric cancer risk at the population level (35
). Although gastric cancer is one of the most common malignancies worldwide, its pathogenesis and the molecular genetic events that contribute to its development are poorly understood (7). One of the most widely studied metabolic polymorphisms examined as a susceptibility factor for gastric cancer is the GSTT1 null allele; its frequency in the Caucasian population is 
13–26% (4). Since Deakin et al. (8) first investigated a possible relationship between GSTT1 deficiency and gastric cancer risk, a further 17 reports have been published examining this hypothesis (3,9–24), with conflicting results.
This led us to undertake the present meta-analysis, which aims to derive an estimate of the gastric cancer risk associated with GSTT1 status. The main finding of this meta-analysis of 18 case–control studies involving 7142 subjects is that the GSTT1 null status seems to be unrelated to gastric cancer risk. Absence of heterogeneity between studies emerged from the statistical analysis; however, as Blettner et al. (36) pointed out, the tests formally used to assess heterogeneity have low statistical power to detect it. Therefore, we decided a priori to perform several subgroup meta-analyses according to ethnicity, study design, quality and power of the studies. Considering separately Caucasian and Asian studies, the association between GSTT1 null status and gastric cancer risk reaches a slightly statistically significant level among Caucasians. In human populations, the frequency of GSTT1 deficiency is 13–26% and 36–52% in Caucasian and Asian individuals, respectively (4). However, the Caucasian reports in the subgroup analysis include a mixture of populations from very distant countries, so the result must be interpreted with caution. Unexpectedly, when only high-quality scored studies were considered, a statistically significant increased risk of gastric cancer for GSTT1 null individuals was detected.
Since GSTT1 is presumed to confer susceptibility to gastric cancer via an interaction with carcinogens, it is interesting to note that no data was collected from the cases or the controls on tobacco usage, alcohol intake, food consumption or Helicobacter pylori infection in many of the studies. By combining the data available from six studies, which investigated the possible interaction between GSTT1 status and cigarette smoking with respect to gastric cancer risk, a slightly increased risk appears for ever-smokers with a GSTT1 null genotype compared with individuals with a GSTT1 normal genotype. Even though the result is not statistically significant, from the z test a statistically significant difference among the estimates computed in ever- and never- smokers appears, so it would be interesting to pool all the missing data to confirm this result. If genetic susceptibility to gastric cancer is, in part, mediated through polymorphic variation, it is probable that the risk associated with any one locus will be small because an interaction is likely to operate in these circumstances. Hence, combinations of certain genotypes may be more discriminating as risk factors than a single locus genotype. Unfortunately, only a few reports investigated this aspect, even though 17 of 18 selected studies collected data on GSTM1 status. By pooling the data from seven available studies investigating a possible interaction between GSTT1 and GSTM1 status and gastric cancer risk, a 95% statistically significant increased risk of gastric cancer appeared for individuals with combined deletion mutations in GSTT1 and GSTM1 genes in comparison with individuals with both homozygous wild genotypes.
The main limitations of the study have to be considered in interpreting the results. First, only published studies were included in the meta-analysis; therefore a publication bias may have occurred. It is known that positive results usually have a greater probability of being published, and even though unpublished studies are generally of lesser quality than published ones (37), if they are not included an overestimation of the GSTT1 null effect may appear.
Secondly, the two subgroup meta-analyses considering interactions between GSTT1 null genotype and cigarette smoking, as well as between GSTT1 null and GSTM1 null genotypes, were performed on the basis of a fraction of all of the possible data to be pooled, so selection bias may have occurred and our results may be over inflated. In this context, it is well known that an important issue in performing a meta-analysis is that literature-based meta-analysis rather than individual data-based meta-analysis could be a potential source of bias. Meta-analyses may be inadequate to calculate a pooled estimate since published estimates are based on heterogeneous populations, different study designs and different statistical models. More reliable results can be expected if individual data are available for a pooled analysis, so that confounding factors can be considered, although this approach requires the authors of all of the published studies to share their data.
Thirdly, the quality score of the individual studies included in our meta-analysis was assessed on the basis of efforts to minimize the potential for selection bias, misclassification related to exposure, collection of data on potential confounders and method of statistical analysis. It is known that any quality assessment system has not yet been validated (38) and it is evident that our quality scale has a subjective component. Despite these limitations, assessment of the quality of individual studies used in our meta-analysis allowed us to draw two conclusions: the possibility of a selection bias and even more misclassification related to exposure cannot be ruled out; most importantly, pooling high-quality scored studies resulted in higher risk estimates than did pooling low-quality scored studies. If high-quality scored studies are more likely to yield valid information than low-quality studies, we can conclude that, on the basis of the currently available data, an additional slight risk of gastric cancer for GSTT1 null individuals may exist.
Despite these remarks, some interesting conclusions have emerged. From the results of this quantitative meta-analysis that combined the data from 7142 people (2508 cases and 4634 controls), it appears that GSTT1 null status has a very small effect on the risk of gastric cancer per se but it may modulate the tobacco-related carcinogenesis of gastric cancer, and that the combination of unfavourable genotypes may result in an additional risk of gastric cancer. A clearer picture of the interaction between different polymorphisms and environmental factors on gastric cancer risk will be adequately addressed only by large and well-designed epidemiological studies.
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Acknowledgments |
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This work was supported by a grant from Catholic University of Sacred Heart (D1 projects 2005). We are indebted to Dr Hsieh Ling-Ling, Dr Ye Mei and Dr Torres María M. for their collaboration and their availability to share their data for the present meta-analysis. We are grateful to Aaron Isaacs for the linguistic revision of the final manuscript.
Conflict of Interest Statement: None declared.
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Notes |
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* To whom correspondence should be addressed. Tel: 0039 06 35001527; Fax: 0039 06 35001522; Email: sboccia{at}rm.unicatt.it
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References |
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Received on July 23, 2005; revised on January 11, 2006; accepted on January 12, 2006.
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