Endometrial cancer (EC) is the fourth most common cancer (after breast, lung, and colorectal cancer) in women in developed countries. Environmental factors have been associated with endometrial cancer in many studies, and a heritable component may predispose to the development of endometrial cancer [1]. In 2010, there were 43,470 newly diagnosed cases and 7950 deaths in the United States [2]. EC has predominantly been considered a genetic disease, characterized by sequential accumulation of genetic alterations [3,4]. Endometrial carcinogenesis is a multi-factorial interaction between environmental triggers and genetic susceptibility. Mutagens in the living environment can create DNA adducts and strand breaks, causing genomic instability. Loss of genomic stability and the resulting gene alterations appear to be a crucial molecular and pathogenic step that occurs early in the endometrial carcinogenesis process. Recent studies have revealed that genetic variants in genes controlling carcinogen metabolism, DNA repair and cell proliferation or apoptosis may be important in determining individual susceptibility to the occurrence and progression of EC [5,6]. Genetic polymorphisms in functionally critical genes have been suggested as risk factors for the development of a variety of cancers, including endometrial cancer [7]. Therefore, the identification of genetic factors may be helpful in better understanding the mechanisms underlying endometrial carcinogenesis and improving cancer detection.

Previous studies showed that the glutathione S-transferases (GSTs) genetic variant is related to human phase II detoxification enzymes. Cytosolic GSTs (GSTM and GSTT) play a role in the detoxification of the carcinogenic electrophiles of aflatoxin and polycyclic aromatic hydrocarbons (PAHs) in tobacco smoke. The mode of action of GSTs is considered to co-effect with activation and detoxification of tobacco carcinogens. Therefore, several studies found the association between the genetic polymorphisms of GSTs and the risk of cancer development [8-10]. GSTM1 facilitates the excretion of a wide range of carcinogens, reactive oxygen species and chemotherapeutic agents with a variety of substrate specificities [11]. The GSTT1 polymorphism is considered in the detoxification of environmental carcinogens, including 1,3 butadiene and ethylene oxide in tobacco smoke and ambient air [12]. The null GST (GST-null genotype) results in a completely loss of enzyme activity to bind with genotoxic substrates, including epoxides derived from aflatoxin and PAHs [13]. There are a large number of epidemiological studies that have been addressed to evaluate the association between GSTM1 and GSTT1 homozygous deletion polymorphisms and risk of endometrial cancer in diverse ethnicities [14-19]. However, this issue remains controversial because of inconsistent results among different studies. The possibilities for this discrepancy may be that some positive results might occur by chance and some negative findings might be caused by insufficient statistical power with small sample size. Additionally, different experimental design and selection bias should also be considered.

In order to provide strong evidence of the effects of GSTM1 and GSTT1 polymorphisms on endometrial cancer risk, we carried out a quantitative meta-analysis by combining data from all published case-control studies.

The glutathiones S-transferases (GSTs) are the most important parts of phase II superfamily of metabolism enzymes. In humans, there are several GST classes that were encoded by distinct gene family [28]. Among them, GSTM1and GSTT1 should be pointed out because a polymorphic deletion of these genes may influence the enzyme activity, and eventually increase vulnerability to genotoxic damage [29,30]. Based on these backgrounds, the association has been intensively investigated between GSTM1and GSTT1 polymorphisms and risk of endometrial cancer [14-19]. Unfortunately, most of the studies had only a few hundred of participants, even less, which is too small to evaluate the overall effects precisely. Meta-analysis has been considered to be a powerful tool to overcome this problem by combining the results from independent studies together. In this meta-analysis, we found that the null genotypes of GSTM1 and GSTT1 polymorphisms were not associated with a significantly increased risk of endometrial cancer, suggesting that GSTM1 and GSTT1 polymorphisms may not be involved in the development of endometrial cancer. Notably, the between-study heterogeneity was observed in both overall analyses and some subgroup analyses, further studies therefore are warranted to confirm these findings.

After subgroup analysis according to ethnicity, not significantly increased risks were observed in European population and in Asian. The possibilities of the conflicting results among diverse ethnicities may be that the GSTM1and GSTT1 polymorphisms have different effects on the risk of endometrial cancer in different genetic backgrounds and environment which are they exposed to. The frequency of GSTM1and GSTT1 null genotype in European and Asian were 88.24%, 11.76% and 75.58%, 24.42% respectively, which indicated ethnic differences. Additionally, the small sample size should also be taken into consideration because limited sample size may not have enough statistical power to detect a real effect or generate a fluctuated estimation.

To investigate potential gene-environment interaction, the lack of GST activities caused by an inherited deletion of the GST has been reported to increase the risk of several tobacco-related cancers [31-34]. In contrast, the studies included in this meta-analysis showed no significant association of endometrial cancer in GSTM1 and GSTT1 polymorphism [14,17,18]. It was therefore hypothesized that smoking and GST genotype may not synergistically influence the endometrial cancer development, which provides strong evidences for the lack of association between GSTs and endometrial cancer risk.

As the publication of findings often depends on the expectation of researchers, false-negative results may be suppressed or false-positive results magnified [35,36]. The results of this study, however, did not show any significant publication bias.

Although our result of this meta-analysis is constructive, its limitations and some potential bias should be addressed. First, despite that a well-designed search strategy was used to identify eligible studies, it was possible that some relevant studies were not included. This study only focused on full-text papers published in English and Chinese, so some eligible studies in other languages or in other databases might be missed. Secondly, adjustments over age, gender and other environmental factors such as drinking of alcohol might help to detect the association between GSTM1, GSTT1 and endometrial cancer. If available detailed individual data are enough for an adjusted estimate in the future, a more precise analysis should be conducted. Thirdly, ethnicity was determined roughly by the subject’s country due to inadequate availability of data, and this classification can help us have a regional concept of functions of these genes. In addition, the sample size was relatively small in the meta-analysis, especially in subgroup analysis. Finally because all the studies were designed with retrospective studies, we cannot clearly determine the causal relationship between the risk factor and endometrial cancer. Given the limitations and biases above, the conclusions or interpretations made from the results of this Meta analysis should be explained with caution.

This meta-analysis involving 6 studies and 3558 subjects suggests that GSTM1 and GSTT1 polymorphism may not be associated with the risk of endometrial cancer among Europeans and Asians. Future well designed large studies might be necessary to validate this association in different populations, taking into account environmental factors in the susceptibility to endometrial cancer.