Null Glutathione S-transferase T 1 and M 1 Genotypes and Oral Cancer Susceptibility in China and India-a Meta-analysis

Oral cancer is one of the most common cancers in the world (Petersen, 2009). The incidence of oral cancer has increased obviously in the last few years in different Asian populations (Sato et al., 1999; Masood et al., 2013). Despite the advances in diagnosis and treatment, the 5-year survival rate for patients is still low. A better understanding of etiology may improve the secondary prevention strategies. Some studies had demonstrated that smoking and alcohol consumption were two risk factors of oral cancer (Katoh et al., 1999; Xie et al., 2004; Sugimura et al., 2006;Cha et al., 2007; Halawany et al., 2013; Menezes et al., 2013). However, other studies were focus on genetic polymorphisms. These genes included glutathione S-transferase (GST). Glutathione S-transferases are a family of phase II xenobiotic metabolizing enzymes and involve in detoxification of carcinogens. GST includes GSTM1 and GSTT1. Three alleles have been identified at GSTM1 locus: GSTM1*0, GSTM1*A, and GSTM1*B. Two alleles have been identified at GSTT1 locus: GSTT1*1 and GSTT1*0. Previous studies demonstrated that null genotype of GSTM1 and GSTT1 was correlated to the susceptibility to oral cancer (Seidegard et al., 1988; Hayes and Pulford, 1995; Gronau et al., 2003; Ma et al., 2011). However, the evidence was not convincing. To derive a more precise estimation of the association


Introduction
Oral cancer is one of the most common cancers in the world (Petersen, 2009).The incidence of oral cancer has increased obviously in the last few years in different Asian populations (Sato et al., 1999;Masood et al., 2013).Despite the advances in diagnosis and treatment, the 5-year survival rate for patients is still low.A better understanding of etiology may improve the secondary prevention strategies.
Some studies had demonstrated that smoking and alcohol consumption were two risk factors of oral cancer (Katoh et al., 1999;Xie et al., 2004;Sugimura et al.,

Literature inclusion and exclusion criteria
(1) The studies must be about Chinese and Indian; (2) Only case-control or cohort studies are considered; (3) The papers should include the risk of oral cancer and GSTT1 or GSTM1 null genotype; (4) The papers must provide the sample size, the OR and 95% confidence interval or provide the related information such as genotype frequency that can calculate OR and 95% CI; (5) When more than one paper used the same study population, only most complete study is included.Exclusion criteria (1) The studies are no controls; (2) The controls are with other malignancies; (3) The studies are reviews; (4) The studies' data is overlapped.

Study selection and data extraction
According to the criteria of inclusion and exclusion, a double-check procedure was carried out to make sure the data accuracy.The following information was extracted from the studies: first author, published year, country, and the number of cases and controls.The information of studies was summarized in Table 1.

Statistical analysis methods
Statistical analysis was did by Review Manager5.1 and STATA 12. OR and 95% CI were calculated to measure the strength of association between GSTT1 and GSTM1 polymorphism and oral cancer.A 95% CI without 1 indicated a significant correlation.Q test was performed to check heterogeneity, and the heterogeneity was considered significant when P<0.10 or I 2 >50%.The fixed effects model was used when P>0.10 and I 2 <50%, while a random effects model was selected when P<0.10 and I 2 >50%.Egger's test and Begg's test were done to check the publication bias.All the tests were two-sided, a P value of 0.05 was considered to be statistically significant.

Characteristics of studies
According to the search strategy, 15 papers were selected in this meta-analysis in Figure 1. 10 studies included 1630 cases and 2728 controls were about GSTM1 and oral cancer in India population.10 studies included 1562 cases and 2526 controls were about GSTM1 and oral cancer in India population.5 studies included 919 cases and 1097 controls were about GSTM1 and oral cancer in Chinese population.5 studies included 619 cases and 797 controls were about GSTT1 and oral cancer in Chinese population.

Evaluation of Heterogeneity
The heterogeneity was showed in Table 2. P Heterogeneity of all groups indicated that heterogeneity could not be ignored (P Heterogeneity <0.01).The detail information was not obtained, such as smoking status, so we could not investigate the source of heterogeneity.

Publication Bias
Egger's test and Begg's test were selected to assess the publication bias of the studies in Table 2.All the results of P Egger's and P Begg's were more than 0.05.It indicated that there was no publication bias in this meta-analysis.

Discussion
Oral cancer is a serious cancer in the world.To find more effective preventions and treatments, it is important to understanding the effect of genes.Genetic polymorphisms could contribute to the etiology of oral cancer (Zheng et al., 2007;Jiang et al., 2013;Wang et al., 2013), such as GSTM1 and GSTT1.Several studies had suggested that null genotype of GSTM1 and GSTT1 was related to the susceptibility to oral cancer in China and India.However, the results were inconsistent.Considering the different incidence of oral cancer in China and India, it might be not reasonable to perform a meta-analysis by group of Asian continent.Therefore, it was convincing to perform this meta-analysis by group of China and India.
15 papers were selected in this meta-analysis, and 10 studies included 1630 cases and 2728 controls were about GSTM1 and oral cancer in India population.5 studies included 919 cases and 1097 controls were about GSTM1 and oral cancer in Chinese population.We found that there was not an increased oral cancer risk among subjects carrying GSTM1 and GSTT1 null genotype (OR=1.35,95%CI=0.68-2.68,P=0.39) and (OR=1.41,95%CI=0.72-2.77,P=0.31) in Chinese population.In India population, a significant association between GSTM1 null genotype and oral cancer was observed (OR=1.59,95%CI=1.20-2.11,P=0.001), but it was not significant in GSTT1 (OR=1.21,95% CI = 0.84 -1.74, P=0.31).The association between GSTM1 null genotype and oral cancer was diverse in China and India.
We made a hypothesis.India and China are in the same stage of social development, and have similar environmental problems, such as industrial pollution.More important, they are yellow.Therefore, we made the hypothesis that GSTM1 deletion polymorphism might be correlated with oral cancer in Chinese population.The number of research literatures limited the efficiency of inspection, and more literatures were need to confirms this hypothesis.
There are some limitations in this meta-analysis.Firstly, the role of environmental interactions is crucial, so detailed information such as smoking status is needed.Secondly, the heterogeneity is difficult to exclude.It may be decided by confounding factors, such as gender and genetic diversities.However, the information is difficult to collect completely.Thirdly, only 4 studies are included in group of Chinese population, so large number of cases and controls is needed.
In a word, GSTM1 null genotype and oral caner has a significant correlation in Indian population.However, further studies should be carried out with larger sample size to confirm the result and hypothesis.

Figure
Figure 3. Forest Plot for the Association Between GSTT1 Null Genotype and Oral Cancer in Chinese Population Figure 4. Forest Plot for the Association Between GSTM1 Null Genotype and Oral Cancer in Indian Population

Figure 5 .
Figure 5. Forest Plot for the Association between GSTT1 Null Genotype and Oral Cancer in Indian Population

Table 2 . Results of Meta-analysis
P=0.31)in Chinese population in Figure