Meta-analysis of the MDM 2 T 309 G Polymorphism and Gastric Cancer Risk

Gastric cancer (GC) is one of the major cancer and the second most frequent cause of cancer in the world (Saeki et al., 2013).The five-year survival rate for Gastric cancer less than 50% (Alakus et al., 2009). As is reported, over 60% of GC cases and deaths are in developing countries, such as China (Jemal et al., 2011; Zhao et al., 2010). The reason of GC development are involved in environment, bacterial infecting, such as Helicobacter pylori which is the one of the important increased risk factors to cause GC (Zou et al., 2013). In recent years, researchers have focused on the relationship between single-nucleotide polymorphisms and GC cases (Li et al., 2011; Xu et al., 2013; Zhang et al., 2013). The fetal tumor suppress gene p53 located chromosome 17p13 is associated with important cellular events, including cell cycle regulation, DNA repair, apoptosis and senescence (Levine & Oren, 2009).The p53 occurs mutant approximately half of all human cancers (Brosh & Rotter, 2009). Mdm2 is an important negative regulator of p53 and has been involved in carcinogenesis. On the one hand, Mdm2 can reduce the expression of p53 by blocking the transcription of p53, and degrade the p53 protein by ubiquitination. On the other hand, p53 can also regulate


Introduction
Gastric cancer (GC) is one of the major cancer and the second most frequent cause of cancer in the world (Saeki et al., 2013).The five-year survival rate for Gastric cancer less than 50% (Alakus et al., 2009).As is reported, over 60% of GC cases and deaths are in developing countries, such as China (Jemal et al., 2011;Zhao et al., 2010).The reason of GC development are involved in environment, bacterial infecting, such as Helicobacter pylori which is the one of the important increased risk factors to cause GC (Zou et al., 2013).In recent years, researchers have focused on the relationship between single-nucleotide polymorphisms and GC cases (Li et al., 2011;Xu et al., 2013;Zhang et al., 2013).
The fetal tumor suppress gene p53 located chromosome 17p13 is associated with important cellular events, including cell cycle regulation, DNA repair, apoptosis and senescence (Levine & Oren, 2009).The p53 occurs mutant approximately half of all human cancers (Brosh & Rotter, 2009).Mdm2 is an important negative regulator of p53 and has been involved in carcinogenesis.On the one hand, Mdm2 can reduce the expression of p53 by blocking the transcription of p53, and degrade the p53 protein by ubiquitination.On the other hand, p53 can also regulate

Meta-analysis of the MDM2 T309G Polymorphism and Gastric Cancer Risk
Bo Song 1,2 , Zhong-Yu Duan 3 , Yun-Hua Zhong 4 , Na Lei 2 , Yu-Qing Yang 2 , Kai-Yuan Luo 1 * the synthesis of Mdm2 (Yang et al., 2012).Mdm2 T309G (rs2279744), located in the first intron of Mdm2 where is the core promoter region, affects binding inefficient of the transcription factor Sp1 resulting in the higher affinity to the G allele than to the T allele.Therefore, the transcription of Mdm2 is higher than normal Mdm2.As a consequence, the tumor suppressor function of p53 has been inhibits (Pan et al., 2013).
In the present studies, the researchers have reported the role of Mdm2 T309G polymorphism in gastric carcinoma risk.Whereas the outcome are indeterminacy.Partially because of the data is due to the relatively small size.Consequently, we carried out a meta-analysis on casecontrol studies to estimate effect of the Mdm2 T309G polymorphism on the risk of gastric risk.

Identification and eligibility of relevant studies
We searched the PubMed, Embase and Chinese biomedicine databases for all correlative articles (the last search update was June 2, 2013).The following terms were used: Mdm2, polymorphism, gastric cancer.The results were identified by a hand search of original studies.We selected the most recent articles.These studies have the following criteria: (a) evaluation of Mdm2 T309G polymorphism and gastric cancer risk, (b) a case-control design was used, and (c) have genotype frequencies for both patients and control populations.

Data Extraction
Two investigators independently extracted the data and reached consensus on all project.For each study, the following data were considered: author name, year of publication, country of study, and numbers of genotyped cases and controls.

Statistical Analysis
For control group of each study, the observed genotype frequencies of the Mdm2 T309G polymorphism were assessed for Hardy Weinberg (HWE) using the χ 2 test.The strength of association between Mdm2 gene and gastric cancer was accessed by calculating crude odds ratios (ORs) and 95% confidence intervals (CIs).The pooled ORs were performed for dominant model (GG/GT versus TT), recessive model (GG vs. GT/TT), codominant model (GG versus TT, GT versus TT).Heterogeneity assumption was evaluated by a chisquare based Q-test.A P-value of <0.05 for the Q-test indicated a lack of heterogeneity among the studies, the summary OR estimate of each study was calculated by the random effects model (DerSimonian & Laird, 1986;Mantel & Haenszel, 1959).The potential for publication bias was examined by a Begg's test (funnel plot method) and Egger's linear regression test (P<0.05considered representative of statistical significance) (Egger et al., 1997).All analyses were performed using Stata software (version 8.2; Stata Corporation, College Station, TX).

Characteristics of Studies
There were 8 published papers were searched.A total of 2651 cases and 3545 controls were included (Table 1).These studies were all in Asia, 6 of them were from China, and the rest were from Japan and Korea.The distribution of genotypes in the controls of all the studies was in agreement with Hardy-Weinberg equilibrium (Ma et al., 2013).

Main results
The results of the association between the Mdm2 T309G polymorphism and gastric cancer test were shown in Table 2. Overall, the Mdm2 T309G genotype with  GG were a higher risk than wild-type TT (OR=1.57;95%CI=1.57-2.12;p=0.003; Figure 1).Simultaneously, the GG genotype could significantly increase the risk of gastric compared with other genotypes (OR=1.52;95%CI=1.217-1.90;p<0.001).

Publication bias
Funnel plot and Egger's test were done to estimate the publication bias of literatures.The results of Egger's test provided statistical evidence for funnel plot symmetry (Figure 2)

Discussion
Gastric cancer is still a serious public health problem in the world.The incidence and mortality rates of gastric cancer have decreased, which is the second leading cause of cancer death around the world (Shibata et al., 2009).However, the mechanism of Gastric Cancer remains relative unclear.Single nucleotide polymorphisms (SNPs) can be used as a tool in investigating genetic variations and disease susceptibility.The previous study has conflicting results about the correlation between the Mdm2 T309G and the risk of gastric cancer, which is limited by the relative small size of samples.The results form Ohmiya et al. (2006) and Yang et al. (2007) showed that subjects with variant G allele in Mdm2 T309G polymorphism had increased risk of gastric cancer.In consideration of the vital function of Mdm2 in the regulation of p53, the Mdm2 T309G polymorphism increases the affinity of Sp1 for the promoter of Mdm2 and results overexpression of Mdm2.The results could be tested by cell test, which showed the cell lines with GG and TG genotypes expressed higher levels of Mdm2 than those with the TT genotypes (Bond et al., 2004).However, Cho et al. and Zhang et al. reported that there was no signification association between the Mdm2 T309G polymorphism and gastric cancer risk.
According to exist the conflict, a meta-analysis of 8 studies including 2651 cases and 3545 controls was analyzed to derive a more precise estimation of the association by relative large and latest data.Our results suggest that the Mdm2 T309G polymorphism is associated with a significantly increased risk of gastric cancer.
There are some limitations of this meta-analysis, which mainly relate to the lack of other factors, such as misclassification on disease status, diet custom.In these cases, few studies reported confirmed status by pathology or gold standard method.And there were seldom researches to investigate patients' diet custom.Secondly, our results were based on unadjusted estimates, while a precise analysis should be employed suppose that individual data were available, which would adjust by other variants, such as environment factors.
In conclusion, this meta-analysis showed that the homozygous GG geotype had increased risk of gastric cancer (OR=1.52;95%CI=1.217-1.90;p<0.001), suggests the Mdm2 T309G polymorphism may be associated with the risk of gastric cancer.Future well designed large studies might be necessary to validate this association in different populations incorporated with environmental factors in the susceptibility of gastric.

Table 2 . Meta-analysis of the MDM2 T309G Polymorphism on Gastric Cancer
a Random-effects model was used when P value for heterogeneity test, 0.05; otherwise, fix-effects model was used.b P value of Q-test for heterogeneity test