Current Evidence on Associations Between the MMP-7 (-181 A > G ) Polymorphism and Digestive System Cancer Risk

Matrix metalloproteinases (MMPs) degrade various components of the extracellular matrix and functional polymorphisms in encoding genes may contribute to genetic susceptibility to many cancers. Up to now, associations between MMP-7 (-181A>G) and digestive system cancer risk have remained inconclusive. To better understand the role of the MMP-7 (-181A>G) genotype in digestive cancer development, we conducted this comprehensive meta-analysis encompassing 3,518 cases and 4,596 controls. Overall, the MMP-7 (-181A>G) polymorphism was associated with higher digestive system cancer risk on homozygote comparison (GG vs. AA, OR=1.21, 95% CI = 1.12-1.60) and in a dominant model (GG/GA vs. AA, OR=1.16, 95% CI =1.03-1.46). On subgroup analysis, this polymorphism was significantly linked to higher risks for gastric cancer (GG vs. AA, OR=1.22, 95% CI = 1.02- 1.46; GA vs. AA, OR=1.82, 95% CI =1.16-2.87; GG/GA vs. AA, OR=1.13, 95% CI =1.01-1.27; GG vs. GA/AA, OR= 1.25, 95% CI = 1.06-2.39. We also observed increased susceptibility to colorectal cancer and esophageal SCC in both homozygote (OR = 1.13, 95% CI = 1.06-1.26) and heterozygote comparisons (OR = 1.45, 95% CI = 1.11-1.91). In the stratified analysis by controls, significant effects were only observed in population-based studies (GA vs. AA, OR=1.16, 95% CI=1.08-1.50; GA/AA vs. GG, OR=1.10, 95% CI=1.01-1.72). According to the source of ethnicity, a significantly increased risk was found among Asian populations in the homozygote model (GG vs. AA, OR=1.40, 95% CI=1.12-1.69), heterozygote model (GA vs. AA, OR=1.26, 95% CI=1.02-1.51), and dominant model (GG/GA vs. AA, OR=1.18, 95% CI=1.08-1.55). Our findings suggest that the MMP-7 (-181A>G) polymorphism may be a risk factor for digestive system cancer, especially among Asian populations.


Introduction
The matrix metalloproteinase (MMPs) family comprise of more than 20 enzymes that are capable of degrading extracellular matrix proteins (Li et al., 2006;Singh et al.,

Current Evidence on Associations Between the MMP-7 (-181A>G) Polymorphism and Digestive System Cancer Risk
Pan Ke, Zhong-De Wu, Hua-Song Wen, Miao-Xiong Ying, Huo-Cheng Long, Liu-Guo Qing* position upstream of the transcription start site of MMP7 gene has been reported.The G allele has greater basal transcriptional activity than A allele in vitro experiment (Jormsjo et al., 2001).Over-expression of MMP7 has been shown to occur in a wide variety of cancers, including tumours of the oesophagus, stomach, colorectal, kidney and breast (Greenwald et al., 2002;Hodi et al., 2003), and this is correlated with tumor size, lymph node involvement and decreased survival.

Search strategy and data extraction
In this analysis, a literature research of the Pub Med database, ISI Web of Knowledge, Medline, Embase and Google Scholar Search (up to date as of October, 2012) were conducted using the search terms including (''MMP7'' or ''matrix metalloproteinase 7''), ''polymorphisms'' , ''cancer'', to obtain all genetic studies on the relationship of MMP-7 (-181A>G) polymorphism and cancer.We also used the combined phrases and a hand search of references of original studies on this topic.
Data extraction was carried out independently by two investigators.We record the following information of each eligible study: the first author, year of publication, country of origin, genotyping methods, source of controls, number of cases and controls with different groups.

Statistical analysis
The strength of relationship between MMP-7 (-181A>G) polymorphism and cancer was assessed by using Crude OR with 95% CI.We examined the association between the MMP-7 (-181A>G) polymorphism and digestive cancer risk using homozygote comparison (GG vs. AA), heterozygote comparison (GA vs. AA), dominant genetic model (GG + GA vs. AA) and recessive genetic model (GG vs. GA + AA).Between-study heterogeneity was evaluated by Q-test.Fixed effects model was used to pool the data when the P-value of Q-test ≥ 0.05, otherwise, random-effects model was selected.Egger's test was used to assess the publication bias.(P<0.10 was considered representative of statistical significance).All statistical analyses were performed using STATA11.0 software and Review Manage (v.5;Oxford,England).

Eligible studies
The main characteristics of these studies are shown in Table 1.Genotype distribution of the MMP-7 (-181A>G) polymorphism among cancer cases and controls of the 16 studies are shown in Table 2.The genotyping method contains the classic polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, DNA sequencing, Affymetrix and Taqman.Among all the studies, seven colorectal cancer studies, six gastric cancer studies, two esophageal squamous cell carcinoma studies, one oral carcinoma and one hepatocellular carcinoma

Publication bias
Both Begg's funnel plot and Egger's test were performed to assess the publication bias of the literature.The shape of the funnel plots did not reveal any evidence of obvious asymmetry in the overall meta-analysis (Figure 1 shows the funnel plot of overall GG vs. AA).Then Egger's test was performed to assess the publication bias of the literature.The results did not present any obvious evidence of publication bias in the subgroup analyses: for GG vs. AA P=0.58, GA vs. AA P=0.87, GG+GA vs. AA p=0.68,GG vs. GA+AA P=0.72.

Discussion
The result of this meta-analysis involving 3,518 cases and 4,596 controls suggested that the MMP-7 -181A/G polymorphism was overall significantly associated with digestive system cancer risk, especially in Asian population.
Recently, Malik et al. (2011) conducted one study indicating that individuals who living in the Kashmir Valley carrying -181 GG genotype were related to high risk of gastric cancer.Besides, Ghilardi et al. (2003) observed the -181A/G polymorphism was associated with increased risk of colorectal cancer development.However, Peng et al. ( 2010) performed a meta-analysis and suggested the association between MMP7 -181 A>G and increased cancer risk was found in the gastric cancer subgroup, no significant difference was found for colorectal cancer.
In this meta-analysis, significant association was found between the MMP7 -181 A>G polymorphism and risk of gastric cancer.Besides, the association was more significant in the recessive model compared with the dominant model.Functional analysis in vitro has shown that nuclear proteins bind with higher affinity to the -181 G allele than to the -181 A allele and promoter activity variation of the -181G allele was about 2-3 times than that of the -181 A allele, which may induce elevation of the protein expression, so individuals with GG genotype could have a higher risk of the gastric cancer than with GA genotype.For ESCC and colorectal cancer, the significant associations were just found in the dominant model and homozygote model respectively.We also found Asians with GG genotype had higher risk of cancer compared to Caucasians.Several factors such as environmental factors and different genetic backgrounds might contribute to the difference.Furthermore, inconsistent results were observed between hospital-based studies and populationbased studies.Controls in population-based studies were more representative of general population than controls from hospital-based studies.
As in all research, our study has limitations.First, the controls were not uniformly defined.Second, studies involved in different ethnicities are warranted to estimate the effects of this functional polymorphism on digestive system cancer risk.Third, due to the original data of the eligible studies are not available.It is difficult to evaluate the roles of diet, alcohol consumption, and smoking status in digestive cancer development.
In conclusion, our meta-analysis suggested that the MMP7 -181 A>G polymorphism may be a risk factor in digestive system cancer development, especially among Asian population.Large well-designed studies are needed to validate our findings in the future.

Figure 1 .
Figure 1.Beggs Funnel Plot with 95% Confidence Limits were included.Twelve studies were Asian descent, four studies were Caucasian descent and one study was South America descent.Hospital based controls were carried out in 5 studies, while population based controls were carried out in twelve studies.