Current Evidence on the Association between Mmp-7 (-181a>G) Polymorphism and Digestive System Cancer Risk

The matrix metalloproteinase (MMPs) can degrade various components of the extracellular matrix and its functional genetic polymorphisms may contribute to genetic susceptibility to many cancers. Up to now, the association between MMP-7 (-181A>G) and digestive system cancer risk remain inconclusive. To better understand the role of 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 in homozygote comparison (GG vs. AA, OR=1.21, 95% CI=1.12-1.60) and dominant model (GG/GA vs. AA, OR=1.16, 95% CI=1.03-1.46). In 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 of colorectal cancer and ESCC in homozygote comparison (OR=1.13, 95% CI=1.06-1.26) and heterozygote comparison (OR=1.45, 95% CI=1.11-1.91) respectively. In the stratified analysis by controls, significant effects were only observed in population-based studies (GA vs. AA, OR=1.16, 95% CI=1.081.50; 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 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=1.081.55). Our findings suggest that the MMP-7 (-181A>G) polymorphism may be a risk factor for digestive system cancer, especially among Asian population. Current Evidence on the Association between Mmp-7 (-181a>G) Polymorphism and Digestive System Cancer Risk


Introduction
The matrix metalloproteinase (MMPs) family comprise of more than 20 enzymes that are capable of degrading extracellular matrix proteins [1][2][3]. MMPs not only play important roles in physiological ECM remodelling, such as wound repair, tissue regeneration and embryo development, but are also associated with pathological conditions, such as arthritis, atherosclerosis and autoimmune blistering disorders of the skin. There is also growing evidence suggesting that MMPs can degrade various components of the extracellular matrix and are involved in cancer development by modulating cell proliferation, apoptosis, angiogenesis, and so on [1,2] MMP7, localised on chromosome 11q21-q22, is one of the smallest members of the MMPs family, which can degrade elastin, proteogylcans, fibronectin and type IV collagen . It also cleaves non-matrix substrates from the cell surface, such as E-cadherin, pro-tumour necrosis factor and Fas ligand. An A to G transition at -181 base pair 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 [24]. 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 [5,6], and this is correlated with tumor size, lymph node involvement and decreased survival. Recently, Many studies indicating that the common MMP-7 (-181A>G) genetic polymorphism was correlated with cancer risk in many cancer types [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. However, this relationship remains controversial in digestive system cancer, this meta-analysis was performed to evaluate the association between the MMP-7 (-181A>G) genetic polymorphism and digestive system cancer risk.   Figure 1 showed the flow diagram of study identification.

Search Strategy and Data Extraction
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

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 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.

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 2 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=0.576, GA vs. AA P=0.872GG+GA vs. AA p=0.675, GG vs. GA+AA P=0.721.

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 MA conducted one study indicating that individuals who living in the Kashmir Valley carrying -181 GG genotype were related to high risk of gastric cancer [9]. Besides, Ghilardi et al. observed the -181A/G polymorphism was associated with increased risk of colorectal cancer development [17]. However, Peng et al. 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 in the colorectal cancer subgroup [23].
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 hospitalbased studies and population-based studies. Controls in populationbased 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.