Dissertation
Dissertation > Medicine, health > Oncology > Gastrointestinal Cancer

Correlation of MMP-2 and TIMP-2 Polymorphism to Gastric Cardiac Adenocarcinoma and Esophageal Squamous Cell Carcinoma

Author SunDongLan
Tutor LiZuo
School Hebei Medical University
Course Oncology
Keywords ESCC GCA MMP-2 TIMP-2 polymorphism hereditary susceptibility
CLC R735
Type Master's thesis
Year 2009
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Objective: The metrix metalloproteinases (MMPs) are a family of highly conserved zinc-dependent proteolytic enzymes and play important roles in cancer development and aggression. MMP-2, of several members in the MMP family, is especially interesting because of its universal expression and multiple functions. The activities of MMPs are regulated by tissue inhibitor of metalloproteinases (TIMPs). The imbalance in the expression of MMPs and TIMPs plays important role in cancer development and aggression. With the molecularbiological development, studies have found that some single nucleotide polymorphism (SNP) located in the promoter of MMP-2 and TIMP-2 genes. They may influence the transcription of the gene and expression of protein and relate to occurrence and development of some tumor. This study was designed to investigate the correlation of SNPs, -1306C/T in the promoter region of MMP-2 and -418G/C in the promoter region of TIMP-2, to susceptibilities of esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA) in a population of high incidence region of Hebei Province.Methods: This population-based of high incidence region case-control study included 592 cancer patients (335 with ESCC and 257 with GCA) and 624 healthy controls. Genomic DNA was extracted by using proteinase K digestion followed by a salting out procedure. Polymorphisms of MMP-2 and TIMP-2 gene were analyzed by PCR-restriction fragment length polymorphism analysis (RFLP).Statistical analysis was performed using SPSS11.5 software package. P<0.05 was considered significant for all statistical analyses. Hardy-Weinberg analysis was performed by comparing the observed and expected genotype frequencies in the control group using Chi-square test. Comparison of the MMP-2 and TIMP-2 genotype, allelotype and haplotype distribution in cancer patients and healthy controls was performed by means of two-sided contingency tables using Chi-square test. The odds ratio (OR) and 95% confidence interval (CI) were calculated using an unconditional logistic regression model and adjusted by age, gender, smoking status and family history of upper gastrointestinal cancer (UGIC) accordingly.Results:1 The frequency of positive family history of upper gastrointestinal cancer (UGIC) in ESCC (48.4%) and GCA (48.2%) patients was significantly higher than that in healthy controls (35.4%) (χ~2=15.22 and 12.58, P=0.00). Family history of UGIC may increase the risk of developing ESCC and GCA (age, gender and smoking status adjusted OR=1.71 and 1.70, 95%CI=1.30~2.24 and 1.27~2.28, respectively).2 The significant differences in allelotype and genotype distributions of MMP-2 -1306C/T SNP were observed between patients with ESCC and controls (P=0.02 and 0.01, respectively). However, no significant differences were observed between GCA and control. Compared with the C/T+T/T genotypes, the C/C genotype could significantly modify the risk of developing ESCC , but could not significantly modify the risk of developing GCA (age, gender, smoking status and family history of UGIC adjusted OR=1.57, 95%CI=1.10~2.23 and OR=1.17, 95%CI=0.81~ 1.67, respectively). Furthermore, when stratified for smoking status and family history of UGIC, the C/C genotype could significantly modify the risk of developing ESCC in the smoker or family history of UGIC groups (adjust OR=1.96, 95%CI=1.10~2.23 and OR=2.06, 95%CI=1.19~3.55, respectively). And MMP-2 -1306C/T SNP in the promoter region showed no significant statistical influence on the risk of developing GCA.3 The allelotype and genotype distribution of the TIMP-2 -418G/C SNP in the overall GCA patients was not significantly different from that in healthy controls (P>0.05). Compared with the G/C+C/C genotypes, the G/G genotype could not significantly modify the risk of developing GCA (age, gender, smoking status and family history of UGIC adjusted OR=1.17, 95%CI=0.85~1.68). Furthermore, when stratified for smoking status and family history of UGIC, the TIMP-2 -418G/C SNP showed no significant statistical influence on the risk of developing GCA.4 The combined effect of MMP-2 -1306C/T and TIMP-2 -418G/C genotypes showed that the -1306C/C﹡-418G/G was the most frequent combined genotypes in the population, which was 54.3% in controls. Compared with the -1306C/T+T/T﹡ -418G/C+C/C genotypes, the other combined genotypes could not modify the risk of developing GCA.Conclusions:1 Family history of UGIC increases the risk of developing ESCC and GCA.2 The MMP-2 promoter -1306C/T SNP was associated with risk of ESCC. Compared with the C/T+T/T genotypes, the C/C genotype could significantly modify the risk of developing ESCC, especially in individuals in smoker group and in the group with positive family history of UGIC.3 The MMP-2 promoter -1306C/T SNP was not associated with risk of GCA. When stratified by smoking status and family history of UGIC, MMP-2 -1306C/T SNP in the promoter region had no significant influence on the risk of GCA.4 The TIMP-2 promoter -418G/C SNP was not associated with risk of GCA. When stratified by smoking status and family history of UGIC, TIMP-2 -418G/C SNP in the promoter region had no significant influence on the risk of GCA.5 The combined effect of MMP-2 -1306C/T and TIMP-2 -418G/C genotypes showed that could not modify the risk of developing GCA.

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