Correlation Of The Matrix Metalloproteinases Polymorphisms To Non-small Cell Lung Cancer

Objective: The metrix metalloproteinases (MMPs) are the main enzymes to degrdn extracellar matrix in human body and play important roles in cancer development and aggression. Polymorphisms in the promoter regions of the MMP genes have been associated with tumor development and progression, via modifying the level of transcription and expression. This study was designed to investigate the correlation of two single nucleotide polymorphisms (SNPs), -82A/G in the promoter region of MMP-12 and -77A/G in the promoter region of MMP-13, to susceptibilities of non-small cell lung cancer (NSCLC) in north China.Methods: This hospital-based case-control study included 300 non-small cell lung cancer patients (161 with squamous carcinoma and 139 with adenocarcinoma) and 300 healthy controls. Genomic DNA was extracted by using proteinase K digestion followed by a salting out procedure. Polymorphisms of MMP-12 and MMP-13 gene were analyzed by PCR-restriction fragment length polymorphism (RFLP).Statistical analysis was performed using SPSS13.0 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 study groups using Chi-square test. Comparison of the MMP-12 and MMP-13 genotype, allelotype and haplotype distribution in NSCLC patients and healthy controls was performed by means of two-sided contingency tables using Chi-square test. The MMP-12 and MMP-13 haplotype frequencies were estimated by using EH linkage software. The odds ratio (OR) and 95% confidence Interval (CI) were calculated using an unconditional logistic regression model and adjusted by age, gender and smoking status accordingly. Results:1 The frequency of smokers in NSCLC patients (62.0%) was signifycantly higher than that in healthy controls (36.3%) (χ2=39.54, P=0.00). Smoking may increase the risk of developing NSCLC (age and gender adjusted OR=3.74, 95%CI=2.451~5.705).2. The distribution of MMP-12 -82A/G SNP in the promoter region genotypes among healthy controls did not significantly deviate from that expected by Hardy-Weinberg equilibrium (P>0.05). The allelotype and genotype distribut- ion of the MMP-12 -82A/G SNP in the overall NSCLC patients was not significantly different from that in healthy controls (P>0.05). Stratification analysis according to smoking status and histologyical type of NSCLC, MMP-12 -82A/G SNP in the promoter region showed no significant statistical influence on the risk of developing NSCLC.3. The distribution of MMP-13 -77A/G SNP in the promoter region genotypes among healthy controls did not significantly deviate from that expected by Hardy-Weinberg equilibrium (P>0.05). Frequency of the A allele in NSCLC patients was 50.33%, which was significantly higher than that in healthy controls 44.33% (χ2=4.332, P<0.05). The genotype distribution of the MMP-13 -77A/G SNP in the overall NSCLC patients was also significantly different from that in healthy controls (χ2=8.638, P=0.013). Compared with G/G genotype, the A/A genotype increased the risk of developing NSCLC (age, gender and smoking status adjusted OR=1.309, 95%CI=1.033~1.659). When stratified by smoking status of NSCLC, MMP-13 -77A/G SNP in the promoter region showed no significant statistical influence on the risk of developing NSCLC. But compared with individuals with G/G genotype, individuals with A/A genotype had a tendency of increasing the risk of developing NSCLC in smokers (age and gender adjusted OR=1.410, 95%CI= 0.992~2.003). Stratification analysis according to histological type, MMP-13 -77A/G SNP in the promoter region showed significant statistical influence on the risk of adenocarcinoma (χ2=10.668, P=0.005). And comparing with G/G genotype, the A/A genotype could increase the risk of adenocarcinoma (age, gender and smoking status adjusted OR=1.512, 95%CI=1.128~2.028). 4 The combined effect of MMP-12 -82A/G and MMP-13 -77A/G SNPs on NSCLC was analyzed by EH software. The combined analysis of the two SNPs indicated that the MMP-12A/MMP-13G haplotype was the most frequent haplotype in the population, which was 54.5%. Frequency of the MMP-12A/MMP-13A haplotype in NSCLC patients was 49.6%, which was significantly higher than that in healthy controls (43.4%), (χ2=4.315, P<0.05). Compared with the MMP-12A/MMP-13G haplotype, the MMP-12A/MMP- 13A haplotype had higher risk in developing NSCLC (OR=1.275, 95%CI= 1.014~1.603).Conclusions:1 Smoking may increase the risk of developing NSCLC.2 The allelotype and genotype distribution of the MMP-12 -82A/G SNP was not associated with the risk of NSCLC.3 The allelotype and genotype distribution of the MMP-13 -77A/G SNP in the overall NSCLC patients was significantly different from that in healthy controls. Compared with G/G genotype, the A/A genotype increased the risk of NSCLC, especially for adenocarcinoma.4 MMP-13 -77A/G SNP in the promoter region was may associated with the risk of NSCLC. Compared with individuals with G/G genotype, individuals with A/A genotype had a tendency of increasing the risk of NSCLC in smokers.5 The combined analysis of the MMP-12 promoter -82A/G SNP and MMP-13 promoter -77A/G SNP indicated that the MMP-12A/MMP-13G haplotype was the most frequent haplotype in the population. Compared with the MMP-12A/ MMP-13G haplotype, the MMP-12A/MMP-13A haplotype had higher risk in developing NSCLC.