Functional Polymorphisms in the Promoter Regions of Matrix Metalloproteinase-2,-3,-7,-9 and TNF-alpha Genes, and the Risk of Colorectal Neoplasm in Japanese

Colorectal carcinogenesis involves environmental factors and genetic predispositions. Recent studies have suggested the associations between colorectal neoplasm and functional polymorphism of matrix metalloproteinases (MMPs) and cytokine genes. In this study, we analyzed polymorphisms of MMPs and tumor necrosis factor (TNF)-alpha genes, focusing on the susceptibility to colorectal neoplasm and the tumor progression. The subjects were 186 patients (95 men and 91 women) who underwent total colonoscopy, and were classified into cancer, adenoma and non-neoplasm (control) groups of 47, 72 and 67 patients, respectively. The polymorphisms at the MMP-2-1306C/T, MMP-3-1171 5A/6A, MMP-7-181A/G, MMP-9-1562C/T and TNF-alpha-308G/A loci were analyzed. Regarding background factors, significant differences were found in the age, sex ratio and alcohol-drinking and cigarette-smoking histories in the adenoma and cancer groups, compared to those in the control group. On these factors-adjusted logistic regression analysis of polymorphisms and disease susceptibility, no significant difference was noted in the frequency of any polymorphism in the adenoma and cancer groups, compared to those in the control group. The analysis of the involvement of polymorphisms in tumor progression in the adenoma and cancer groups revealed that the odds ratio for the MMP-3 5A allele was significantly higher in the cancer group (2.74; 95% confidence interval = 1.11-6.74, P = 0.02). The polymorphisms of MMP genes and TNF-alpha genes were not associated with the susceptibility to colorectal neoplasm, but the involvement of the MMP-3 5A allele in the progression of adenoma to cancer was suggested.