Gastric cancers express enhanced levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Single-nucleotide polymorphisms (SNPs) in MMP and TIMP genes may be associated with disease susceptibility and might also affect their antigen expression. We studied the genotype distribution and allele frequencies of SNPs of MMP-2, -7, -8 and -9 and TIMP-1 and -2 in gastric cancer patients in relation to tumour progression, patient survival and tissue antigen expression. The genotype distribution and allele frequencies were similar in gastric cancer patients and controls, except for MMP-7_−181A>G. In addition, the genotype distribution of MMP-7_−181A>G was associated with Helicobacter pylori status (χ² 7.8, P=0.005) and tumour-related survival of the patients. Single-nucleotide polymorphism TIMP-2_303C>T correlated significantly with the WHO classification (χ² 5.9, P=0.03) and also strongly with tumour-related survival (log rank 11.74, P=0.0006). Single-nucleotide polymorphisms of MMP-2, -8, -9 and TIMP-1 were not associated with tumour-related survival. Only the gene promoter MMP-2_−1306C>T polymorphism correlated significantly with the protein level within the tumours. First-order dendrogram cluster analysis combined with Cox analysis identified the MMP-7_−181A>G and TIMP-2_303C>T polymorphism combination to have a major impact on patients survival outcome. We conclude that MMP-related SNPs, especially MMP-7_−181A>G and TIMP-2_303C>T, may be helpful in identifying gastric cancer patients with a poor clinical outcome.

Role of matrix metalloproteinase, tissue inhibitor of metalloproteinase and tumor necrosis factor-α single nucleotide gene polymorphisms in inflammatory bowel disease

In a pioneer study, we showed 10 years ago that enhanced tissue levels of the matrix metalloproteinases (MMPs) MMP-2 and MMP-9 in gastric cancers, as determined by zymography, were related with worse overall survival of the patients. To corroborate these observations, we now assessed MMP-2 and MMP-9 with new techniques in an expanded group of gastric cancer patients (n=81) and included for comparison MMP-7, MMP-8 and the tissue inhibitors of MMPs, TIMP-1 and -2. All MMPs and TIMP-1 were significantly increased in tumour tissue compared to normal gastric mucosa. Matrix metalloproteinase-7, -8 and -9, and the TIMPs showed some correlations with the clinicopathologic parameters TNM, WHO and Laurén classification, but their levels were not related with survival. Regardless of the determination method used, that is, enzyme-linked immunosorbent assay or bioactivity assay, an enhanced tumour MMP-2 level did not show a significant correlation with any of the clinicopathological parameters, but was confirmed to be an independent prognostic factor in gastric cancer.