Genetic Polymorphisms of Matrix Metalloproteinases and Clinical Outcomes in Colorectal Cancer Patients

Background: Colorectal cancer metastasis is a multistep process involving degradation of extracellular matrix components by proteolytic enzymes. Among them, matrix metalloproteinases (MMPs) are the principal degrading enzymes and their expressions/activities are also correlated with survival. Much research has showed the associations between genetic polymorphisms in MMPs and risk of colorectal cancer; however, their prognostic significance has not been well determined. Methods: We selected and genotyped 4 cancer-associated single nucleotide polymorphisms (SNPs) in a cohort of 282 colorectal cancer patients. The associations of these SNPs with distant metastasis-free survival and overall survival were evaluated by Kaplan-Meier analysis, Cox regression model, and survival tree analysis. Results: The relative risks of developing distant metastasis after curative surgery were higher in individuals with minor homozygote AA genotype than in those with GG/GA genotypes at MMP2 rs243866 (P = 0.012). Survival tree analysis also identified a higher-order genetic interaction profile consisting of MMP2 rs243866 and MMP2 rs2285053 that was significantly associated with distant metastasis-free survival (P(trend) = 0.016). After adjusting for possible confounders, the genetic interaction profile remained significant (P(trend) = 0.050). Conclusions: These results suggest that genetic variations in the MMP2 might be potential predictors of distant metastasis-free survival after curative surgery.