1. Department of Colorectal Surgery, China Medical University Hospital, Taichung, Taiwan
2. Division of Colorectal Surgery, Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
3. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
4. Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan
5. Department of Pharmacy, Yangming Branch, Taipei City Hospital, Taipei, Taiwan
6. Department of Chinese Medicine Resources, China Medical University, Taichung, Taiwan
7. Department of Occupational Safety and Health, China Medical University, Taichung, Taiwan
8. Department of Pharmacy, China Medical University, Taichung, Taiwan
9. Sex Hormone Research Center, China Medical University Hospital, Taichung, Taiwan
* Wen-Chien Ting, Lu-Min Chen, and Jiunn-Bey Pao contributed equally to this work.
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 (Ptrend = 0.016). After adjusting for possible confounders, the genetic interaction profile remained significant (Ptrend = 0.050).
Conclusions: These results suggest that genetic variations in the MMP2 might be potential predictors of distant metastasis-free survival after curative surgery.
Keywords: colorectal cancer, matrix metalloproteinases, single nucleotide polymorphism, metastasis, survival.