Polymorphisms in matrix metalloproteinases 2, 3, and 8 increase recurrence and mortality risk by regulating enzyme activity in gastric adenocarcinoma

Abstract

The association of polymorphisms in matrix metalloproteinases (MMPs) with clinical outcomes of gastric adenocarcinoma has not been examined. Ten polymorphisms in MMP1, 2, 3, 7, 8, 9, 12, and 13 were genotyped and investigated, and patients were followed for an average of 58 months. The activities of MMP2, 3, and 8 were measured. Recurrence risk increased in patients with the MMP2 rs2285053 CC genotype (hazard ratio [HR], 1.85), MMP3 rs679620 AA genotype (HR, 2.15), and MMP8 rs1940475 TT genotype (HR, 2.22) on recurrence free survival (RFS). Co-presence of the unfavorable MMP2 rs2285053 CC and MMP8 rs1940475 TT genotypes resulted in an additional increased risk of recurrence (RFS: HR, 4.42; 95% confidence interval [CI], 2.15–9.09; p<0.0001) and risk of death (overall survival ( OS) : HR, 6.59; 95% CI, 3.15–13.19; p<0.0001). Theoretical survival tree analysis revealed that recurrence-free survival significantly varied from 15.5 to 87 months among patients with different polymorphisms in MMP2, 3, and 8. The enzymatic activities of MMP2 and MMP3 increased (MMP2 rs2285053 CC: 888.60 vs. CT: 392.00, p <0.0001; MMP3 rs679620 AA: 131.10 vs. GG: 107.74, p=0.015), whereas those of MMP8 decreased (MMP8 rs1940475 TT: 133.78 vs. CC: 147.54, p=0.011) in gastric cancer tissues. These results suggest that polymorphisms in MMP2, 3, and 8 may increase cancer recurrence and patient death by increasing or decreasing enzyme activity in patients with gastric adenocarcinoma.