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

Youdong Lin,Long Jin,Jinsheng Liu,Yun Jiang

doi:10.18632/oncotarget.22516

Youdong Lin, Long Jin + Show 2 more

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https://doi.org/10.18632/oncotarget.22516

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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.

Highlights

Gastric cancer is the third most common cause of cancer-related deaths worldwide
The results showed that single nucleotide polymorphisms (SNP) in MMP2 rs2285053, MMP3 rs679620, and MMP8 rs1940475 were associated with increased recurrence risk (Table 3)
We found an association between SNPs in MMP2, 3, and 8 with recurrence and death of gastric adenocarcinoma (GA) patients

Summary

Introduction

Gastric cancer is the third most common cause of cancer-related deaths worldwide. Surgery remains the primary treatment for this disease, and postoperative chemotherapy is a common clinical practice except in very early-stage cancers [2]. Similar to many other cancers, fluoropyrimidines and platinum compounds are currently the first-line chemotherapy drugs. The outcome of GA significantly varies even in patients with a similar stage and degree of disease, indicating that genetic and epigenetic variations may be important contributors to GA. Single nucleotide polymorphisms (SNPs) are common genetic variations that may directly cause differences in gene expression and protein function, resulting in altered disease pathogenesis and different pharmacokinetic responses to chemotherapy [3,4,5,6]

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