Cumulative evidence for associations between matrix metalloproteinase-1, -3 and -8 variants and cancer risk

Matrix metalloproteinase (MMP) gene polymorphisms have been implicated in cancer susceptibility; however, the results from previous studies have been inconsistent across populations and tumor types. The present study aimed to systematically evaluate the associations between MMP-1, MMP-3 and MMP-8 polymorphisms and cancer risk through a comprehensive meta-analysis. A total of 36,368 cancer cases and 40,246 controls from eligible studies were included. Pooled odds ratios and 95% confidence intervals were calculated to assess the associations between selected MMP polymorphisms and cancer risk. Venice criteria and false-positive report probability were applied to evaluate the cumulative evidence. Subgroup analyses according to ethnicity, genetic model and cancer type were conducted. Functional annotation was also integrated to explore potential biological mechanisms. In total, three polymorphisms (MMP-3 rs35068180, MMP-3 rs3025058 and MMP-1 rs1799750) were found to be significantly associated with the risk of seven types of cancer. Of these, strong evidence was assigned to two single nucleotide polymorphisms for three cancer risks (four associations), including MMP-3 rs3025058 with esophageal cancer in all populations under the dominant model, MMP-1 rs1799750 with glioblastoma in all populations under the recessive model and MMP-1 rs1799750 with renal cancer in all populations under both the recessive and allelic models. A total of six associations showed moderate evidence, while 14 were classified as weak. Notably, the effect sizes and statistical significance varied by ethnicity, genetic model and cancer type, suggesting context-dependent and population-specific effects. Functional annotation indicated that key variants may affect gene expression and tumor biology via regulation of promoter or enhancer activity. No significant association was observed between MMP-8 polymorphisms and cancer risk. The findings provide new insights into the complexity of gene-environment interactions underlying cancer susceptibility. This comprehensive meta-analysis highlights the complex, context-dependent associations of MMP-1, MMP-3 and MMP-8 polymorphisms with cancer risk. The results of the present study underscore the need for large, multi-ethnic studies and integrated genomic, functional and environmental analyses to clarify the roles of MMP variants in cancer development and to identify high-risk populations for precision prevention.