Association between matrix metalloproteinase 1 gene polymorphisms and the prognosis of patients with invasive cervical cancer

Abstract

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Objective: Beyond the human papillomavirus (HPV) infection, host genetic factors may confer individual susceptibility to cervical carcinogenesis, which so far largely remain unknown. Matrix metalloproteinase-1 (MMP-1) has been recognized as an important modulator during carcinogenesis. A guanine insertion (2G) polymorhism at –1607 bp of the MMP-1 gene creates an Ets-1 binding site that results in a higher transcriptional activity. The aim of this study was to investigate the role of MMP-1 polymorphisms in cervical carcinogenesis as well as the prognostic significance in patients with invasive cervical cancer. Methods: We performed MMP-1 polymorphisms analysis on 135 high grade squamous intraepithelial lesion (HSIL) and 197 invasive squamous cell carcinoma (SCC) as well as age-matched controls by capillary electrophoresis. The association of clinic pathological factors including clinical stages, regional lymph node metastasis and HPV status with MMP-1 genotypes was tested. The Kaplan-Meier plot was constructed and stratified by MMP-1 genotypes. The Log-rank test and Cox-proportional hazards model were used to test the independence of significance of MMP-1 genotypes. Results: The frequency of 2G-allele in HSIL and SCC was 64% and 65%, not different with controls (66% and 64%, respectively). The 2G-allele was associated with advanced stages (p=0.0313) whilst G allele was more common in patients with regional lymph node metastasis (p=0.0210). The median survival time in patients with heterozygous genotype G/2G was 55.3 months, significantly better than those with either G/G (median= 50.3 months) or 2G/2G genotype (median= 43.9 months) (p=0.02). No significant correlation between HPV status and MMP-1 genotypes could be identified. Conclusion: The paradox of MMP-1 polymorphisms in local invasiveness and lymphatic metastasis suggests the complicated role of MMP-1 in cervical carcinogenesis. Heterozygous advantage in the prognosis implied a conditionally protective role of MMP-1 in cervical cancer, which also shed light on the future trials of MMP inhibitors.