Abstract:
Objectives: Inflammation is a hallmark of HPV-mediated cervical cancer; Matrix metalloproteinase [MMP]-2 and tissue inhibitor of metalloproteinase [TIMP]-2 are emerging as pivotal players in inflammation and carcinogenesis. My study aimed to evaluate the role of MMP-2 (-735C>T) [rs2285053] and TIMP-2 (-418G>C) [rs8179090] gene polymorphisms in HPV-mediated cervical cancer susceptibility in North Indian women.
Methods: Hospital-based case-control epidemiology study in Lucknow, Uttar Pradesh, India; power-analysis sample size was calculated by Quanto-software (version1.0) (http://hydra.usc.edu/gxe) with input of variables: significance-level (α)<0.05 (2-sided), model-of-inheritance:log additive, allele frequency lowest in controls, genetic effect for Odds Ratio (OR)≥1.65 yielding >80% statistical power: N=400 study subjects viz. 200 histopathologically confirmed cervical cancer cases and 200 healthy controls: age-matched and similar ethnicity i.e. North Indian. Genomic DNA extraction from peripheral blood samples collected from study-subjects was carried out using salting-out method. MMP-2 and TIMP-2 genotyping was performed using polymerase chain reaction-based restriction fragment length polymorphism. χ2 goodness-of-fit test was used for any deviation from Hardy-Weinberg equilibrium in controls; chi-square analysis was utilized to determine differences in genotype and allele frequencies. Binary logistic regression was applied to estimate age-adjusted Odds Ratio (OR) with Bonferroni’s correction for multiple comparisons.
Results and Conclusions: My findings demonstrated no significant association between MMP-2(-735C>T) and TIMP-2 (-418G>C) gene polymorphisms and risk of developing cervical cancer in the study-population. Interestingly, stratified-analysis using a case-only approach revealed no effect of MMP-2/TIMP-2 polymorphisms on early (FIGO I, II) and advanced stages (FIGO III, IV) of cervical cancer; MMP-2 and TIMP-2 polymorphisms did not modulate risk in cervical cancer patients who smoked tobacco/cigarettes. Overall, my innovative study demonstrated lack of association between MMP-2 and TIMP-2 gene polymorphisms and cervical cancer susceptibility in women of North Indian ethnicity; HPV-genotyping suggested that higher the viral load in terms of test cut-off value, higher was susceptibility to develop cervical cancer. Therefore, understanding the ecological diversity of HPV prevalence and genotype distribution among genetically susceptible populations in different geographical regions worldwide is essential for optimizing HPV screening, vaccination and maximizing cost-effective public health-oriented strategic efforts for pragmatic evidence-based cervical cancer prevention. Further, bio-specimens viz. HPV-mediated cervical cancer patients’ blood, tissue, DNA, and oocytes may be collected and frozen/stored for long-term usage in individualized pregnancy/family-planning post-cancer chemo-radiotherapy treatment and/or conducting multi-centric public health-gynecologic oncology causal association prevention-epidemiology studies in fertility preservation amongst cervical cancer patients/susceptible women of varying genetic landscapes and socio-cultural exposures.
