Role of MMP-3 and MMP-9 and Their Haplotypes in Risk of Bladder Cancer in North Indian Cohort
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Matrix metalloproteinases (MMPs) play critical roles in cancer development and progression. Nonsynonymous single nucleotide polymorphisms (SNPs) in functional domain of MMP-3 and MMP-9 contribute appreciably to cancer predisposition and aggression. To test this proposition we examined whether six SNPs of the MMP-3 and MMP-9 genes are associated with risk of bladder cancer (BC) in a North Indian population.
Six SNPs of MMP-3 and MMP-9 were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in a case–control study including 200 BC patients and 200 age/gender/ethnicity-matched controls.
Increased risk for BC susceptibility was observed in MMP-3 (1171) 5A/5A [P = 0.022; odds ratio (OR), 3.46; 95% confidence interval (CI), 1.20–9.98], MMP-9 (Q279R) QQ (P = 0.048; OR, 1.92; 95%CI, 1.01–3.66), MMP-9 (P574R) PR (P < 0.001; OR, 2.62; 95%CI, 1.71–4.03) and PR + RR (P < 0.001; OR, 2.59; 95%CI, 1.72–3.91) genotypes, and in R allele (P < 0.001; OR, 2.05; 95%CI, 1.47–2.85). Furthermore, significant association between MMP-9 Q279R, P574R polymorphism and smoking was observed in BC risk. Haplotype analysis too revealed significant association with 5A-A-G of MMP-3 haplotype (P = 0.022; OR, 1.99; 95%CI, 1.11–3.60) and with R-R (P = 0.001; OR, 2.00; 95%CI, 1.35–2.97) and Q-R (P < 0.001; OR, 2.97; 95%CI, 1.65–5.37) of MMP-9 haplotype. Genotype 5A/6A of MMP-3-1171 showed borderline risk and high recurrence-free survival in Bacillus Calmette–Guérin (BCG)-treated non-muscle-invasive BC (NMIBC) patients (log-rank P = 0.025).
Our data suggested that MMP-3-1171 5A/5A and MMP-9 (Q279R) QQ, MMP-9 (P574R) PR, PR + RR, and R allele are associated with high risk of BC.
The study was funded by Department of Science and Technology, New Delhi, Govt. of India.