Role of MMP-3 and MMP-9 and Their Haplotypes in Risk of Bladder Cancer in North Indian Cohort

Abstract

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.