Matrix metalloproteinase polymorphisms and bladder cancer risk

Matrix metalloproteinases (MMP) contribute to tumor microenvironment and are associated with bladder cancer. A study examining the association between MMP polymorphisms and bladder cancer risk has never been published. We analyzed the association of 11 single nucleotide polymorphisms (SNPs) and one microsatellite polymorphism in MMP genes MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, and MMP-12 with bladder cancer risk in 560 Caucasian patients and 560 controls matched on age, gender, and ethnicity. Individual, combination, haplotype, and diplotype analyses were done. No associations between individual MMP polymorphisms and overall bladder cancer risk were seen. The MMP-9 microsatellite ≥24 CA repeat allele and the MMP-12-82 GG polymorphisms were associated with invasive bladder cancer risk [odds ratio (OR), 2.60; 95% confidence interval (95% CI), 1.07-6.26; and OR, 4.59; 95% CI, 1.21-17.32, respectively]. Smoke-stratified analyses revealed several associations between MMP polymorphisms, alone and in combination, with bladder cancer risk, particularly in light smokers. Linkage disequilibrium was seen in all of the MMP-1, MMP-3, MMP-8, and MMP-12 SNPs and in four of five MMP-9 polymorphisms tested. Several MMP-9 haplotype and diplotypes were associated with overall and invasive bladder cancer risk. Our study suggests that genetic variations in the MMP family are associated with bladder cancer risk. Heavy carcinogen exposure may overwhelm some of the genetic effects of MMP polymorphisms. Our study confirms the importance of taking a multigenic pathway-based approach to risk assessment.