Haplotypes in matrix metalloproteinase gene cluster on chromosome 11q22 contribute to the risk of lung cancer development and progression

Purpose: Matrix metalloproteinases (MMP) play important roles in cancer development and single nucleotide polymorphisms (SNP) in some MMP genes were shown to confer susceptibility to certain cancers. This study examined the association between genotypes and haplotypes in the MMP1-MMP3-MMP12 gene cluster and risk of lung cancer development and metastasis. Experimental Design: A two-stage investigation was conducted. First, 35 SNPs covering these genes were selected and validated in 190 patients and 190 controls. Twenty-two validated SNPs were then analyzed in an entire case-control panel consisting of 711 patients and 716 controls. Associations with the risk of lung cancer were estimated by logistic regression. Results: The investigated MMP gene region could be partitioned into two major haplotype blocks. One common haplotype in the block composed of major part of MMP1 transcription region was significantly associated with increased risk for the development [odds ratio (OR), 1.35; 95% confidence interval (95% CI), 1.11-1.63; P = 0.01; permutated P = 0.134] and distant metastasis of lung cancer (ORs for stage IV versus stages I-III,1.67; 95% Cl, 1.12-2.50; P = 0.009; permutated P = 0.048) and the other showed a protective effect against metastasis (ORs for stage IV versus stages I-III, 0.22; 95% CI, 0.07-0.62; P = 0.001; permutated P = 0.011). Another common haplotype in the block across MMP3 was significantly associated with decreased risk for developing lung cancer (OR, 0.71; 95% CI, 0.59-0.86; P = 0.003; permutated P = 0.027). Conclusions: The observed multiple cancer-associated genetic variants suggested that the MMP1-MMP3-MMP12 gene cluster plays important roles in lung cancer development and progression.