A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter enhances lung cancer susceptibility

Extracellular matrix-degrading matrix metalloproteinase-1 (MMP-1) is one of the interstitial collagenases likely to be involved in tumor invasion and metastasis. MMP-1 may also contribute to tumor initiation and development b y altering the cellular microenvironment that facilitates tumor formation. Recent studies have found that overexpression of MMP-1 is associated with t he initial stages of cancer development in addition to promoting cellular i nvasion; however, preexisting oncogenic mutations or chemical carcinogens a re required to initiate tumorigenesis as well. There is a single nucleotide polymorphism located in the promoter region of MMP-1 that partially regula tes gene expression. The 2G/2G genotype enhances transcriptional activity a nd may be associated with an increased lung cancer risk. Using a case-contr ol study, we tested the hypotheses that (a) individuals with the 2G/2G geno type may be at an increased risk for lung cancer; and (b) the risk should b e greatly elevated in smoking individuals. PCR-RFLP was used to determine t he MMP-1 genotypes in 456 lung-cancer cases and 451 frequency-matched contr ols of Caucasian ethnicity. Overall, there was a significant association be tween the 2G/2G genotype and lung cancer risk [odds ratio (OR), 1.76; 95% c onfidence interval (CI), 1.29-239]. In current smokers, the lung cancer ris k associated with the 2G/2G genotype was significantly elevated (OR, 3.16; 95% CI, 1.87-5.35). However, this association was less evident in former sm okers (OR, 1.23; 95% CI, 0.81-1.87) and absent in never smokers (OR, 1.09; 95% CI, 0.31-3.91). Similarly, this risk was more evident in heavy smokers (OR, 2.55; 95% CI, 1.61-4.03) than in light smokers (OR, 1.40; 95% CI, 0.84 -2.32). Interestingly, men were observed to have a 2.15-fold increased lung cancer risk (OR, 2.15; 95% CI, 1.42-3.26) compared with women (OR, 1-34; 9 5% CI, 0.84-2.15). Furthermore, subjects with 2G/2G genotype developed lung cancer earlier (60.94 +/- 0.64 years old) than patients with 1G/1G and 1G/ 2G genotypes (62.91 +/- 0.59 years old; P = 0.024). Our data demonstrate th at the 2G/2G genotype enhances lung cancer susceptibility especially in cur rent smokers. To our knowledge, these results report the first molecular ep idemiological evidence of the MMP-1 promoter polymorphism associated with t he development of lung cancer in the presence of continuing carcinogenic ex posure.