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 by altering the cellular microenvironment that facilitates tumor formation. Recent studies have found that overexpression of MMP-1 is associated with the initial stages of cancer development in addition to promoting cellular invasion; however, preexisting oncogenic mutations or chemical carcinogens are required to initiate tumorigenesis as well. There is a single nucleotide polymorphism located in the promoter region of MMP-1 that partially regulates gene expression. The 2G/2G genotype enhances transcriptional activity and may be associated with an increased lung cancer risk. Using a case-control study, we tested the hypotheses that (a) individuals with the 2G/2G genotype may be at an increased risk for lung cancer; and (b) the risk should be greatly elevated in smoking individuals. PCR-RFLP was used to determine the MMP-1 genotypes in 456 lung-cancer cases and 451 frequency-matched controls of Caucasian ethnicity. Overall, there was a significant association between the 2G/2G genotype and lung cancer risk [odds ratio (OR), 1.76; 95% confidence interval (CI), 1.29-2.39]. In current smokers, the lung cancer risk 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 smokers (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; 95% 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 that the 2G/2G genotype enhances lung cancer susceptibility especially in current smokers. To our knowledge, these results report the first molecular epidemiological evidence of the MMP-1 promoter polymorphism associated with the development of lung cancer in the presence of continuing carcinogenic exposure.
Zhu
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Y
Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Spitz
M R
MR
Lei
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L
Mills
G B
GB
Wu
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X
D000367:Age Factors; D016022:Case-Control Studies; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012737:Sex Factors; D012907:Smoking / Q000009:adverse effects / Q000235:genetics
D004273:DNA, Neoplasm; D020781:Matrix Metalloproteinase 1