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

Y. Zhu, M. R. Spitz, L. Lei, Gordon Mills, X. Wu

Research output: Contribution to journalArticle

211 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7825-7829
Number of pages5
JournalCancer Research
Volume61
Issue number21
StatePublished - Nov 1 2001
Externally publishedYes

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Matrix Metalloproteinase 1
Single Nucleotide Polymorphism
Lung Neoplasms
Odds Ratio
Genotype
Confidence Intervals
Neoplasms
Cellular Microenvironment
Genetic Promoter Regions
Restriction Fragment Length Polymorphisms
Carcinogens
Extracellular Matrix
Case-Control Studies
Carcinogenesis
Smoking
Neoplasm Metastasis
Gene Expression
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter enhances lung cancer susceptibility. / Zhu, Y.; Spitz, M. R.; Lei, L.; Mills, Gordon; Wu, X.

In: Cancer Research, Vol. 61, No. 21, 01.11.2001, p. 7825-7829.

Research output: Contribution to journalArticle

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abstract = "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.",
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