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Matrix Metalloproteinase 1 (MMP1) Is Associated with Early-Onset Lung Cancer

¹ Institute of Epidemiology, GSF-National Research Center for Environment and Health, Neuherberg, Germany; ² Department of Genetic Epidemiology, Georg-August University of Göttingen, Medical School, Göttingen, Germany; ³ Division of Clinical Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany; ⁴ Division of Toxicology and Cancer Risk Factors, German Cancer Research Centre (DKFZ), Heidelberg, Germany; ⁵ Institute of Human Genetics, University of the Saarland, Saarbrücken, Germany; ⁶ Institute of Internal Medicine V, Medical School, University of the Saarland, Saarbrücken, Germany; ⁷ Division of Genetic Epidemiology, Department of Medical Genetics, Molecular, and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria; ⁸ Thoraxklinik, Heidelberg, Germany; ⁹ Department of Medical Informatics, Biometrics, and Epidemiology (IBE), University of Munich, Munich, Germany

Requests for reprints: Wiebke Sauter, Institute of Epidemiology, GSF-National Research Center for Environment and Health, D-85764 Neuherberg, Germany. Phone: 49-89-3187-3527; Fax: 49-89-3187-4567. E-mail: wiebke.sauter{at}gsf.de

Matrix metalloproteinases (MMP) play a key role in the breakdown of extracellular matrix and in inflammatory processes. MMP1 is the most highly expressed interstitial collagenase degrading fibrillar collagens. Overexpression of MMP1 has been shown in tumor tissues and has been suggested to be associated with tumor invasion and metastasis. Nine haplotype tagging and additional two intronic single nucleotide polymorphisms (SNP) of MMP1 were genotyped in a case control sample, consisting of 635 lung cancer cases with onset of disease below 51 years of age and 1,300 age- and sex-matched cancer-free controls. Two regions of linkage disequilibrium (LD) of MMP1 could be observed: a region of low LD comprising the 5' region including the promoter and a region of high LD starting from exon 1 to the end of the gene and including the 3' flanking region. Several SNPs were identified to be individually significantly associated with risk of early-onset lung cancer. The most significant effect was seen for rs1938901 (P = 0.0089), rs193008 (P = 0.0108), and rs996999 (P = 0.0459). For rs996999, significance vanished after correction for multiple testing. For each of these SNPs, the major allele was associated with an increase in risk with an odds ratio between 1.2 and 1.3 (95% confidence interval, 1.0-1.5). The haplotype analysis supported these findings, especially for subgroups with high smoking intensity. In summary, we identified MMP1 to be associated with an increased risk for lung cancer, which was modified by smoking. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1127–35)