Carcinogenesis Advance Access published online on March 25, 2009
Carcinogenesis, doi:10.1093/carcin/bgp065
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Matrix Metalloproteinase 1, 3, and 12 Polymorphisms and Esophageal Adenocarcinoma Risk and Prognosis
1 Princess Margaret Hospital and University of Toronto, ON
2 Harvard School of Public Health, Boston, MA
3 Dana-Farber Cancer Institute, Boston, MA
4 Massachusetts General Hospital, Boston, MA
5 Toronto Sunnybrook Regional Cancer Centre, Toronto, ON
6 Applied Molecular Oncology, Medical Biophysics, Ontario Cancer Institute, Toronto, ON
Corresponding Author: Dr. Geoffrey Liu, Princess Margaret Hospital/Ontario Cancer Institute, 610 University Avenue, Suite 7-124, Toronto, Ontario, M5G 2M9; T:416-946-4501 ext 3428 F: 416-946-6546, Geoffrey.Liu{at}uhn.on.ca
The matrix metalloproteinase (MMP) family degrade extracellular matrix, and mediate pathways including apoptosis, angiogenesis and immunity. We studied the association between four MMP polymorphisms within three MMP genes and esophageal adenocarcinoma (EA) risk and prognosis. 313 EA cases and 455 age and gender frequency matched controls were genotyped for MMP1 1G/2G, MMP3 6A/5A, MMP12 -82A/G and MMP12 1082A/G. The association between individual MMP polymorphisms and EA risk was evaluated using regression models and adjusted for age, gender, adult body mass index (BMI), and smoking status. Haplotype analysis was performed to investigate the combined effect of all four linked MMP polymorphisms and EA risk. The MMP1 and MMP3 polymorphisms were associated with increased EA risk: MMP1 1G/2G and 2G/2G had adjusted odds ratios (AOR) of 1.46 (95% confidence interval (CI) 1.0-2.1; p=0.04) and AOR 1.83 (1.2-2.8; p=0.005) respectively, while MMP3 6A/5A had AOR 1.40 (95% CI 1.0-2.1; p=0.09) and MMP3 5A/5A had 1.61 (95% CI 1.0-2.5; p=0.03). Two MMP haplotypes (MMP1-MMP3-MMP12(–82) 2G-5A-A (AOR 1.36, 95% CI 1.0-1.8; p=0.03) and 2G-5A-G (AOR 1.70, 95% CI 1.1-2.6; p=0.01) were also associated with increased EA risk. The relationship between BE cases with the same set of controls was similar. No association was identified between the MMP polymorphisms and overall survival or progression free survival of patients with EA. MMP1, MMP3 and possibly MMP12 –82A/G polymorphisms and their haplotypes are associated with increased EA risk.
Key Words: Polymorphism • matrix metalloproteinase • esophageal adenocarcinoma • risk analysis
Received August 20, 2008; revised February 17, 2009; accepted March 20, 2009.