Carcinogenesis Advance Access originally published online on February 24, 2005
Carcinogenesis 2005 26(6):1117-1121; doi:10.1093/carcin/bgi057
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Carcinogenesis vol.26 no.6 © Oxford University Press 2005; all rights reserved.
Functional haplotypes in the promoter of matrix metalloproteinase-2 and lung cancer susceptibility
1 Departments of Etiology and Carcinogenesis and 2 Department of Thoracic Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
3 Current address: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
* To whom correspondence should be addressed. Tel: +86 10 87788491; Fax: 86 10 67722460; Email: dlin{at}public.bta.net.cn
Matrix metalloproteinase-2 (MMP-2) plays important roles in cancer initiation and progression. Our previous studies revealed that the –1306C
T and –735CT polymorphisms in MMP2 promoter significantly influence transcriptional activity and their genotypes and haplotypes are associated with susceptibility to several cancers. This case–control study examined the contribution of these two polymorphisms to the risk of developing lung cancer. MMP2 genotypes and haplotypes were determined in 770 cases and 777 controls and the associations with risk of lung cancer were estimated by logistic regression. We observed a 2-fold [odds ratio (OR), 2.12; 95% confidence interval (CI), 1.64–2.72] or 1.6-fold (OR, 1.57; 95% CI, 1.27–1.95) excess risk of developing lung cancer for the –1306CC or –735CC genotype carriers compared with non-carriers, respectively. A greater risk of lung cancer was associated with the C–1306–C–735 haplotype (OR, 5.01; 95% CI, 2.57–9.78) compared with the T–1306–T–735 haplotype, suggesting a synergic effect of these two polymorphisms. Furthermore, a greater than additive joint effect of the polymorphisms and smoking increased an even higher risk of lung cancer. The OR for smokers with the C–1306–C–735 haplotype was 6.24 (95% CI, 4.51–8.64), which was significantly higher than that (OR, 4.10; 95% CI, 2.89–5.81) of smokers with the T–1306 or T–735-containing haplotypes (P < 0.001). These results are consistent with our previous findings and further support the hypothesis that gain-of-function of MMP2 resulting from genetic polymorphisms plays an important role in human carcinogenesis.
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