Matrix metalloproteinase-2 (MMP-2) has been shown to play an importantrole in multiple ways to all stages of cancer initiation and development.We have reported previously a strong association between a functional single nucleotide polymorphism (-1306C/T) in the MMP2 promoter and risk of lung cancer (C. Yu et al., Cancer Res., 62: 6430-6433, 2002). This case control study was to assess the contribution of this MMP2 polymorphism to risk of development and metastasis of gastric cardia adenocarcinoma (GCA). MMP2 genotypes were determined by PCR-based denaturing high-performance liquid chromatography analysis and direct DNA sequencing in 356 patients with GCA and 789 frequency-matched controls in an ethnic Chinese population. We found that subjects with the CC genotype had >3-fold increased risk [adjusted odds ratio 3.36, 95% confidence interval 2.34-4.97] for developing GCA compared with those with the variant CT or TT genotype. Furthermore, the increased risk was found to be more pronounced in smokers and younger subjects. However, no significant association was demonstrated between the MMP2 polymorphism and risk of metastasis of the cancer at the time of diagnosis, with the odds ratio being 0.90 (95% confidence interval 0.36-2.20) for the CC genotype. These findings are consistent with our initial observation for lung cancer and further support the hypothesis that MMP2 genotype may influence individual susceptibility to the development of certain cancer.