Functional -1562 C-to-T polymorphism in matrix metalloproteinase-9 (MMP-9) promoter is associated with the risk for oral squamous cell carcinoma in younger male areca users

Background: Circulating matrix metalloproteinase-9 (MMP-9) is a prognostic factor for gastric cancer and vascular diseases, and has been associated with head and neck cancers. The -1562 C-to-T polymorphism in MMP-9 promoter (abbreviated MMP-9-1562 C>T polymorphism) leads to differential transcription, and is associated with increased susceptibility to neoplastic and vascular diseases. Thus, our aim was to determine whether a functional MMP-9 polymorphism might also influence the risk or affect the progression of areca-associated oral cancers. Methods: Genomic DNAs were obtained from peripheral blood cells of male subjects with areca-associated oral squamous cell carcinoma (OSCC) (n = 192), oral submucosal fibrosis (OSF) (n = 73), and non-diseased areca users (n = 191). The PCR-based restriction fragment length polymorphism analysis was performed for MMP-9 genotyping. Results: MMP-9-1562 C>T polymorphism was not associated with the risk of OSCC or OSF. However, when subjects were stratified by the median age, an association with the risk of OSCC was found in younger patients (P = 0.029). The T allele frequency was significantly higher in the subset of older patients with buccal mucosa OSCC than older patients with OSCC in counterpart locations. The joint MMP-9-1562 C>T and MMP-3-1171 5A>6A functional polymorphisms were not associated with OSCC risk or patient survival. Conclusion: Aberrant MMP-9 expression is closely related to tumor invasiveness and the prognosis of head and neck cancers. However, functional MMP-9-1562 C>T polymorphism is associated with OSCC risk only in younger areca chewers. The impact of aging or areca-related effect on this functional polymorphism should be elucidated.