CHROMOSOME 18 TUMOR SUPPRESSOR GENES IN ORAL CANCER

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Squamous cell carcinoma (SCC) of oral cavity is a devastating and deadly disease. At present, there are few definitive indicators for predicting outcome and determining the clinical management other than tumor state and lymph node involvement. Studies over the past two decades have shown that gene defects underlie cancer development and progression, and play a critical role in defining the natural history and biological behavior of cancers. The Principal Investigator has shown that losses affecting the long arm of chromosome 18 (18q) occur in 55-60 percent of oral SCC. The preliminary data indicate that 18q loss is associated with poor prognosis and death from cancer in head and neck SCCs. Moreover, loss of heterozygosity (LOH) on 18q is associated with progression in individual patients. If the Principal Investigator can identify the basis for these findings, then genetic markers could be used in selecting high-risk patients for more aggressive therapy, and spare low risk patients from unnecessary treatment morbidity. Chromosomal regions frequently affected by LOH are thought to indicate the presence of a tumor suppressor gene (TSG) within the affected region. Three candidate TSGs have been identified on 18q; DCC (deleted in colon cancer), DPC4 (deleted in pancreatic cancer), and MADR2 (mad related gene 2). The goals of the application are: to establish the smallest region of loss on 18q in oral SCC, to test the hypothesis that one or more TSGs within the smallest region of loss on 18q is associated with tumor progression; to test the hypothesis that restoration of the affected TSG will affect tumor growth or invasive behavior; and using markers identified in Aim 1 and the tissue specimens from a large, controlled, randomized treatment trial for SCC, test the hypothesis that 18q LOH is associated with survival and/or response to therapy. From these studies, the Principal Investigator expects to further define chromosome 18q alterations as an important feature of biologically advanced disease and to develop the knowledge for designing new strategies to counter the effect of tumor suppressor gene inactivation.