This proposal is built upon the epidemiologic and molecular genetic findings from our 20-year experience intranslational research in oral premalignant lesions (OPLs), a hallmark of oral cancer development. Althoughthe etiology of OPLs is not fully understood, these lesions are often associated with tobacco and alcoholexposures; however, it is unclear why only a fraction of exposed individuals with OPL subsequently developoral cancer. We have previously shown that OPL patients with certain genetic backgrounds are moresusceptible to developing oral cancer, and that certain molecular abnormalities that present in OPL targettissues predict a higher rate of malignant transformation of these lesions, independent of clinicopathologicparameters. These predictive markers include OPL histology and the combined biomarker scores ofchromosomal polysomy, p53 protein expression, and loss of heterozygosity (LOH) at 3p and 9p in OPLtissues. We have demonstrated a successful strategy for comprehensive cancer risk assessment in OPLpatients by combining conventional medical/demographic variables and a panel of biomarkers; however, allof these studies have utilized small sample sizes. We propose to extend our studies by utilizing the largestavailable resource of OPL specimens that allows us the unprecedented opportunity to study 350 patientswith OPLs, prospectively followed, to parallel our investigation of genetic markers in surrogate and targettissues, critical molecular candidates, and global genetic aberrations and expression profiles to identifypredictors of oral cancer risk in these patients. Using this unique resource, we will integrate clinical,epidemiologic, and genetic data to build a quantitative risk assessment model for oral cancer development.
Our Specific Aims i nclude: 1) Assess susceptibility markers in surrogate tissue (lymphocytes); 2) Assessglobal genomic and transcriptomic abnormalities as well as critical candidate molecules in OPL targettissues; and 3) Complete comprehensive analyses of data from clinical, epidemiologic, surrogate-targettissue, genotype-phenotype, global-candidate biomarker panels with patients' clinical outcomes to build arisk assessment model for oral cancer development. The identification of subgroups of OPL patients athigher risk for oral cancer development will allow the development of individually tailored, mechanism-basedchemopreventive interventions and strategies for more effective screening and treatment.
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