This project will build upon the patient population (300 patients with aneuploid oral premalignant lesions (OPLs)) from Project 1 to identify epidemiologic and genetic predictors of oral cancer development and of response to the intervention. In addition to establishing epidemiologic profiles, we will evaluate the role of DNA damage and repair capacity as a predictor of cancer development. To accomplish this, we will first quantify benzo[a]pyrene diol-epoxide (BPDE)- induced genetic damage (reflecting sum results of initial DNA damage and nucleotide excision repair (NER) capacity) in peripheral blood lymphocytes (PBLs), measured by the Komet 4.0 image system. Our hypothesis is that patients who show increased levels of BPDE-induced damage are at greater risk for oral cancer development than those who do not exhibit this sensitivity. Next, we will estimate the frequencies of polymorphisms in DNA repair genes implicated in the NER pathway (i,e., ERCC1, XPC, XPD/ERCC2, XPF/ERCC4, XPA, RAD23B, CLNH, ERCC5, LIG1, etc.) and correlate genotype with BPDE-induced genetic damage. We hypothesize that specific (adverse) genotypes of the NER pathway genes will predict higher levels of genetic damage and a higher risk for oral cancer development. Then, we will determine the frequencies of BPDE-induced chromosome aberrations on 3p12.3, 3p14.2, 3p21.3, and 3p25.2 in PBLs of all patients. Our hypothesis is that patients who exhibit higher frequencies of BPDE-induced chromosome aberrations on 3p are at greater risk for oral cancer development than those who do not exhibit these sensitivities. These BPDE-induced 3p hotspots in lymphocyte will also be compared with tissue LOH data from Project 3. We hypothesize that there will be concordance in the severity of site-specific chromosomal lesions in target (OPL) and surrogate (PBL) tissues. We will also assess interindividual differences in modulation or response to celecoxib and EKB-569. We will determine if genetic variation in genes related to metabolism of celecoxib and EKB-569 or their mechanism of action, modulate the response to celecoxib and EKB-569 in patients with aneuploid OPLs. Our hypothesis is that specific, adverse genotypes of COX2, CYP1A1, CYP2C9, CYP3A4, ADH1, ADH2, UGT1A6, EGFR, and ErbB-2 may negatively impact the response of patients with oral premalignant lesions to celecoxib and EKB-569. There is an important translational implication to this project. Identification of high risk subgroups for oral cancer development of OPL patients has considerable implication in prevention and early detection. The high risk OPL patients can be more intensively screened and treated for cancer prevention. In addition, identification of those less likely to respond to the intervention has great implications for developing tailored interventions. This project will have interactions with Cores A, B, and C and Projects 1,2 and 3.
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