We propose to create a Clinical and Epidemiologic Center focused on Biomarkers for Upper Aerodigestive Tract (UADT) Lesions, an Excellent model for studying markers of risk, early detection and response to intervention. We will build upon funded intergroup chemopreventive trials and epidemiologic studies that span the continuum of UADT disease, from pre-malignant lesions to risk of second primary tumors. We propose: 1. A Clinical Resource: We have approved protocols, tracking systems, active follow-up and substantial preliminary data on subjects enrolled in chemoprevention and epidemiologic UADT studies. We can expand the resource with our diverse patient population, comparison subjects from epidemiologic studies, and the infrastructure from our own center's Cancer Genetics Network. 2. Biomarker Resource: Integration of a comprehensive panel of biomarkers of risk, early detection and response to intervention expressed in germline DNA, premalignant lesions, adjacent normal epithelium, and invasive cancers. These include tissue markers-e.g., genomic instability markers (chromosomal polysomy, LOH of 9p21, 3p14, and 17p), proliferation, p53, cyclin D1, EGFR, and RAR expression- and risk markers-e.g., phenotypic (in vitro lymphocyte assays) and genotypic (metabolic polymorphisms). 3. Inter-related research projects (3) to evaluate promising candidate genetic and phenotypic cellular and molecular biomarkers useful for characterizing the field and the multi-step UADT tumorigenesis process; and for assessment of risk, early detection, and response in early and advanced pore-malignant lesions and first and multiple cancers of the UADT. 4. Statistical methodologies for combining biomarker data; for assessing genotype/phenotype and surrogate/target tissue marker correlations; and to develop a risk assessment model for second primary tumors. 5. Developmental projects in biomarkers for tobacco-induced epithelial cancers e.g. bladder cancer. 6. Collaboration with industry to validate microarray technology to perform large scale genotyping of a range of polymorphic metabolic susceptibility genes. 7. Collaboration with a pending Biomarker Development Grant on Bladder Cancer (B. Czerniak, P.I.) Collectively, we have a long and successful track record of basic, clinical, translational, and epidemiologic research in susceptibility to tobacco carcinogenesis, in chemopreventive interventions, and in biomarker analysis. Thus, we have the relevant subjects for our proposed studies; we have compelling preliminary data; and we have the necessary expertise and organization structure to maximize success. The team of investigators is multi-disciplinary and will be able to respond in a timely and flexible manner to network directives, and to enhance and augment the network's research capabilities.
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