This application brings together an experienced team of investigators into a P01 to study Barrett's esophagus (BE), the only established precursor of esophageal adenocarcinoma (EA), a rapidly increasing, highly lethal malignancy. BE is also a unique in vivo model of human epithelial neoplasia, and the P01 theme of genomic instability: its etiology, manifestations and progression focuses on fundamental mechanisms of human neoplastic progression. Thus, our primary and secondary goals are to (1) reduce morbidity and mortality of EA by early detection, prevention, or both and (2) elucidate mechanisms of human neoplastic progression in vivo that may be shared by other neoplasms whose early stages are less amenable to investigation. Our study design is a prospective investigation of the Seattle Barrett's Esophagus Cohort, one of the largest and best characterized in the world. All data in the P01 will be derived from this cohort, maintained by Core B (Clinical Research). Project 1 (Clonal Evolution) hypothesizes that the evolution of clonal lesions in p16, p53 and ploidy are intrinsic to mechanisms of neoplastic progression. It seeks to determine the extent to which they predict neoplastic progression in BE and to identify transcription patterns that mediate transitions from one stage of progression to another and give rise to EA. Project 2 (Epidemiology) hypothesizes that environmental exposures and host factors, including NSAIDs, serum selenium, bile reflux, high fat, low fruit and vegetable diet and being overweight, modulate progression. It seeks to determine the extent to which these factors are associated with the genetic markers that are developed in Projects 1 and 3, as well as clinical outcome as assessed by Core B. Project 3 (Genetic Instability) hypothesizes that loss of normal mechanisms that insure genomic stability is an early event that contributes to neoplastic progression in BE. The mechanisms that contribute to chromosomal and mitotic instability will be studied, and the utility of measures of genetic instability as predictors of clinical prognosis and as targets for therapeutic intervention will be determined. The P01 is highly collaborative and all projects and cores interact with each other. Thus, the clonal markers and measures of instability provided by Projects 1 and 3, respectively, become shared resources to advance the common goals of the P01. These interactions are facilitated by Core C (Bioinformatics/Biostatistics), which provides a framework for analysis of the complicated datasets of the projects and a vehicle for interproject and core communications.
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