Project 3 will assess chromosomal and mitotic instability in Barrett's Esophagus (BE) and collaborate closely with Project 1 in assessing relationships between markers of genetic instability and p16 and p53 abnormalities, and with Project 2 in evaluating the interactions of genetic instability markers with environmental risk and protective factors. These understandings will give insight into the mechanisms of neoplastic progression in this model system, will further refine the prediction of cancer risk in BE patients and will help elucidate both the mechanisms of environmental damage and new strategies for intervention to prevent disease progression. We hypothesize that the loss of normal mechanisms that insure genomic stability may be an early event in neoplastic progression in BE, one that facilitates progression to cancer through the progressive loss of tumor suppressors by genetic deletion and rearrangement. We also hypothesize that there are multiple mechanisms of genetic instability at play during neoplastic progression and that they may be important at different stages of progression. In this project, we will: (1) quantitate chromosomal instability; (2) determine when genetic instability arises within the sequence of genetic events that leads to cancer in Barrett's esophagus; (3) examine mechanisms that contribute to genetic instability; and (4) determine the potential role of measures of genetic instability as predictors of clinical prognosis and as targets for therapeutic intervention.
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