Project 1 assesses the evolution of neoplastic clones with lesions in p16, p53 and ploidy to determine the extent to which they predict neoplastic progression in Barrett's esophagus (BE). It also seeks to identify transcription patterns mediating transitions from one stage of progression to another and giving rise to esophageal adenocarcinoma (EA). Project 1 provides Project 2 with high-volume assessments of p16 (promoter methylation, mutation, 9p LOH), p53 (mutation, 17p LOH) and ploidy (aneuploidy, elevated 4N fractions) status for collaborative investigations to determine the molecular stages of progression with which environmental risk and protective factors are most closely associated. Project 1 also assesses p16 and p53 status as well as LOH mapping of chromosomes 9 and 17 for Project 3 to evaluate mechanisms by which p16, p53 and telomere dynamics promote chromosomal and mitotic instability in humans in vivo. These studies will provide insight into mechanisms of genomic instability, clonal expansion and clonal evolution during human neoplastic progression in vivo; improve risk assessment in patients with BE and provide a foundation for prevention trials tailored to specific patient subsets. We hypothesize that I) evolution of p16, p53 and ploidy abnormalities are intrinsic to neoplastic progression; ii) squamous esophageal epithelium and BE arise from the same (or different) stem cells, and that, therefore, regenerative neosquamous epithelium may (or may not) have the same genetic instability and neoplastic potential as BE; iii) transitions from one stage of clonal evolution to another give rise to defined transcription patterns in biologic networks mediating neoplastic progression; and iv) specific transcription patterns will identify biological pathways or networks that place patients at low- and high-risk for progression to EA.
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