In spite of abundant evidence from multiple laboratories that epigenetic and genetic develop duringneoplastic evolution in Barrett's esophagus, relationships among genetic and epigenetic alterations are stillpoorly understood, in part because many studies investigate only one or the other and in part because fewlongitudinal studies have been performed. Project 1 will use novel and innovative methods to assess theevolution of clones with genetic and epigenetic alterations to determine the extent to which they predictneoplastic progression in a longitudinal cohort study of 614 patients with Barrett's esophagus (BE) with ananticipated 52,167 person-months of follow-up. We hypothesize that i) epigenetic abnormalities arise asearly events in a limited number of CpG islands before widespread genomic instability; ii) earlychromosomal instability in BE progression is characterized by localized regions of LOH and copy numberchange involving a relatively small number of genes (p16, p18INKc, PI3KR3) that in combination with earlydifferential methylation of CpG islands in selected genes predispose to loss of TP53 and widespreadchromosomal instability that develops as a late event in progression and iii) NSAID use modulates earlyevolution of genetic and epigenetic alternations in BE. Project 1will compare the sensitivity and specificity ofa combined panel of epigenetic and genetic alterations to previously reported genetic (p16 LOH, TP53 LOH,tetraploidy, aneuploidy) and epigenetic (p16, RUNX3, HPP1) panels. Project 1 provides Project 2 with clonalgenetic (LOH, copy number change and DNA content abnormalities) and epigenetic (differential methylationof CpG islands) biomarkers, as well as assessmentof clonal evolutionary dynamics to determine the geneticand epigenetic stages of progression that are most closely associated with host and environmental risk andprotective factors. Project 1 also provides these measures to Project 3 to investigate the association ofgenetic instability biomakers (telomeres, fragile sites) with clonal evolution. Finally, Project 1 will developclinically compatible DNA biomarker platforms for our validated markers so that they can be used in othercenters and multicenter studies.
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