To focus on Prevention, Prediction and Personalization of management of the risk of esophagealadenocarcinoma in Barrett's esophagus patients, this project will examine some of the earliest processescontributing to neoplastic progression in BE: genomic damage, genomic instability, and the roles of telomereshortening and telomerase reactivation. We hypothesize that neoplastic evolution in BE begins withinflammation-induced DNA damage, followed by telomere shortening and chromosomal instability, and wehave shown that these are all early event in the evolution of BE. While DNA damage, telomere attrition andchromosomal instability may initially initiate checkpoint-suppression of progression to cancer, escapethrough reactivation of telomerase is almost always required before cancer in BE.
In Aim 1, we will quantitatetelomere shortening and reactivation of telomerase in BE patients and we will perform prospectivelongitudinal analyses of our BE surveillance cohort to define their utility in predicting an individual patient'scancer risk. We also believe that understanding these mechanisms will contribute to new and betterstrategies for chemoprevention, and demonstrate this in our cohort by showing an interaction of telomerelength and NSAIDs in modulating cancer risk. Secondly, we hypothesize that genetic instability atchromosomal fragile sites is a sensitive marker of genotoxic stress and genetic damage to the esophagealepithelium. Analysis of copy changes and loss of heterozygosity at fragile sites has the features required tobe a practical clinical biomarker, and therefore we will determine its predictive value for cancer riskassessment in prospective study and longitudinal follow-up of BE patients. Together, Aims 1 and 2 have thepotential to define clinical biomarkers of BE cancer risk that are based on basic underlying mechanisms ofgenomic instability that facilitate neoplastic evolution. Strong collaborations with Projects 1 and 2 and CoresB and C help to define relationships to other molecular markers, host and environmental factors andchemoprevention strategies.
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