GENETIC INSTABILITY

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