Barrett’s esophagus is a condition in which the normal stratified squamous epithelium of the distal esophagus is replaced by intestinal metaplasia. For more than three decades the prevailing clinical paradigm has been that Barrett’s esophagus is a complication of symptomatic reflux disease that predisposes to esophageal adenocarcinoma, yet no clinical strategy for cancer prevention or early detection based on this paradigm has been proven to reduce esophageal adenocarcinoma mortality in a randomized clinical trial in part because only about 5-10% of individuals with Barrett’s esophagus develop esophageal adenocarcinoma. Recent research indicates that Barrett’s metaplasia is an adaptation for mucosal defense in response to chronic reflux in most individuals. The risk of progressing to esophageal adenocarcinoma is determined by development of genomic instability and dynamic clonal evolution in the distal esophagus modulated by host and environmental risk and protective factors, including inherited genotype. The challenge in Barrett’s esophagus lies in integrating knowledge about genomic instability and clonal evolution into clinical management to increase the lifespans and quality of life of individuals with this condition.
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