Clonal evolution in Barrett's esophagus

CN17-01

Barrett’s esophagus (BE) is both a clinically important intraepithelial neoplasm and one of the best models for studying neoplastic progression in human solid tumors. Because of the morbidity and mortality associated with esophagectomies, and the fact that only approximately 0.5% of BE patients progress to esophageal adenocarcinoma (EA) per year, the current standard of care includes endoscopic biopsy surveillance for the early detection of cancer. In addition to these longitudinal biopsies, it is common practice to take multiple biopsies per time point. The result is a unique opportunity to study the genetics and epigenetics of neoplastic progression over both time and space as well as intervene in those processes. Thus, we have devoted an entire session to the discussion of recent results from leaders in the field of Barrett’s esophagus.
 There are a variety of open problems in Barrett’s esophagus. The origin of BE has been a long standing problem that Rebecca Fitzgerald has started to solve. Chronic gastroesophageal reflux disease (GERD) is known to predispose to the development of BE, and 10% of patients with GERD have BE when first endoscoped. However, it has been practically difficult to study the transition from GERD to BE, for there are no GERD cohorts with longitudinal endoscopic biopsies. Dr. Fitzgerald and her team have been able to keep both esophageal squamous and Barrett’s esophagus biopsies alive long enough ex vivo, to be able to study the effects of exposures on those biopsies and discovered an important role of retinoic acid in their transformation.
 Brian Reid and his team have recently conducted the first genome wide combined epigenetic and genetic assays of Barrett’s epithelium and varying stages of progression. Little is known about the epigenetic modifications in Barrett’s neoplastic progression, though given the frequency of epigenetic lesions and the evidence that it is often involved in silencing p16 (CDKN2A/INK4a), epigenetic alterations are likely to be important events throughout Barrett’s neoplastic progression.
 Because BE takes so long to evolve into EA, it not only offers a model for studying neoplastic progression, but also a long window in which we can intervene so as to delay progression. Kenneth Wang is a world leader in the treatment of BE and the prevention of EA. He will report on recent advances in the treatment of BE at the Mayo clinic.
 Thus, the speakers for this session will cover Barrett’s neoplastic progression from initiation through treatment. I will set the context to help communicate the importance of the advances of the speakers in this session. I will also present some of our own recent work on the first longitudinal analyses of clonal evolution in a solid tumor, including fixation events, in which a clone expands to fill the entire neoplasm, the results of competition between Barrett’s clones, and changes in the genetic diversity of the neoplasms over time. I will also discuss relationships between the evolutionary dynamics of these clones and exposures in their microenvironment associated with obesity, smoking behavior, non-steroidal anti-inflammatory drug use, age and sex.