Battling Barrett's esophagus: uncovering the genetics and epigenetics of Barrrett's esophagus and esophageal adenocarcinoma

Abstract

Barrett’s esophagus (BE) is a common premalignant condition of the distal esophagus with a high incidence among Caucasian males. It is an important risk factor for the development of esophageal adenocarcinoma (EAC). EACs arise in BE following a multistep sequence through low- and high-grade dysplasia, finally culminating in an invasive adenocarcinoma. Because of this increased risk of developing an EAC and poor prognosis of EAC patients, BE patients are offered endoscopic surveillance in order to detect early signs of EAC development. However, recent studies have shown that these surveillance programs are not cost-effective and not able to reduce EAC-related mortality. This thesis contains several studies with the aims: 1) to enhance our understanding of BE development and neoplastic progression towards EAC, 2) to contribute to developing a risk stratification index that may eventually replace the endoscopic surveillance program, 3) to improve current treatment modalities, and 4) to predict the prognosis of EAC patients. In order to fulfill these goals, we performed studies to discover genetic and epigenetic changes that contribute to the development and/or neoplastic progression of BE, and EAC progression, and investigated the function of these changes using in vitro models. The dissertation launches with a review article that provides an overview of traditional and novel hypotheses on the development of BE. Also, the role of activated developmental signaling pathways are discussed. In this thesis it is further demonstrated that next-generation sequencing (NGS) can be utilized to create microRNA (miR) profiles and genomic landscapes of endoscopically obtained mucosal biopsies consisting of neoplasia. In chapter 3, using NGS several miRs that may play a role in the development of BE are identified. In addition, it is shown that miR-203 is down-regulated in all columnar epithelial lesions of the esophagus and may initiate BE through activation of Hedgehog signaling and attenuation of intestinal differentiation markers. The objective of the study presented in chapter 4 was to uncover genomic alterations during BE pathogenesis and neoplastic progression of BE. The data suggested that genomic alterations in the metaplasia – carcinoma sequence of BE occur much earlier than the histological changes of frank dysplasia. Furthermore, it was demonstrated that ARID1A inactivation represents a driver event in a subset of the EAC patients and enhances cell growth and invasion of EAC cells. The mutations identified in this chapter may be utilized to predict neoplastic progression of BE. In chapter 6 and 7 it is shown that genetic and epigenetic markers can also function as predictors of therapy sensitivity and patient outcome, respectively. We determined that miR-223 is up-regulated during neoplastic progression of BE and modulates the sensitivity to DNA-damaging agents by targeting PARP1. The results of this study suggest that EAC patients with high miR-223 levels in their tumors might benefit from current chemotherapies. In chapter 7 it is demonstrated that MUC16 presence bears on the prognosis of digestive adenocarcinoma patients.