Molecular Biology and Clinical Management of Esophageal Adenocarcinoma

SIMPLE SUMMARY: Esophageal adenocarcinoma (EAC) is one of the two main subtypes of esophageal cancer. EAC is a highly lethal disease with rising incidence in Western countries. EAC is associated with chronic gastroesophageal reflux disease and Barrett’s esophagus and mostly occurs in the distal esophagus. In the past decades, much effort has been made to improve treatment strategies, including regimens with chemoradiotherapy, targeted and immune therapies. Despite the multi-modal therapies, the survival of EAC patients has improved only marginally, and major breakthroughs in EAC treatment have not been achieved. We aim to summarize the literature on the comprehensive molecular landscape of EAC to elucidate factors underlying the EAC malignant behavior and poor outcomes. We discuss in detail the etiology, genetics, epigenetics and histology of EAC, as well as the currently employed therapies. Better knowledge about the molecular biology of EAC learned from this review may provide leads for developing novel therapies in the future. ABSTRACT: Esophageal adenocarcinoma (EAC) is a highly lethal malignancy. Due to its rising incidence, EAC has become a severe health challenge in Western countries. Current treatment strategies are mainly chosen based on disease stage and clinical features, whereas the biological background is hardly considered. In this study, we performed a comprehensive review of existing studies and discussed how etiology, genetics and epigenetic characteristics, together with the tumor microenvironment, contribute to the malignant behavior and dismal prognosis of EAC. During the development of EAC, several intestinal-type proteins and signaling cascades are induced. The anti-inflammatory and immunosuppressive microenvironment is associated with poor survival. The accumulation of somatic mutations at the early phase and chromosomal structural rearrangements at relatively later time points contribute to the dynamic and heterogeneous genetic landscape of EAC. EAC is also characterized by frequent DNA methylation and dysregulation of microRNAs. We summarize the findings of dysregulations of specific cytokines, chemokines and immune cells in the tumor microenvironment and conclude that DNA methylation and microRNAs vary with each different phase of BE, LGD, HGD, early EAC and invasive EAC. Furthermore, we discuss the suitability of the currently employed therapies in the clinic and possible new therapies in the future. The development of targeted and immune therapies has been hampered by the heterogeneous genetic characteristics of EAC. In view of this, the up-to-date knowledge revealed by this work is absolutely important for future EAC studies and the discovery of new therapeutics.