Genomic and Transcriptomic Characteristics of Esophageal Adenocarcinoma

SIMPLE SUMMARY: Cancer of the esophagus is a deadly disease. There are two main subtypes, adenocarcinoma and squamous cell carcinoma, with adenocarcinoma of the esophagus (EAC) being more common in Western countries. Barrett’s esophagus (BE) describes a change in the esophageal surface near the stomach in response to reflux of gastric acid into the esophagus. BE increases the risk of developing EAC, and the incidence of EAC has risen dramatically over recent decades. One likely reason for the poor prognosis of EAC is based on the fact that each tumor has many genes affected by mutations, and most of these genes differ across patients, hampering the efficacy of therapies that target specific cancer driver proteins. In this review, we provide an overview of the gene mutations and gene activity changes in EAC and how these features can be used to divide patients into groups that might have different clinical characteristics. ABSTRACT: Esophageal adenocarcinoma (EAC) is a deadly disease with limited options for targeted therapy. With the help of next-generation sequencing studies over the last decade, we gained an understanding of the genomic architecture of EAC. The tumor suppressor gene TP53 is mutated in 70 to 80% of tumors followed by genomic alterations in CDKN2A, KRAS, ERBB2, ARID1A, SMAD4 and a long tail of less frequently mutated genes. EAC is characterized by a high burden of point mutations and genomic rearrangements, resulting in amplifications and deletions of genomic regions. The genomic complexity is likely hampering the efficacy of targeted therapies. Barrett’s esophagus (BE), a metaplastic response of the esophagus to gastro-esophageal reflux disease, is the main risk factor for the development of EAC. Almost all EACs are derived from BE. The sequence from BE to EAC provides an opportunity to study the genomic evolution towards EAC. While the overlap of point mutations between BE and EAC within the same patient is, at times, surprisingly low, there is a correlation between the complexity of the genomic copy number profile and the development of EAC. Transcriptomic analyses separated EAC into a basal and a classical subtype, with the basal subtype showing a higher level of resistance to chemotherapy. In this review, we provide an overview of the current knowledge of the genomic and transcriptomic characteristics of EAC and their relevance for the development of the disease and patient care.