Overview of genetic and epigenetic alterations in the pathogenesis of esophagogastric junctional adenocarcinoma and esophageal adenocarcinoma: recent findings by next generation sequencing

Abstract

Esophagogastric junctional adenocarcinoma is commonly treated as esophageal adenocarcinoma (EAC) and has dramatically increased in Western countries for several decades. The similar trend has been observed in Asian countries (not in China). Barrett's esophagus (BE) is a widely accepted precursor of EAC. Recent advances of next-generation sequencing could provide researchers with a better understanding of genetic and epigenetic alterations in the carcinogenesis of EAC. In this review, we have summarized the recently reported major genetic and epigenetic alterations in both BE and EAC. Sonic hedgehog/bone morphogenetic protein axis, which is a key signaling for esophageal development, plays an important role in BE intestinal metaplasia. Single nucleotide polymorphisms related to esophageal organogenesis, such as FOXF1 and FOXP3, are frequently detected in BE patients. During the progression of BE to adenocarcinoma, lacking of normal function of TP53 and CDKN2A by loss of heterozygosity (LOH), mutation, or promoter methylation has been frequently observed. LOH at 9p (coding CDKN2A) is an earlier event to EAC carcinogenesis compared to that at 17q (coding TP53) LOH. In order to further elucidate the pathogenesis of BE and EAC, it will be necessary to analyze these genetic/epigenetic alterations in combination with clinical data in a large-scale cohort.