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

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.

Management of metastatic esophagogastric junction adenocarcinoma

The prognosis of metastatic disease of esophagogastric junction adenocarcinoma remains poor,despite using a variety of regimens using cytotoxic agents.Recent understanding of molecular characteristic and tumor microenvironment of this cancer is currently instigating new therapeutic options.In this review,we summarized previous evidences of cytotoxic agents widely used worldwide,and updated recent developments of molecular targeted drugs,and immune checkpoint inhibitors.

Recent updates of therapeutic strategy of esophagogastric junction adenocarcinoma

The incidence of esophagogastric junction(EGJ)adenocarcinoma has been increasing in Asian countries.Despite the recent advances in multidisciplinary treatments,EGJ adenocarcinoma remains aggressive with unfavorable outcomes.Regarding surgical strategy,EGJ adenocarcinoma arises between the esophagus and the stomach,and thus tumor cells spread through the lymphatic system both upward to the mediastinum and downward to the abdomen.Nevertheless,an optimal extent of lymphadenectomy remains controversial.Regarding drug therapy,the latest topic in gastric and EGJ adenocarcinoma is trastuzumab deruxtecan,which is an antibody-drug conjugate consisting of an anti-HER2 antibody.In addition,many clinical trials have recently demonstrated the efficacy of immune checkpoint inhibitors.Meanwhile,recent advances in sequencing technology have revealed that gastroesophageal adenocarcinoma could be categorized into four molecular subtypes:epstein-Barr virus-associated,high-level microsatellite instability,genomically stable,and chromosomal instability tumors.Furthermore,these subtypes show distinct clinical phenotypes and molecular alterations.We review the current surgical strategy and drug treatment such as molecular-targeted agents,immune checkpoint inhibitors,and molecular-subtype-based therapeutic strategies in EGJ adenocarcinoma.Clinical and molecular characteristics and response to immune checkpoint inhibitors differ among molecular subtypes.Treatment strategies based on molecular subtypes may be clinically beneficial for patients with EGJ adenocarcinoma.