Comprehensive Molecular Characterization of Adenocarcinoma of the Gastroesophageal Junction Between Esophageal and Gastric Adenocarcinomas

Abstract

Objective: To investigate the molecular characteristics of AGEJ compared with EAC and gastric adenocarcinoma. Summary of Background Data: Classification of AGEJ based on differential molecular characteristics between EAC and gastric adenocarcinoma has been long-standing controversy but rarely conducted due to anatomical ambiguity and epidemiologic difference. Methods: The molecular classification model with Bayesian compound covariate predictor was developed based on differential mRNA expression of EAC (N ¼ 78) and GCFB (N ¼ 102) from the Cancer Genome Atlas (TCGA) cohort. AGEJ/cardia (N ¼ 48) in TCGA cohort and AGEJ/upper third GC (N ¼ 46 pairs) in Seoul National University cohort were classified into the EAC-like or GCFB-like groups whose genomic, transcriptomic, and proteomic characteristics were compared. Results: AGEJ in both cohorts was similarly classified as EAC-like (31.2%) or GCFB-like (68.8%) based on the 400-gene classifier. The GCFB-like group showed significantly activated phosphoinositide 3-kinase-AKT signaling with decreased expression of ERBB2. The EAC-like group presented significantly different alternative splicing including the skipped exon of RPS24, a significantly higher copy number amplification including ERBB2 amplification, and increased protein expression of ERBB2 and EGFR compared with GCFB-like group. High-throughput 3D drug test using independent cell lines revealed that the EAC-like group showed a significantly better response to lapatinib than the GCFB-like group (P ¼ 0.015). Conclusions: AGEJ was the combined entity of the EAC-like and GCFB-like groups with consistently different molecular characteristics in both Seoul National University and TCGA cohorts. The EAC-like group with a high Bayesian compound covariate predictor score could be effectively targeted by dual inhibition of ERBB2 and EGFR.

Identification of Mutator-Derived Alternative Splicing Signatures of Genomic Instability for Improving the Clinical Outcome of Cholangiocarcinoma

“…Some formula based on alternative splicing signature have been applied to quantify genomic instability degree (20). Recent studies have focused on the AS network, leading to the construction of prognostic signature models based on comprehensive AS events which suitable levels of predictivity and efficiency for carcinoma prognosis (21)(22)(23). Whether genomic instability-related AS events could effectively predict prognosis of cholangiocarcinoma remains unclear.…”

Progress of Gastric Cancer Surgery in the era of Precision Medicine

“…Gastric cancer can be classified into Borrmann's classification and Siewert's classification according to anatomical origin, WHO classification and Lauren's classification according to histological structure, and early stage and late stage according to disease severity 6 . In recent years, with the rapid development of cancer genomics and transcriptomics, cancer is classified into “molecular” subtypes, which theoretically better reflect the biological behavior of gastric cancer 7 (Figure 1 ).…”

Where to Start and What to Do Next: The Sequencing of Treatments in Metastatic Esophagogastric Cancer

“…A study evaluating genomic, transcriptomic, and proteomic characteristics of AGEJ samples from The Cancer Genome Atlas cohort and Seoul National University cohort identified two molecularly distinct subgroups: the EAC-like group, with a significantly higher copy number amplification and increased protein expression of ERBB2 and EGFR; and the gastric adenocarcinoma located at the fundus or body of the stomach-like group, with significantly activated phosphoinositide 3-kinase-AKT signaling with decreased expression of ERBB2. 12 Finally, comprehensive molecular analysis of primary gastric adenocarcinoma tumors from The Cancer Genome Atlas has suggested four distinct molecular subtypes, including tumors positive for Epstein-Barr virus, with recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, PD-L1, and PD-L2; microsatellite unstable tumors, with elevated mutation rates; gnomically stable tumors, with mutations or fusions involving RHO family GTPase-activating proteins; and tumors with chromosomal instability, with marked aneuploidy and focal amplification of receptor tyrosine kinases. 13 Interestingly, the proportion of microsatellite instability-high (MSI-H) tumors increases with more distal location of the primary tumor within the upper gastrointestinal tract.…”