Comprehensive Molecular Characterization of Adenocarcinoma of the Gastroesophageal Junction Between Esophageal and Gastric Adenocarcinomas. Issue 4 (19th April 2022)

• Record Type: Journal Article
• Authors: Suh, Yun-Suhk; Na, Deukchae; Lee, Ju-Seog; Chae, Jeesoo; Kim, EuiHyun; Jang, Giyong; Lee, Jieun; Min, Jimin; Ock, Chan-Young; Kong, Seong-Ho; George, Joshy; Zhang, Chengsheng; Lee, Hyuk-Joon; Kim, Jong-Il; Kim, Seong-Jin; Kim, Woo Ho; Lee, Charles; Yang, Han-Kwang
• Is Part Of: Annals of surgery. Volume 275:Issue 4(2022)
• Page Start: 706
• Page End: 717
• Publication Date: 2022-04-19
• Subjects: adenocarcinoma -- classification -- ERBB2 -- esophagogastric junction -- esophagus -- genome -- neoplasm -- proteome -- sequencing -- stomach -- TCGA -- transcriptome; Surgery -- Periodicals; 617.005
• DOI: 10.1097/SLA.0000000000004303
• Languages: English
• ISSNs: 0003-4932

Abstract

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 = 78) and GCFB (N = 102) from the Cancer Genome Atlas (TCGA) cohort. AGEJ/cardia (N = 48) in TCGA cohort and AGEJ/upper third GC (N = 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 = 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.