ORIGINAL ARTICLESComprehensive Molecular Characterization of Adenocarcinoma of the Gastroesophageal Junction Between Esophageal and Gastric AdenocarcinomasSuh, Yun-Suhk MD, PhD∗,†,‡; Na, Deukchae PhD§; Lee, Ju-Seog PhD¶; Chae, Jeesoo PhD||; Kim, EuiHyun MD, PhD¶; Jang, Giyong PhD§; Lee, Jieun PhD‡,§; Min, Jimin PhD∗∗; Ock, Chan-Young MD, PhD††; Kong, Seong-Ho MD, PhD∗; George, Joshy PhD†; Zhang, Chengsheng PhD†; Lee, Hyuk-Joon MD, PhD∗,∗∗; Kim, Jong-Il PhD||; Kim, Seong-Jin PhD‡‡; Kim, Woo Ho MD, PhD§§; Lee, Charles PhD†,§,¶¶; Yang, Han-Kwang MD, PhD∗,∗∗ Author Information ∗Department of Surgery, Seoul National University College of Medicine, Seoul, Korea †The Jackson Laboratory for Genomic Medicine, Farmington, CT ‡Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea §Department of Life Science, Ewha Womans University, Seoul, Korea ¶Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas ||Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea ∗∗Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea ††Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea ‡‡Precision Medicine Research Center, Advanced Institutes of Convergence Technology and Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Suwon, Korea §§Department of Pathology, Seoul National University College of Medicine, Seoul, Korea ¶¶Precision Medicine Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People's Republic of China. [email protected]; [email protected]. Yun-Suhk Suh and Deukchae Na contributed equally to this study as co-first authors. This research was supported by funding to HKY from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea (HI14C1277); funding to CL from the International Research & Development Program of the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (grant no. 2015K1A4A3047851) CL was supported in part by the operational funds from The First Affiliated Hospital of Xi’an Jiaotong University, and the Ewha Womans University Research grant of 2019; funding to JSL from Cancer Prevention & Research Institute of Texas (RP170307) and Congressionally Directed Medical Research Programs (CA160616); JG was partially supported by the National Cancer Institute of the National Institutes of Health under Award Number P30CA034196; funding to ND from the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (grant no. 2018R1D1A1B07045381). The authors declare no conflicts of interest. Author contributions: Study concept and design: Yun-Suhk Suh, and Han-Kwang Yang. Data collection: Yun-Suhk Suh, Deukchae Na, Ju-Seog Lee, EuiHyun Kim, Jeesoo Chae, Giyong Jang, Jieun Lee. Jimin Min, Chan-Young Ock, Seong-Ho Kong, and Seong-Jin Kim. Analysis and interpretation of data: Yun-Suhk Suh, Deukchae Na, Ju-Seog Lee, EuiHyun Kim, Jeesoo Chae, Giyong Jang, Jieun Lee, Jimin Min, Chan-Young Ock, CZ Zhang, Hyuk-Joon Lee, Jong-Il Kim, Seong-Jin Kim, Woo Ho Kim, Charles Lee, and Han-Kwang Yang. Drafting of the manuscript: Yun-Suhk Suh, Deukchae Na, EuiHyun Kim, Jeesoo Chae, Giyong Jang, Jieun Lee, CZ Zhang, Charles Lee, and Han-Kwang Yang. Statistical analysis: Yun-Suhk Suh, Deukchae Na, Ju-Seog Lee, EuiHyun Kim, Jeesoo Chae, Chan-Young Ock, and Jong-Il Kim. Critical revision: Seong-Ho Kong, CZ Zhang, Hyuk-Joon Lee, Jong-Il Kim, Seong-Jin Kim, Woo Ho Kim, Ju-Seog Lee, Charles Lee, and Han-Kwang Yang. Obtained funding and Study supervision: Ju-Seog Lee, Charles Lee, and Han-Kwang Yang. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.annalsofsurgery.com). Annals of Surgery: April 2022 - Volume 275 - Issue 4 - p 706-717 doi: 10.1097/SLA.0000000000004303 Buy SDC Metrics 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. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.