Yun-Suhk Suh1,2,3, Deukchae Na4, Ju-Seog Lee5, Jeesoo Chae6, EuiHyun Kim5, Giyong Jang4, Jieun Lee3,4, Jimin Min7, Chan-Young Ock8, Seong-Ho Kong1, Joshy George2, Chengsheng Zhang2, Hyuk-Joon Lee1,7, Jong-Il Kim6, Seong-Jin Kim9, Woo Ho Kim10, Charles Lee2,4,11, Han-Kwang Yang1,7. 1. Department of Surgery, Seoul National University College of Medicine, Seoul, Korea. 2. The Jackson Laboratory for Genomic Medicine, Farmington, CT. 3. Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea. 4. Department of Life Science, Ewha Womans University, Seoul, Korea. 5. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 6. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea. 7. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. 8. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea. 9. 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. 10. Department of Pathology, Seoul National University College of Medicine, Seoul, Korea. 11. Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
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.
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.
Authors: E L Vos; R A Carr; M Hsu; M Nakauchi; T Nobel; A Russo; A Barbetta; K S Tan; L Tang; D Ilson; G Y Ku; A J Wu; Y Y Janjigian; S S Yoon; M S Bains; D R Jones; D Coit; D Molena; V E Strong Journal: Br J Surg Date: 2021-11-11 Impact factor: 6.939