Genes co-amplified with ERBB2 or MET as novel potential cancer-promoting genes in gastric cancer

// Mi Jeong Kwon 1, 2, * , Ryong Nam Kim 3, 4, * , Kyoung Song 5 , Sinyoung Jeon 3 , Hae Min Jeong 3 , Joo Seok Kim 3 , Jinil Han 6 , Sungyoul Hong 3 , Ensel Oh 7 , Jong-Sun Choi 8 , Jungsuk An 9 , Jonathan R. Pollack 10 , Yoon-La Choi 7, 11, 12 , Cheol-Keun Park 11 and Young Kee Shin 3, 4, 8, 13 1 College of Pharmacy, Kyungpook National University, Daegu, Korea 2 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Korea 3 Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy, Seoul National University, Seoul, Korea 4 Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, Korea 5 R&D center, ABION Inc., Guro-gu, Seoul, Korea 6 Gencurix, Inc., Guro-gu, Seoul, Korea 7 Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 8 The Center for Anti-cancer Companion Diagnostics, Institutes of Entrepreneurial BioConvergence, Seoul National University, Seoul, Korea 9 Department of Pathology, Gachon University Gil Medical Center, Incheon, Korea 10 Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America 11 Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 12 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea 13 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea * These authors have contributed equally to this study Correspondence to: Cheol-Keun Park, email: ckpark@skku.edu Young Kee Shin, email: ykeeshin@snu.ac.kr Keywords: gastric cancer, DNA copy number alterations, potential cancer-promoting genes, ERBB2, MET Received: August 05, 2016     Accepted: August 27, 2017     Published: September 21, 2017 ABSTRACT Gastric cancer (GC), one of the most common cancers worldwide, has a high mortality rate due to limited treatment options. Identifying novel and promising molecular targets is a major challenge that must be overcome if treatment of advanced GC is to be successful. Here, we used comparative genomic hybridization and gene expression microarrays to examine genome-wide DNA copy number alterations (CNAs) and global gene expression in 38 GC samples from old and young patients. We identified frequent CNAs, which included copy number gains on chromosomes 3q, 7p, 8q, 20p, and 20q and copy number losses on chromosomes 19p and 21p. The most frequently gained region was 7p21.1 (55%), whereas the most frequently deleted region was 21p11.1 (50%). Recurrent highly amplified regions 17q12 and 7q31.1-7q31.31 harbored two well-known oncogenes: ERBB2 and MET . Correlation analysis of CNAs and gene expression levels identified CAPZA2 (co-amplified with MET ) and genes GRB7 , MIEN1 , PGAP3 , and STARD3 (co-amplified with ERBB2 ) as potential candidate cancer-promoting genes (CPGs). Public dataset analysis confirmed co-amplification of these genes with MET or ERBB2 in GC tissue samples, and revealed that high expression (except for PGAP3 ) was significantly associated with shorter overall survival. Knockdown of these genes using small interfering RNA led to significant suppression of GC cell proliferation and migration. Reduced GC cell proliferation mediated by CAPZA2 knockdown was attributable to attenuated cell cycle progression and increased apoptosis. This study identified novel candidate CPGs co-amplified with MET or ERBB2 , and suggests that they play a functional role in GC.