title: An updated review of gastric cancer in the next-generation sequencing era: insights from bench to bedside and vice versa.
abstract: Gastric cancer (GC) is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. There is an increasing understanding of the roles that genetic and epigenetic alterations play in GCs. Recent studies using next-generation sequencing (NGS) have revealed a number of potential cancer-driving genes in GC. Whole-exome sequencing of GC has identified recurrent somatic mutations in the chromatin remodeling gene ARID1A and alterations in the cell adhesion gene FAT4, a member of the cadherin gene family. Mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) have been found in 47% of GCs. Whole-genome sequencing and whole-transcriptome sequencing analyses have also discovered novel alterations in GC. Recent studies of cancer epigenetics have revealed widespread alterations in genes involved in the epigenetic machinery, such as DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs and microRNAs. Recent advances in molecular research on GC have resulted in the introduction of new diagnostic and therapeutic strategies into clinical settings. The anti-human epidermal growth receptor 2 (HER2) antibody trastuzumab has led to an era of personalized therapy in GC. In addition, ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor (VEGFR)-2, is the first biological treatment that showed survival benefits as a single-agent therapy in patients with advanced GC who progressed after first-line chemotherapy. Using NGS to systematically identify gene alterations in GC is a promising approach with remarkable potential for investigating the pathogenesis of GC and identifying novel therapeutic targets, as well as useful biomarkers. In this review, we will summarize the recent advances in the understanding of the molecular pathogenesis of GC, focusing on the potential use of these genetic and epigenetic alterations as diagnostic biomarkers and novel therapeutic targets.
authors.affiliation: Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroshi Yasuda, Fumio Itoh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroshi Yasuda, Fumio Itoh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroshi Yasuda, Fumio Itoh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Tadateru
authors.initials: T
authors.lastname: Maehata
authors.affiliation: Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroshi Yasuda, Fumio Itoh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Morita
authors.affiliation: Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroshi Yasuda, Fumio Itoh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroshi Yasuda, Fumio Itoh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Oikawa
authors.affiliation: Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroshi Yasuda, Fumio Itoh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ishigooka
authors.affiliation: Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroshi Yasuda, Fumio Itoh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Shun-Ichiro
authors.initials: S
authors.lastname: Ozawa
authors.affiliation: Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroshi Yasuda, Fumio Itoh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Matsuo
authors.affiliation: Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroshi Yasuda, Fumio Itoh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Hosoya
authors.affiliation: Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroshi Yasuda, Fumio Itoh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Yamashita
authors.affiliation: Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroshi Yasuda, Fumio Itoh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Taniguchi
authors.affiliation: Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroshi Yasuda, Fumio Itoh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.affiliation: Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroshi Yasuda, Fumio Itoh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroshi Yasuda, Fumio Itoh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yasuda
authors.affiliation: Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroshi Yasuda, Fumio Itoh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
authors.affiliation: Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroshi Yasuda, Fumio Itoh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Itoh
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002448:Cell Adhesion; D002843:Chromatin / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D044127:Epigenesis, Genetic; D059472:Exome; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D053842:Microsatellite Instability; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D022661:RNA, Untranslated / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013274:Stomach Neoplasms / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: C112476:ARID1A protein, human; D015415:Biomarkers; D002843:Chromatin; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D022661:RNA, Untranslated; D014157:Transcription Factors; D017526:Receptor, IGF Type 1; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Epigenetic field defect; Gastric washes; Insulin-like growth factor 1 receptor; MicroRNA; Microsatellite instability; Next-generation sequencing
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