title: Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma.
abstract: Diffuse-type gastric carcinoma (DGC) is characterized by a highly malignant phenotype with prominent infiltration and stromal induction. We performed whole-exome sequencing on 30 DGC cases and found recurrent RHOA nonsynonymous mutations. With validation sequencing of an additional 57 cases, RHOA mutation was observed in 25.3% (22/87) of DGCs, with mutational hotspots affecting the Tyr42, Arg5 and Gly17 residues in RHOA protein. These positions are highly conserved among RHO family members, and Tyr42 and Arg5 are located outside the guanine nucleotide-binding pocket. Several lines of functional evidence indicated that mutant RHOA works in a gain-of-function manner. Comparison of mutational profiles for the major gastric cancer subtypes showed that RHOA mutations occur specifically in DGCs, the majority of which were histopathologically characterized by the presence of poorly differentiated adenocarcinomas together with more differentiated components in the gastric mucosa. Our findings identify a potential therapeutic target for this poor-prognosis subtype of gastric cancer with no available molecularly targeted drugs.
authors.affiliation: 1] Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. [2] Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Miwako
authors.initials: M
authors.lastname: Kakiuchi
authors.affiliation: Forerunner Pharma Research Co., Ltd., Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishizawa
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ueda
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Gotoh
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Akimasa
authors.initials: A
authors.lastname: Hayashi
authors.affiliation: 1] Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. [2] Translational Systems Biology and Medicine Initiative (TSBMI), The University of Tokyo, Tokyo, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: 1] Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. [2] Translational Systems Biology and Medicine Initiative (TSBMI), The University of Tokyo, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tatsuno
authors.affiliation: Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Katoh
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kanagawa, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ichimura
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ushiku
authors.affiliation: Forerunner Pharma Research Co., Ltd., Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Funahashi
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tateishi
authors.affiliation: Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Wada
authors.affiliation: Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shimizu
authors.affiliation: Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Nomura
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.affiliation: Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Seto
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.affiliation: 1] Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. [2] Translational Systems Biology and Medicine Initiative (TSBMI), The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: 1] Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. [2] Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. [3] Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shumpei
authors.initials: S
authors.lastname: Ishikawa
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000595:Amino Acid Sequence; D002277:Carcinoma / Q000235:genetics*; D002454:Cell Differentiation; D004252:DNA Mutational Analysis; D005753:Gastric Mucosa / Q000473:pathology; D015723:Gene Library; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011379:Prognosis; D034741:RNA, Small Interfering / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013274:Stomach Neoplasms / Q000235:genetics*; D017154:Stromal Cells / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics*
chemical_list: D034741:RNA, Small Interfering; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein