title: Muscle RAS oncogene homolog (MRAS) recurrent mutation in Borrmann type IV gastric cancer.
abstract: The prognosis of patients with Borrmann type IV gastric cancer (Type IV) is extremely poor. Thus, there is an urgent need to elucidate the molecular mechanisms underlying the oncogenesis of Type IV and to identify new therapeutic targets. Although previous studies using whole-exome and whole-genome sequencing have elucidated genomic alterations in gastric cancer, none has focused on comprehensive genetic analysis of Type IV. To discover cancer-relevant genes in Type IV, we performed whole-exome sequencing and genome-wide copy number analysis on 13 patients with Type IV. Exome sequencing identified 178 somatic mutations in protein-coding sequences or at splice sites. Among the mutations, we found a mutation in muscle RAS oncogene homolog (MRAS), which is predicted to cause molecular dysfunction. MRAS belongs to the Ras subgroup of small G proteins, which includes the prototypic RAS oncogenes. We analyzed an additional 46 Type IV samples to investigate the frequency of MRAS mutation. There were eight nonsynonymous mutations (mutation frequency, 17%), showing that MRAS is recurrently mutated in Type IV. Copy number analysis identified six focal amplifications and one homozygous deletion, including insulin-like growth factor 1 receptor (IGF1R) amplification. The samples with IGF1R amplification had remarkably higher IGF1R mRNA and protein expression levels compared with the other samples. This is the first report of MRAS recurrent mutation in human tumor samples. Our results suggest that MRAS mutation and IGF1R amplification could drive tumorigenesis of Type IV and could be new therapeutic targets.
authors.affiliation: Department of Pathology, Kurume University School of Medicine, Kurume, Japan.|Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine Kurume, Kurume, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Yasumoto
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Sakamoto
authors.affiliation: Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Ogasawara
authors.affiliation: Department of Surgery, Kurume General Hospital, Kurume, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Isobe
authors.affiliation: Department of Surgery, Kurume General Hospital, Kurume, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Kizaki
authors.affiliation: Department of Pathology, Kurume University School of Medicine, Kurume, Japan.|Department of Radiology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Sumi
authors.affiliation: Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Kusano
authors.affiliation: Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Akiba
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine Kurume, Kurume, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Torimura
authors.affiliation: Department of Surgery, Kurume General Hospital, Kurume, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Akagi
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.
authors.forename: Hiraku
authors.initials: H
authors.lastname: Itadani
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hasako
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kumazaki
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Mizuarai
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Oie
authors.affiliation: Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Yano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D059472:Exome; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics* / Q000378:metabolism*; D017422:Sequence Analysis, DNA / Q000379:methods*; D017384:Sequence Deletion; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018631:ras Proteins / Q000235:genetics*
chemical_list: C000597236:IGF1R protein, human; C109523:MRAS protein, human; D017451:Receptors, Somatomedin; D017526:Receptor, IGF Type 1; D018631:ras Proteins
keywords: 
  
  MRAS
  
  ; 
  IGF1R
  ; Borrmann type IV; gastric cancer; mutation