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Accumulation of somatic mutations in TP53 in gastric epithelium with Helicobacter pylori infection.
Shimizu, Takahiro; Marusawa, Hiroyuki; Matsumoto, Yuko; Inuzuka, Tadashi; Ikeda, Atsuyuki; Fujii, Yosuke; Minamiguchi, Sachiko; Miyamoto, Shin'ichi; Kou, Tadayuki; Sakai, Yoshiharu; Crabtree, Jean E; Chiba, Tsutomu.
Afiliación
  • Shimizu T; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Marusawa H; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: maru@kuhp.kyoto-u.ac.jp.
  • Matsumoto Y; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Inuzuka T; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Ikeda A; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Fujii Y; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Minamiguchi S; Department of Diagnostic Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Miyamoto S; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Kou T; Digestive Disease Center, The Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan.
  • Sakai Y; Department of Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Crabtree JE; Leeds Institute Molecular Medicine, University of Leeds, Leeds, United Kingdom.
  • Chiba T; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Gastroenterology ; 147(2): 407-17.e3, 2014 Aug.
Article en En | MEDLINE | ID: mdl-24786892
BACKGROUND & AIMS: Helicobacter pylori infection is a risk factor for gastric cancer. To explore the genetic basis of gastric cancer that develops in inflamed gastric mucosa, we investigated genetic aberrations that latently accumulate in nontumorous gastric epithelium with H pylori infection. METHODS: We performed whole-exome sequencing of gastric tumors, noncancerous tissues with gastritis, and peripheral lymphocytes from 5 patients. We performed additional deep-sequencing analyses of selected tumor-related genes using 34 gastritis mucosal samples from patients with or without gastric cancer. We also performed deep sequencing analyses of gastric mucosal tissues from mice that express transgenic human TP53 and constitutively express activation-induced cytidine deaminase (AICDA or AID) (human TP53 knock-in/AID-transgenic mice). RESULTS: Whole-exome sequencing revealed that somatic mutations accumulated in various genes in inflamed gastric tissues. Additional deep-sequencing analyses of tissues from regions of gastritis confirmed nonsynonymous low-abundance mutations in TP53 in 15 cases (44.1%) and ARID1A in 5 cases (14.7%). The mutations that accumulated in gastric mucosal tissues with H pylori-induced gastritis, as well as gastric tumors, were predominantly C:G>T:A transitions in GpCpX motifs-a marker of cytidine deamination induced by AID. Constitutive expression of AID in the gastric mucosa of mice led to mutations in the human TP53, at amino acid coding positions identical to those detected in human gastric cancers. CONCLUSIONS: Studies of gastric tumors and tissues from humans and mice indicate that somatic mutations accumulate in various genes in gastric mucosal tissues with H pylori infection. Increased cytidine deaminase activity in these tissues appears to promote the accumulation of these mutations and might promote gastric carcinogenesis in patients with H pylori infection.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Lesiones Precancerosas / Neoplasias Gástricas / Transformación Celular Neoplásica / Proteína p53 Supresora de Tumor / Helicobacter pylori / Infecciones por Helicobacter / Mucosa Gástrica / Gastritis / Mutación Tipo de estudio: Diagnostic_studies / Etiology_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Gastroenterology Año: 2014 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Lesiones Precancerosas / Neoplasias Gástricas / Transformación Celular Neoplásica / Proteína p53 Supresora de Tumor / Helicobacter pylori / Infecciones por Helicobacter / Mucosa Gástrica / Gastritis / Mutación Tipo de estudio: Diagnostic_studies / Etiology_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Gastroenterology Año: 2014 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos