Abstract 5366: Mutation signature of TP53 gene in H. pylori-associated inflamed gastric mucosa during gastric carcinogenesis

Abstract

Abstract Helicobacter pylori (H. pylori) infection and the resultant chronic gastric inflammation is an important etiologic factor for gastric cancer development. To explore the genetic basis of gastric cancer that develops in inflamed gastric mucosa, we investigated genetic aberrations that latently accumulate in non-tumorous gastric epithelium with H. pylori infection. Whole exome sequencing on gastric cancer, non-cancerous gastritis tissues and peripheral lymphocytes of 5 patients revealed that somatic mutations accumulated in various genes in inflamed gastric tissues. Additional deep sequencing analyses of selected tumor-related genes in 34 gastritis mucosa samples from patients with, or without, gastric cancer revealed non-synonymous low-abundance mutations in TP53 in 15 cases (44.1%) and ARID1A in 5 cases (14.7%). The mutation signature of whole exome sequences in gastric cancer genomes as well as low-abundance TP53 mutations latently accumulated in H. pylori-inflamed gastritis mucosa were predominantly biased to C:G>T:A transitions in the context of GpCpX motifs, the typical footprints of cytidine deamination triggered by activation-induced cytidine deaminase (AID). In vivo studies with a human TP53 knock-in mouse model revealed that constitutive AID expression in the gastric mucosa caused the emergence of human TP53 mutations at the amino acid positions identical to those detected in human gastric cancers. These findings provide novel evidence that somatic mutations latently accumulated in various genes in inflamed gastric mucosa with H. pylori infection, and cytidine deaminase activity might provide a putative genetic basis for the increased susceptibility to gastric carcinogenesis in patients with H. pylori infection. Citation Format: Takahiro Shimizu, Hiroyuki Marusawa, Tsutomu Chiba. Mutation signature of TP53 gene in H. pylori-associated inflamed gastric mucosa during gastric carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5366. doi:10.1158/1538-7445.AM2014-5366