Abstract 2325: Anatomical genomic and transcriptomic analyses of Helicobacter pylori-driven gastric transformation

Abstract Helicobacter pylori (HP) drives a chronic inflammation in the gastric mucosa, leading to atrophic gastritis, intestinal metaplasia (IM), and further culminating in gastric cancer. Oncogenesis by HP infection has been mainly attributed to epigenetic dysregulation, and recent advances in the understanding of clonal expansion have shed light on the mutational architecture of IM. However, these analyses have been performed separately, leaving our understanding fragmented. Furthermore, analyses on small-sized tissue cannot determine the spatial events in the entire stomach. These limitations of previous studies highlight the necessity for integrative genomic and transcriptomic analyses using the entire stomach samples. Here, we conducted exome sequencing on 295 crypts isolated from the gastric mucosa and 13 tumors of 13 individuals. In addition, we performed an extensive investigation of the spatial distribution of cell clones by characterizing crypts at 5 mm intervals from 360 areas in the pyloric region to the body regions throughout the stomach in 2 patients, which underwent RNA and exome sequencing. Mutational analyses revealed that the expansion of cell clones with gene mutations was accelerated by HP infection and smoking habits. Mutations in cancer-related genes, including MUC6, were positively selected in the crypts, specifically in the pylorus region. However, such gene sets mutated in the crypts were different from those in gastric cancer. Macroscopic spatial genomic analyses revealed the distribution profiles of these clones, and spatial transcriptomic examination further clarified an IM-specific expression profile with oncogenic potential. These results suggest a coordinated role for mutation acquisition and transcriptomic activation of the AP-1 signaling pathway or stem-like expression in HP-infected mucosa to drive oncogenesis. Our study elucidated the previously unknown coordinated relationship between clone formation and transcriptomic remodeling of HP-infected gastric mucosa. Given the oncogenic transcriptional circuit of IM, early Helicobacter pylori eradication, smoking cessation, and close monitoring of IM may be beneficial to reduce the opportunity of additional hazardous mutation acquisition. Citation Format: Yosuke Tanaka, Fumishi Kishigami, Toshihide Ueno, Shinya Kojima, Taiki Hashimoto, Yukinori Yamagata, Takaki Yoshikawa, Shigeki Sekine, Hiroyuki Mano. Anatomical genomic and transcriptomic analyses of Helicobacter pylori-driven gastric transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2325.