Expansion of Gastric Intestinal Metaplasia with Copy Number Aberrations Contributes to Field Cancerization

Autor: Ken Kumagai, Takahiro Shimizu, Atsushi Takai, Nobuyuki Kakiuchi, Yasuhide Takeuchi, Tomonori Hirano, Haruhiko Takeda, Aya Mizuguchi, Mari Teramura, Takahiko Ito, Eriko Iguchi, Mitsuhiro Nikaido, Yuji Eso, Ken Takahashi, Yoshihide Ueda, Shin'ichi Miyamoto, Kazutaka Obama, Seishi Ogawa, Hiroyuki Marusawa, Hiroshi Seno
Rok vydání: 2022
Předmět:
Zdroj: Cancer Research. 82:1712-1723
ISSN: 1538-7445
0008-5472
DOI: 10.1158/0008-5472.can-21-1523
Popis: Intestinal metaplasia (IM) is a risk factor for gastric cancer following infection with Helicobacter pylori. To explore the susceptibility of pure gastric IM to cancer development, we investigated genetic alterations in single IM gastric glands. We isolated 50 single IM or non-IM glands from the inflamed gastric mucosa of 11 patients with intramucosal gastric carcinoma (IGC) and 4 patients without IGC; 19 single glands in the noninflamed gastric mucosa of 11 individuals from our cohort and previous dataset were also included as controls. Whole-exome sequencing of single glands revealed significantly higher accumulation of somatic mutations in various genes within IM glands compared with non-IM glands. Clonal ordering analysis showed that IM glands expanded to form clusters with shared mutations. In addition, targeted-capture deep sequencing and copy number (CN) analyses were performed in 96 clustered IM or non-IM gastric glands from 26 patients with IGC. CN analyses were also performed on 41 IGC samples and The Cancer Genome Atlas-Stomach Adenocarcinoma datasets. These analyses revealed that polyclonally expanded IM commonly acquired CN aberrations (CNA), including amplification of chromosomes 8, 20, and 2. A large portion of clustered IM glands typically consisted of common CNAs rather than other cancer-related mutations. Moreover, the CNA patterns of clustered IM glands were similar to those of IGC, indicative of precancerous conditions. Taken together, these findings suggest that, in the gastric mucosa inflamed with H. pylori infection, IM glands expand via acquisition of CNAs comparable with those of IGC, contributing to field cancerization. Significance: This study contributes to our understanding of gastric intestinal metaplasia as a risk factor for gastric adenocarcinoma via their multifocal expansion and acquisition of CNAs and somatic mutations.
Databáze: OpenAIRE
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