Severe induction of aberrant DNA methylation by nodular gastritis in adults

• Published in: Journal of gastroenterology 2024-06, Vol.59 (6), p.442-456
• Main Authors: Sasaki, Akiko, Takeshima, Hideyuki, Yamashita, Satoshi, Ichita, Chikamasa, Kawachi, Jun, Naito, Wataru, Ohashi, Yui, Takeuchi, Chihiro, Fukuda, Masahide, Furuichi, Yumi, Yamamichi, Nobutake, Ando, Takayuki, Kobara, Hideki, Kotera, Tohru, Itoi, Takao, Sumida, Chihiro, Hamada, Akinobu, Koizumi, Kazuya, Ushijima, Toshikazu
• Format: Article
• Language: English
• Subjects: Abdominal Surgery; Adult; Aged; Antigens, CD - genetics; Antigens, CD - metabolism; Cadherins - genetics; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Chemokine CXCL13 - genetics; Chemokine CXCL13 - metabolism; Colorectal Surgery; CpG islands; CpG Islands - genetics; CXCL12 protein; CXCL13 protein; CXCR4 protein; CXCR5 protein; Death-associated protein kinase; Demethylation; Dioxygenases - genetics; DNA Methylation; DNA-Binding Proteins - genetics; E-cadherin; Female; Gastric cancer; Gastric mucosa; Gastric Mucosa - metabolism; Gastric Mucosa - pathology; Gastritis; Gastritis - genetics; Gastritis, Atrophic - genetics; Gastroenterology; Genomes; Hepatology; Humans; Male; Medicine; Medicine & Public Health; Middle Aged; Original Article—Alimentary Tract; Promoter Regions, Genetic; Proto-Oncogene Proteins - genetics; Pyloric Antrum - metabolism; Pyloric Antrum - pathology; Risk Factors; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Surgical Oncology; Tumor suppressor genes; Tumors
• ISSN: 0944-1174; 1435-5922
• DOI: 10.1007/s00535-024-02094-y

Background Nodular gastritis (NG) is characterized by marked antral lymphoid follicle formation, and is a strong risk factor for diffuse-type gastric cancer in adults. However, it is unknown whether aberrant DNA methylation, which is induced by atrophic gastritis (AG) and is a risk for gastric cancer, is induced by NG. Here, we analyzed methylation induction by NG. Methods Gastric mucosal samples were obtained from non-cancerous antral tissues of 16 NG and 20 AG patients with gastric cancer and 5 NG and 6 AG patients without, all age- and gender-matched. Genome-wide methylation analysis and expression analysis were conducted by a BeadChip array and RNA-sequencing, respectively. Results Clustering analysis of non-cancerous antral tissues of NG and AG patients with gastric cancer was conducted using methylation levels of 585 promoter CpG islands (CGIs) of methylation-resistant genes, and a large fraction of NG samples formed a cluster with strong methylation induction. Promoter CGIs of CDH1 and DAPK1 tumor-suppressor genes were more methylated in NG than in AG. Notably, methylation levels of these genes were also higher in the antrum of NG patients without cancer. Genes related to lymphoid follicle formation, such as CXCL13 / CXCR5 and CXCL12 / CXCR4 , had higher expression in NG, and genes involved in DNA demethylation TET2 and IDH1 , had only half the expression in NG. Conclusions Severe aberrant methylation, involving multiple tumor-suppressor genes, was induced in the gastric antrum and body of patients with NG, in accordance with their high gastric cancer risk.