Chihiro Takeuchi1, Junichi Sato2, Satoshi Yamashita1, Akiko Sasaki3, Takemi Akahane4, Rika Aoki5, Mitsue Yamamichi2, Yu-Yu Liu1, Masayoshi Ito6, Takahisa Furuta7, Shigemi Nakajima8, Yoshiki Sakaguchi2, Yu Takahashi2, Yosuke Tsuji2, Keiko Niimi9, Shuta Tomida10, Mitsuhiro Fujishiro2, Nobutake Yamamichi9, Toshikazu Ushijima11. 1. Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan. 2. Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 3. Department of Gastroenterology, Medicine Center, Shonan Kamakura General Hospital, Kanagawa, Japan. 4. Department of Gastroenterology, Nara Medical University, Nara, Japan. 5. Tokushima Health Screening Center, Tokushima, Japan. 6. Department of Gastroenterology, Yotsuya Medical Cube, Tokyo, Japan. 7. Center for Clinical Research, Hamamatsu University School of Medicine, Shizuoka, Japan. 8. Department of General Medicine, Consortium for Community Medicine, Japan Community Healthcare Organization Shiga Hospital, Shiga University of Medical Science, Shiga, Japan. 9. Center for Epidemiology and Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 10. Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan. 11. Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan. tushijim@ncc.go.jp.
Abstract
BACKGROUND: Autoimmune gastritis (AIG) is a chronic inflammatory condition in gastric mucosa and is associated with increased cancer risk, though not as high as that by Helicobacter pylori (H. pylori)-associated gastritis (HPG). Although aberrant DNA methylation is induced by HPG and the level correlates with the risk of gastric cancer, DNA methylation induction by AIG is unknown. METHODS: Gastric mucosa samples from the corpus were collected from 12 people with AIG without H. pylori infection, 10 people with HPG, and eight healthy volunteers. Genome-wide DNA methylation analysis was conducted using Infinium Methylation EPIC array. Gene expression was analyzed by quantitative RT-PCR. RESULTS: The AIG samples had extensive aberrant DNA methylation but presented unique methylation profiles against the HPG samples after correction of leucocyte fractions. Comparison between the AIG and HPG samples showed that AIG induced methylation, but less than HPG, in overall CpG sites and also in promoter CpG islands. Promoter CpG islands of tumor-suppressor genes in the pathway of cell cycle, cell adhesion, p53, and WNT were highly methylated in the AIG samples, but more so in the HPG samples. The expression levels of IL1B and IL8, secreted by macrophage, were significantly lower in the AIG samples than in the HPG samples, suggesting that a difference in inflammatory response affected the degree and patterns of aberrant DNA methylation. CONCLUSIONS: AIG induced aberrant DNA methylation in gastric mucosa. However, the degree of DNA methylation was less than that by HPG, which reflected carcinogenic risk.
BACKGROUND: Autoimmune gastritis (AIG) is a chronic inflammatory condition in gastric mucosa and is associated with increased cancer risk, though not as high as that by Helicobacter pylori (H. pylori)-associated gastritis (HPG). Although aberrant DNA methylation is induced by HPG and the level correlates with the risk of gastric cancer, DNA methylation induction by AIG is unknown. METHODS: Gastric mucosa samples from the corpus were collected from 12 people with AIG without H. pylori infection, 10 people with HPG, and eight healthy volunteers. Genome-wide DNA methylation analysis was conducted using Infinium Methylation EPIC array. Gene expression was analyzed by quantitative RT-PCR. RESULTS: The AIG samples had extensive aberrant DNA methylation but presented unique methylation profiles against the HPG samples after correction of leucocyte fractions. Comparison between the AIG and HPG samples showed that AIG induced methylation, but less than HPG, in overall CpG sites and also in promoter CpG islands. Promoter CpG islands of tumor-suppressor genes in the pathway of cell cycle, cell adhesion, p53, and WNT were highly methylated in the AIG samples, but more so in the HPG samples. The expression levels of IL1B and IL8, secreted by macrophage, were significantly lower in the AIG samples than in the HPG samples, suggesting that a difference in inflammatory response affected the degree and patterns of aberrant DNA methylation. CONCLUSIONS: AIG induced aberrant DNA methylation in gastric mucosa. However, the degree of DNA methylation was less than that by HPG, which reflected carcinogenic risk.
Authors: William L Neumann; Elizabeth Coss; Massimo Rugge; Robert M Genta Journal: Nat Rev Gastroenterol Hepatol Date: 2013-06-18 Impact factor: 46.802