title: Slow overmethylation of housekeeping genes in the body mucosa is associated with the risk for gastric cancer.
abstract: Helicobacter pylori infection increases age-related diverse overmethylation in gene-control regions, which increases the risk of gastric cancer. The H. pylori-associated overmethylation changes subsequently disappear when gastric atrophy and cancer develop. To identify cancer-risk epigenotypes, we traced dynamic methylation changes in the background mucosa of the stomach depending on the extent of gastric atrophy. Paired biopsy specimens were obtained from the noncancerous antrum and body mucosa of 102 patients with cancer and 114 H. pylori-positive and 112 H. pylori-negative controls. The grade of gastric atrophy was evaluated using the endoscopic atrophic border score. The methylation-variable sites at the CpG-island margins and near the transcriptional start sites lacking CpG islands were semiquantitatively analyzed by radioisotope-labeling methylation-specific PCR. We selected eight housekeeping genes adjacent to Alu (CDH1, ARRDC4, PPARG, and TRAPPC2L) or LTR retroelements (MMP2, CDKN2A, RUNX2, and RUNX3) and eight stomach-specific genes (TFF2, PGC, ATP4B, TFF1, TFF3, GHRL, PGA, and ATP4A). Analysis of age-related methylation in the H. pylori-positive controls revealed slow overmethylation in the body and in the LTR-adjacent genes. A high-frequency overmethylation defined based on the slowly overmethylated genes was frequently observed in the body of patients with gastric cancer with open-type atrophy (OR, 12.7; 95% confidence interval, 3.2-49.8). The rapidly changing methylation of Alu-adjacent genes was barely increased in the antrum of patients with gastric cancer. Among diverse methylation changes associated with H. pylori infection, an increase in slowly changing methylation could serve as a cancer-risk marker.
authors.affiliation: Authors' Affiliations: Departments of Internal Medicine, Microbiology, and Preventive Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Oh
authors.affiliation: Authors' Affiliations: Departments of Internal Medicine, Microbiology, and Preventive Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Mun-Gan
authors.initials: MG
authors.lastname: Rhyu
authors.affiliation: Authors' Affiliations: Departments of Internal Medicine, Microbiology, and Preventive Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Jung
authors.affiliation: Authors' Affiliations: Departments of Internal Medicine, Microbiology, and Preventive Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Choi
authors.affiliation: Authors' Affiliations: Departments of Internal Medicine, Microbiology, and Preventive Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Suk-Il
authors.initials: SI
authors.lastname: Kim
authors.affiliation: Authors' Affiliations: Departments of Internal Medicine, Microbiology, and Preventive Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea hongsjin@catholic.ac.kr.
authors.forename: Seung-Jin
authors.initials: SJ
authors.lastname: Hong
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D020043:Genes, Essential; D016481:Helicobacter Infections / Q000150:complications; D016480:Helicobacter pylori / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane / Q000378:metabolism* / Q000473:pathology; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000071164:Trefoil Factor-2
chemical_list: C000604007:TFF2 protein, human; D000071164:Trefoil Factor-2