Gastric Mucosal Atrophy Impedes Housekeeping Gene Methylation in Gastric Cancer Patients

• Published in: Cancer research and treatment 2019, 51(1), , pp.267-279
• Main Authors: Oh, Jung-Hwan, Rhyu, Mun-Gan, Kim, Suk-Il, Yun, Mi-Ri, Shin, Jung-Ha, Hong, Seung-Jin
• Format: Article
• Language: English
• Subjects: Age Factors; Aged; Alu Elements; Biopsy; CpG Islands; Disease Progression; DNA Methylation; Female; Gastritis, Atrophic - genetics; Gastritis, Atrophic - microbiology; Gastritis, Atrophic - pathology; Genes, Essential; Helicobacter Infections - complications; Helicobacter Infections - genetics; Helicobacter Infections - pathology; Humans; Male; Middle Aged; Original; Promoter Regions, Genetic; Stomach Neoplasms - genetics; Stomach Neoplasms - microbiology; Stomach Neoplasms - pathology; Trefoil Factor-3 - genetics; 의약학
• ISSN: 1598-2998; 2005-9256
• DOI: 10.4143/crt.2018.085

Helicobacter pylori infection induces phenotype-stabilizing methylation and promotes gastric mucosal atrophy that can inhibit CpG-island methylation. Relationship between the progression of gastric mucosal atrophy and the initiation of CpG-island methylation was analyzed to delineate epigenetic period for neoplastic transformation. Normal-appearing gastric mucosa was biopsied from 110 H. pylori-positive controls, 95 H. pylori-negative controls, 99 gastric cancer patients, and 118 gastric dysplasia patients. Gastric atrophy was assessed using endoscopic-atrophic-border score. Methylation-variable sites of eight CpG-island genes adjacent to Alu (CDH1, ARRDC4, PPARG, and TRAPPC2L) or LTR (MMP2, CDKN2A, RUNX2, and RUNX3) retroelements and stomach-specific TFF3 gene were analyzed using radioisotope-labeled methylation-specific polymerase chain reaction. Mean ages of H. pylori-positive controls with mild, moderate, and severe atrophy were 51, 54, and 65 years and those of H. pylori-associated TFF3 overmethylation at the three atrophic levels (51, 58, and 63 years) tended to be periodic. Alu-adjacent overmethylation (50 years) was earlier than TFF3 overmethylation (58 years) in H. pylori-positive controls with moderate atrophy. Cancer patients with moderate atrophy showed late Alu-adjacent (58 years) overmethylation and frequent LTR-adjacent overmethylation. LTR-adjacent overmethylation was frequent in cancer (66 years) and dysplasia (68 years) patients with severe atrophy. Atrophic progression is associated with gastric cancer at moderate level by impeding the initiation of Alu-adjacent methylation. LTR-adjacent methylation is increased in cancer patients and subsequently in dysplasia patients.