Long-term effects of H. pylori eradication on epigenetic alterations related to gastric carcinogenesis

Abstract

The risk of gastric cancer (GC) remains in precancerous conditions, including atrophic mucosa and intestinal mucosa (IM), even after H. pylori treatment. To define the molecular changes following H. pylori eradication, molecular alterations in the gastric mucosa with and without GC were evaluated in a long-term follow-up study. A total of 232 biopsy specimens from 78 consecutive patients, including atrophic gastritis patients with follow-up ≥3 y after successful H. pylori eradication (AG group), patients who developed early GC after successful eradication (≥3 y) (GC group), and patients with H. pylori-positive atrophic gastritis (Hp group), were analyzed. H. pylori eradication was associated with significant reductions of methylation of several genes/loci in atrophic mucosa (non-IM), but not in IM. In contrast, the incidence of CpG island methylator phenotype (CIMP) in IM was significantly higher in the GC group than in the AG group. miR-124a-3 methylation and miR-34c methylation were more frequently identified in IM, with very few in non-IM mucosa among the three groups. H. pylori eradication can reverse methylation only in non-IM mucosa. CIMP in IM may have potential as a surrogate maker of GC development, and methylation of miR-124a-3 and miR-34c is a molecular event in IM that may not be associated with GC development.

DNA Methylation Silencing of microRNA Gene Methylater in the Precancerous Background Mucosa with and without Gastric Cancer: Analysis of Effects of <em>Helicobacter pylori</em> Eradication and Long-Term Aspirin Use

“…In eradication was associated with a significant reduction of miR-124a-3 methylation in both groups, which was consistent with our previous study [34]. In addition, miR-34c independent predictor of metachronous GC risk [37].…”

“…In the present study, the methylation of tumor-suppressor miRNAs was identified more frequently in IM and very infrequently in AM. It thus appears that the methylation of these genes is a molecular event that occurs specifically in IM, and also that IM might exhibit a more aggressive state than AM with regard to molecular alterations, as shown in our previous reports [33,34]. Intriguingly, only in H. pylori-eradicated patients, the number of IM samples obtained from three parts of the stomach was significantly higher in patients with GC (the Hp-/GC and Hp-/LDA/GC groups) than in those without GC (the Hp-/AG and Hp-/LDA/AG groups).…”

“…Japanese investigators have recently reported that miR-124a-3 and miR-34b/c methylation are informative markers for predicting the risk of metachronous GC in patients after endoscopic resection of early GC [29,36,37]. However, we reported that the incidences of methylation of miR-124a-3 and miR-34c were mostly observed in IM, with very few in AM [33,34]. Thus, our previous results indicate that the methylation of these miRNA genes might be a specific marker expressed in IM and might not necessarily be a risk marker for GC.…”

“…GC develops through the accumulation of genetic and epigenetic alterations. Many studies have reported that several epigenetic alterations, including promoter hypermethylation of multiple tumor-related genes, are associated with GC and precancerous conditions of the stomach from the viewpoint of H. pylori infection [22][23][24][25][26][27][28][29][30][31][32][33][34]. These reports demonstrate that H. pylori eradication led to a decrease in methylation levels at some genes [22][23][24][25][26][27], thus suggesting that the reduction of gene methylation reverse H. pylori-induced gastric carcinogenesis.…”

“…These reports demonstrate that H. pylori eradication led to a decrease in methylation levels at some genes [22][23][24][25][26][27], thus suggesting that the reduction of gene methylation reverse H. pylori-induced gastric carcinogenesis. However, there are no studies except ours [33,34] and a study by Huang et al [32] in which molecular events were analyzed in AM and IM separately using laser capture microdissection (LCM); thus, the actual effects of eradication therapy on molecular alteration in the precancerous conditions are not well known.…”