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.
Highlights
The risk of gastric cancer (GC) remains in precancerous conditions, including atrophic mucosa and intestinal mucosa (IM), even after H. pylori treatment
H. pylori eradication was associated with a significant reduction of CpG island methylator phenotype (CIMP), including CDH1, CDKN2A, MINT1, MINT31, and miR-124a-3 methylation, in non-IM mucosa but not in IM
MiR-124a-3 methylation and miR-34c methylation are markers of dysregulation of noncoding RNA that occurred in IM but not in non-IM, and may not necessarily be associated with GC risk, unlike in previous reports[24,26,27,28,29]
Summary
In patients with non-IM, there were no significant differences of molecular events among the three sites of the stomach in both the Hp and AG groups. In the GC group, methylated-in-tumor-1 (MINT1), MINT31, and miR-124a-3 methylation tended to be frequently observed in the antrum to the angulus (P = 0.08, P = 0.05, and P = 0.02, respectively). In patients with IM, MINT31 and miR-34c methylation in the Hp group was significantly identified in the angulus (P = 0.02) and from the antrum to angulus (P = 0.046), respectively. In the GC group, the incidence of CIMP including MINT1, MINT31, and runt-related transcription factor 3 (RUNX3) methylation, tended to be frequently found from the antrum to the angulus compared to the corpus the number of IM samples in the corpus was very small. The methylation of miR-124a-3 and miR-34c showed a high incidence throughout the stomach in each group, being different from the incidences in non-IM (Table 2)
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