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.

Figure 1

Changes of MSI and CIMP in the AG and GC groups. (A) The data points within the shaded t = 0 region indicate the Hp group. In non-IM, both MSI and CIMP have mostly disappeared after H. pylori eradication in the AG group. The incidence of CIMP increases gradually, but does not show a significant change in the GC group. (B) In IM, the incidence of MSI and CIMP do not show significant changes after treatment in the AG group. The incidence of CIMP remains persistently high in the GC group.

Figure 2

Changes of molecular alterations in non-IM after H. pylori eradication in the AG and GC groups. The data points within the shaded t = 0 region indicate the Hp group. In non-IM, methylation of most genes evaluated disappears after eradication. Although the incidence of CDH1 gene methylation decreases over time, the methylation does not disappear completely for up to more than 11 years. In the GC group, the incidence of CDH1, CDKN2A (P trend = 0.04), MINT1 (P trend = 0.02), and MINT31 gene methylation increases gradually after 11 years of eradication. miR-124a-3 methylation and miR-34c methylation are minimally detected after H. pylori treatment in both the AG and GC groups.

Figure 3

Changes of molecular alterations in IM after H. pylori eradication in the AG and GC groups. In IM, MINT1 methylation and MINT31 methylation maintain a high incidence, and methylation of other genes does not also show a significant change in the AG group. In the GC group, the incidences of MINT1, MINT31, and RUNX3 methylation remain persistently high, and that of MGMT methylation gradually increases more than 11 years after eradication (P trend = 0.0004). miR-124a-3 methylation and miR-34c methylation in IM are persistently high even after eradication in both groups.

Figure 4

mAb Das-1 reactivity to IM in different parts of the stomach in the three groups. The reactivity is the highest in the angulus compared to the other parts in each group, especially in the Hp group (P = 0.02). In the GC group, mAb Das-1 reactivity is high throughout the stomach, and thus there is a significant difference in reactivity in the antrum and corpus sites between the Hp (0%, 0 of 9) and GC groups (55.6%, 10 of 18) (P = 0.009).