Helicobacter pylori-Induced Chronic Gastritis and Assessing Risks for Gastric Cancer

Gonzalo Carrasco, Alejandro H Corvalan, Gonzalo Carrasco, Alejandro H Corvalan

Abstract

Chronic gastritis is an inflammation of the gastric mucosa and has multiple etiologies. Here we discuss the pathological alterations induced by Helicobacter pylori (HP) leading to chronic gastritis and the epigenetic bases underlying these changes. We review the histology of the normal gastric mucosa and overview the role of HP in the multistep cascade of GC. We attempt to define the role of the Operative Link for Gastritis Assessment (OLGA) staging system in assessing the risk of GC. The epigenetic bases of chronic gastritis, mainly DNA methylation, are presented through examples such as (i) the methylation of the promoter region of E-cadherin in HP-induced chronic gastritis and its reversion after HP eradication and (ii) the association of methylation of the promoter region of Reprimo, a p53-mediated cell cycle arrest gene, with aggressive HP strains in high risk areas for GC. In addition, we discuss the finding of RPRM as a circulating cell-free DNA, offering the opportunity for noninvasive risk assessment of GC. Finally, the integration of OLGA and tissue biomarkers, by systems pathology approach, suggests that severe atrophy has a greater risk for GC development if, in addition, overexpressed p73. This trial is registered with ClinicalTrials.gov NCT01774266.

Figures

Figure 1
Figure 1
Normal gastric mucosa histology. ((a); H&E 10x; square 40x) Fundic glands are simple, branched tubular glands that extend from the bottom of the gastric pits to the muscularis mucosae; the more distinctive cells are parietal cells. ((b); H&E 10x; square 40x) Antral mucosa is formed by branched coiled tubular glands lined by secretory cells similar in appearance to the surface mucus cells.
Figure 2
Figure 2
Early acute superficial gastritis. ((a); H&E 20x) Marked neutrophilic infiltrates appear in the mucous neck region and lamina with a pit micoabscess. ((b); H. pylori immunostaining: rabbit polyclonal; clone CH-20 429, Novocastra; 40x) Numerous H. pylori bacteria are present in the superficial foveolar epithelium.
Figure 3
Figure 3
The Updated Sydney System visual standardized visual analogue scale. Each feature is assigned either a numeric or descriptive value: 0 for absent, 1 for mild, 2 for moderate, and 3 for marked (or severe). Taken from Dixon et al. [11].
Figure 4
Figure 4
Multistep cascade of gastric cancer. This sequence begins with the infection of H. pylori to sequential steps of the precancerous cascades. Taken from Correa and Piazuelo [20].
Figure 5
Figure 5
Atrophy is the loss of appropriate glands. ((a); H&E 10x) Antral gastric mucosa with accentuated atrophy because replacement by extensive intestinal metaplasia. ((b); H&E 10x; square 20x) Fundic-corporal gastric mucosa with extensive loss of gastric glands, partially replaced by pseudo-pyloric metaplasia.
Figure 6
Figure 6
CpG island methylation pattern at the E-cadherin gene in gastric mucosa from patients with dyspepsia. (a) Before eradication of H. pylori (week 0), methylation was present in patients 3, 5, and 6. (b) The methylated product was confirmed by sequencing using the same methylated primer. (c) After eradication of H. pylori (week 6), methylation was not present in any patient. (d) The methylated product was again confirmed by sequencing using the same methylated primer. No methylated cytosine was seen. MW: molecular weight marker, U: unmethylated band, M: methylated band, red color: unmethylated cytosines converted to thymidine, blue color: methylated cytosines. Taken from Chan and Rashid [45].
Figure 7
Figure 7
Serial analysis for microarray from nontumor adjacent mucosa (NTAM) and chronic gastritis controls. NTAM group is significantly characterized by the overexpression of p73, OLGA stages III to IV, and severe atrophy (ATR-3), intestinal metaplasia (IM-3), and chronic inflammation (CI-3) according to the Sydney System. Control group cases were significantly characterized by lack of intestinal metaplasia (IM-0), atrophy (ATR-0), and chronic inflammation (CI-0). False discovery rate = 0. Taken from Carrasco et al., [51].

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