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. 1. Introduction Since 1870, both human and veterinary pathologists have described bacterial infections based on the observation of tiny curved bacteria within gastric mucosa [1, 2]. However, these organisms were dismissed as irrelevant contaminants. In 1947, when gastroscopy was first being used, Schindler deemed gastritis as “one of the most debated diseases of the human body” and predicted that its significance would be discussed “for some time to come” [3]. Schindler himself claimed that the “bacteriological etiology of chronic gastritis has not been convincingly proved in a single case” [3]. In 1984, Marshall and Warren proposed that chronic “idiopathic” gastritis had a bacterial cause, that is, Helicobacter pylori [4]. Their hypothesis was met with great skepticism. However, within a few years, the association between H. pylori gastritis, peptic ulcer, and gastric cancer came to be acknowledged and ultimately accepted [4]. For the purpose of this paper, we will focus mainly on the cascade of events produced by Helicobacter pylori infection leading to chronic changes in the gastric mucosa and the risk assessment for the development of gastric cancer. In addition, we will explore the epigenetic bases that underlie the changes of chronic gastritis. 2. Normal Gastric Histology In order to
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