Genome‐wide profiling of normal gastric mucosa identifies Helicobacter pylori‐ and cancer‐associated DNA methylome changes

Abstract

The large geographic variations in the incidence of gastric cancer (GC) are likely due to differential environmental exposures, in particular to Helicobacter pylori (H. pylori) infection. We aimed to investigate the impact of H. pylori on the epigenome in normal gastric mucosa and methylation changes associated with cancer risk independent of H. pylori. A discovery set of normal gastric mucosa from GC cases (n = 42) and controls (n = 42), nested in a large case-control study and stratified by H. pylori status, were subjected to genome-wide methylation profiling. Single-nucleotide polymorphism arrays from peripheral blood leukocytes were used to conduct methylation quantitative trait loci (mQTL) analysis. A validation set of gastric mucosa samples (n = 180) was used in the replication phase. We found 1,924 differentially methylated positions (DMPs) and 438 differentially methylated regions (DMRs) associated with H. pylori infection, most of which were hypermethylated. Significant methylation alterations identified in the initial set were successfully replicated. Furthermore, the H. pylori-associated DMP/Rs showed marked stability ('epigenetic memory') after H. pylori clearance. Interestingly, we found 152 DMRs associated with cancer risk independent of the H. pylori status in normal gastric mucosa. The methylation score derived from three biomarkers was a strong predictor of GC. Finally, the mQTL analysis indicated that the H. pylori- and cancer-specific methylation signatures were minimally affected by genetic variation. The comprehensively characterized methylome changes associated with H. pylori infection and GC risk in our study might serve as potential biomarkers for early cancer progression in tumour-free gastric mucosa.

Endoscopic and Pathological Characteristics of <b><i>Helicobacter pylori</i></b> Infection-Negative Early Gastric Cancer

“…The relationship between HP infection and gastric carcinogenesis has been substantially demonstrated. The carcinogenicity of HP has been well established, involving the injection of CagA by type IV secretion systems [4][5][6][7] or alterations to the DNA methylome [8][9][10][11]. Importantly, several prospective studies had stated that gastric cancer develops only in patients with HP infection [12,13].…”

The Promises and Challenges of Toxico-Epigenomics: Environmental Chemicals and Their Impacts on the Epigenome

“…Following the frequent inclusion of epigenetics as a parameter in environmental epidemiology studies, numerous reports have been made in recent years associating alterations in DNA methylation with various environmental factors, including biological agents, dietary habits, and air pollution (Ambatipudi et al 2016;Barouki et al 2018;de FC Lichtenfels et al 2018;Degli Esposti et al 2017;Fasanelli et al 2019;Feil and Fraga 2012;Hattori and Ushijima 2016;Herceg et al 2018;Martin and Fry 2018;Perrier et al 2019;Woo et al 2018). Similarly, many reports indicate that microRNA (miRNA) profiles are responsive to various environmental exposures, including air pollution ; Espín-Pérez et al (2018), both epidemiological studies], nanoparticles [Brzóska et al (2019), utilizing human liver cells], endocrine disruptors, such as bisphenol A (BPA) [Chou et al (2017), using human endometrial cells, and Martínez-Ibarra et al (2019), using human blood samples], and dichlorodiphenyltrichloroethane (DDT) [Krauskopf et al (2017), using human blood]. Long noncoding RNAs (lncRNAs), although still a relatively new area of research, have been reported to be associated with levels of phthalates in first trimester urine of pregnant women (LaRocca et al 2014), benzene in seven exposed individuals (Bai et al 2014b), and occupational exposure to cadmium (Zhou et al 2015) and to be responsive to developmental exposure to BPA in mice (Kumamoto and Oshio 2013) and to certain heavy metals in in vitro (Tani et al 2014;Zhou et al 2015) and in vivo experimental systems (Zhou et al 2015).…”

Alterations in Gastric Microbial Communities Are Associated with Risk of Gastric Cancer in a Korean Population: A Case-Control Study

“…The HP status was determined via Wright-Giemsa staining of the biopsy specimens by a pathologist who specialized in GC. A current infection was defined as at least one positive test result in the rapid urease test or histological evaluation of four biopsy sites [62]. Participants were asked to complete a self-administered questionnaire.…”