Genome-wide DNA methylation profiles altered by Helicobacter pylori in gastric mucosa and blood leukocyte DNA

Zhang, Yang; Zhang, Xinran; Park, Jong‐Lyul; Kim, Jong-Hwan; Ma, Junling; Liu, Weidong; Deng, Dajun; You, Wei‐Cheng; Kim, Yongsung; Pan, Kai-Feng

doi:10.18632/oncotarget.9469

Cited by 19 publications

(15 citation statements)

References 36 publications

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“…A large number of DMPs (1,924) associated with H. pylori infection were identified, demonstrating the widespread deregulation of the methylome in normal gastric mucosa infected by H. pylori . A few previous studies have investigated the impact of H. pylori infection on DNA methylation in normal gastric mucosa . However, compared with these works, our study was not limited by sample size nor methylome coverage.…”

Section: Discussionmentioning

confidence: 99%

“…A number of studies have conducted DNA methylation analysis in GC tumours and their adjacent tissues using candidate gene or genome‐wide approaches; however, these studies were limited to cancer tissue, and the effects of H. pylori were not considered. Three studies have identified methylation signatures in normal gastric mucosa in response to H. pylori infection, but these involved only several genes or partial DNA methylome coverage or did not include GC patients . Two studies, which tested three candidate genes to identify risk markers for gastric metachronous cancer, were focused on the progression of cancer after excluding the effect of H. pylori infection .…”

Section: Introductionmentioning

confidence: 99%

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

Woo

Fernández-Jiménez

Ghantous

et al. 2018

Intl Journal of Cancer

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Woo

Fernández-Jiménez

Ghantous

et al. 2018

Intl Journal of Cancer

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“…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].…”

Section: Introductionmentioning

confidence: 99%

Endoscopic and Pathological Characteristics of Helicobacter pylori Infection-Negative Early Gastric Cancer

Mizutani

Araki

Saigo

et al. 2020

Dig Dis

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Background: The characteristics of Helicobacter pylori (HP) infection-negative gastric cancer (HPINGC) have not been well documented because of the rareness. The aim of this study was to classify HPINGC endoscopically and clinicopathologically. Methods: This retrospective study included 1,741 early gastric cancer lesions and evaluated their HP infection status. Expression levels of MUC5AC, MUC6, MUC2, CD10, p53, MIB-1, pepsinogen-I, H+/K+ ATPase, chromogranin A, E-cadherin, and gastrin were evaluated in tumors by immunohistochemistry (IHC). Results: Among the analyzed lesions, 19 (1.1%) were diagnosed as HPINGC and classified into 6 types: undifferentiated (5 lesions), fundic gland (2 lesions), cardiac gland (1 lesion), pyloric gland (3 lesions), foveolar (5 lesions), and mixed (3 lesions) types. Undifferentiated lesions were of pale color, with unclear demarcation and decreased E-cadherin expression. Fundic-type lesions were tan to reddish in color, with submucosal tumor-like protrusions, and positive for pepsinogen-I and H+/K+ ATPase. The cardiac gland type was located in the gastroesophageal junction and was positive for MUC6 and pepsinogen-I. Pyloric gland-type lesions were of the same color as normal mucosa, with mild elevation and unclear demarcation, likely positive for CD10 and chromogranin A. Foveolar epithelial-type lesions were white and elevated, with defined demarcation, and contained MUC5AC-positive cells. Mixed-type lesions, showing various staining patterns in IHC, had both elevated and depressed shape and reddish color. Conclusion: Endoscopic observation and IHC were useful for classifying the characteristics of HPINGC, which may preserve the characteristics of its region of origin.

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“…Aberrant methylation of regional promoter CpG islands frequently occurs in H pylori ‐infected gastric epithelia and is accompanied by severe inflammation and atrophy . Blood leukocyte DNA methylation at some tumor‐related genes is a powerful noninvasive biomarker to evaluate the risk of GC . However, the role of the methylation status of tumor‐related genes in blood samples of patients with GC lacks assessment.…”

Section: Discussionmentioning

confidence: 99%

Combined effect between WT1 methylation and Helicobacter pylori infection, smoking, and alcohol consumption on the risk of gastric cancer

Zhou

Sun

et al. 2019

Helicobacter

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Background: Peripheral blood leukocyte DNA methylation status has been proposed to be a surrogate marker for evaluating susceptibility to gastric cancer (GC).Helicobacter pylori (H pylori) infection, smoking, and alcohol consumption are known to induce gene methylation. A case-control study was performed to investigate the interactions between the methylation of two candidate genes and H pylori infection, smoking, and alcohol consumption in the risk of GC. Methods:A total of 400 GC cases and 402 controls were included in this study.The methylation status of WT1 and IGF2 was semiquantitatively determined by using methylation-sensitive high-resolution melting assays. H pylori IgG antibodies were detected by ELISA method.Results: Based on the area under the curve (AUC), 0% methylated DNA and 0.5% methylated DNA were used as the cutoff values for WT1 and IGF2, respectively. WT1 methylation was significantly associated with increased GC risk (OR = 1.65, 95% CI = 1.09-2.51, P = .019), especially in males (OR = 1.80, 95% CI: 1.10-2.95, P = .019) and older individuals (≥60 years) (OR = 2.03, 95% CI: 1.15-3.57, P = .014). A significant combination was observed between WT1 methylation and H pylori infection, alcohol consumption, and smoking for the risk of GC (OR c = 2.28, 95% CI = 1.47-3.55, P = .003, OR c = 2.19, 95% CI = 1.37-3.51, P = .001, OR c = 2.21, 95% CI = 1.39-3.51, P = .001, respectively). However, no association between IGF2 methylation and the risk of GC was found in this study.Conclusions: WT1 methylation may serve as a new potential biomarker for GC susceptibility and can combine with H pylori infection, smoking, and alcohol consumption to influence GC risk. K E Y W O R D SDNA methylation, gastric cancer, Helicobacter pylori, methylation-sensitive high-resolution melting, WT1

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Genome-wide DNA methylation profiles altered by Helicobacter pylori in gastric mucosa and blood leukocyte DNA

Cited by 19 publications

References 36 publications

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

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

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

Combined effect between WT1 methylation and Helicobacter pylori infection, smoking, and alcohol consumption on the risk of gastric cancer

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