Can Epigenetic and Gastric Microbiome Markers Predict the Risk of Helicobacter pylori-Negative Gastric Cancer - Research Perspectives

Sep 21, 2026

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Helicobacter pylori infection is a major gastric cancer risk factor, and eradication substantially lowers incidence, yet gastric cancer risk persists in H. pylori-negative disease. The article reviews field cancerization mechanisms in which temporary versus permanent DNA methylation changes remain differentially after eradication, enabling future risk prediction via aberrant promoter methylation. It also summarizes microbiome-based clues, where long-standing infection drives atrophy, dysbiosis, and bacterial populations linked to inflammation and genotoxin production, supporting combined biomarker research.

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Can epigenetic and microbiome markers predict H. pylori-negative gastric cancer risk?

Persistent risk after eradication and post-eradication surveillance needs

Field cancerization and persistent DNA methylation

Gastric mucosa-associated microbiome and dysbiosis mechanisms

Combined roles of DNA methylation and microbiome markers

Gut and Liver [https://doi.org/10.5009/gnl240280](https://doi.org/10.5009/gnl240280)[ ](https://doi.org/10.5009/gnl240280)[pISSN 1976-2283 eISSN 2005-1212](pISSN 1976-2283 eISSN 2005-1212) Can Epigenetic and Gastric Microbiome Markers Predict the Risk of Helicobacter pylori-Negative Gastric Cancer? Cheol Min Shin Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea Corresponding Author Cheol Min Shin ORCID [https://orcid.org/0000-0003-2265-9845](https://orcid.org/0000-0003-2265-9845)[ ](https://orcid.org/0000-0003-2265-9845)[E-mail](E-mailscm6md@gmail.com)[scm6md@gmail.com](E-mailscm6md@gmail.com) See “Combined DNA Methylation and Gastric Microbiome Marker Predicts Helicobacter pylori-Negative Gastric Cancer” by Min-Jeong Kim, et al. on page 611, Vol. 18, No. 4, 2024 Helicobacter pylori infection is a well-established risk factor for gastric cancer, increasing the risk by more than 2-fold, while its eradication reduces this risk by over 30%.1 Consequently, in regions with high gastric cancer prevalence, especially in Japan, aggressive eradication therapy has been implemented, resulting in a decreasing trend in gastric cancer incidence.2 While the incidence of H. pylorinegative gastric cancer is not high, the risk of developing gastric cancer remains even after H. pylori eradication. Recent studies have focused on identifying risk factors for gastric cancer in H. pylori-negative patients or those post-eradication. Identifying at-risk patients after eradication could facilitate targeted endoscopic surveillance and individualized scheduling of endoscopic examinations based on risk assessment. First, from the perspective of field cancerization, changes in the gastric mucosa due to H. pylori infection or chronic inflammation appear to be irreversible. It has been hypothesized that there are two types of methylation, one is a temporary methylation induced in progenitor or differentiated cells, and the other is a permanent methylation induced in stem cells (Fig. 1).3 During active H. pylori infection, both temporary and permanent components of methylation are induced in the gastric epithelium. However, when H. pylori infection discontinues, the temporary component of methylation will disappear (epithelial cells shedding out), leaving only the permanent component. As a result, the remaining permanent components correlate with the risk for gastric cancer. From this perspective, future risk of gastric cancer can be predicted through the analysis of aberrant DNA methylation in the promoters of micro-RNA genes or tumor suppressor genes or passenger (marker) genes. The aberrant methylation of marker genes does not decrease even after eradication and is closely associated with the risk of developing gastric cancer and metachronous recurrence after endoscopic treatment of early gastric cancer.4,5 Additionally, evidence suggested that the analysis of gastric mucosa-associated microbiome may provide clues to the development of gastric cancer after H. pylori eradication or in H. pylori-negative patients.6 Long-standing H. pylori infection induces gastric atrophy, leading to intragastric bacterial overgrowth due to increased gastric pH. Colonization of the gastric mucosa by lactic acid-producing bacteria, nitrate-reducing bacteria, or oral commensal bacteria is closely associated with the risk of gastric cancer.7 Especially, the lactic acid-producing bacteria promote the development of gastric cancer through the production of reactive oxygen species and N-nitroso compounds, which leads to an increase of intraepithelial inflammation, angiogenesis, and the metastasis. If the atrophic changes in the gastric mucosa do not improve after eradication therapy, persistent gastric dysbiosis may continuously increase the risk of gastric cancer. A recent study reported that gastric dysbiosis after H. pylori eradication, particularly with an increase in relative abundances of Fusobacterium and

FAQs

Why does gastric cancer risk remain even after H. pylori eradication?

Even after eradication, the risk of developing gastric cancer can persist because underlying molecular alterations and dysbiosis may not fully reverse. The article links this persistence to remaining permanent epigenetic changes and ongoing dysbiosis in the gastric mucosa.

How does field cancerization explain persistent DNA methylation signals?

Field cancerization proposes that methylation includes a temporary component induced during active infection and a permanent component established in stem cells. After infection stops and temporary methylation disappears, the remaining permanent methylation correlates with cancer risk.

What microbiome changes may contribute to H. pylori-negative gastric cancer development?

Long-standing infection can cause gastric atrophy and increase gastric pH, promoting intragastric bacterial overgrowth. The article highlights that specific bacterial populations and persistent dysbiosis may promote inflammation and genotoxin-related mechanisms.

Sep 21, 2026

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