31 Jan Mutational Signatures and Clonal Hematopoiesis in Intestinal Metaplasia across Countries with Varying Stomach Cancer Incidence

MedicalResearch.com Interview with:

Prof. Yeoh Khay Guan & Prof Patrick Tan

Professor Patrick Tan, MD PhD
Dean, Duke-NUS Medical School;
Cancer and Stem Cell Biology Signature Research Programme,
Duke-NUS Medical School; and

Professor Yeoh Khay Guan, MBBS
Chief Executive, National University Health System;
Senior Consultant
Division of Gastroenterology and Hepatology
National University Hospital.

MedicalResearch.com: What is the background for this study?

Response: Gastric intestinal metaplasia (IM) is a precancerous condition that can arise in the stomach after long-term infection with Helicobacter pylori (a common stomach bacterium).

Clinically, IM is recognised as a risk state for gastric cancer (GC), as individuals with IM have 6-fold higher risk of eventually developing GC. However, not all IM patients will develop GC, and we lack an understanding of the biological processes operating within IM to transition to GC. Also, we don’t know if these processes are commonly found across the world, particularly since different countries have different rates of GC incidence.

In this study, we looked at DNA mutations and mutational signatures in IM samples collected from six countries with varying GC incidence (including accompanying blood-derived genetic variants). We wanted to understand potential risk factors for GC and how this information can be harnessed to improve the clinical management of IM patients and to reduce their GC risk.

MedicalResearch.com: What are the main findings?

• IM samples from patients exhibit a substantial burden of DNA mutations compared to normal tissues. We detected a specific mutation pattern in IMs (“SBS17”), not commonly observed in normal stomach tissues, that may contribute to these mutations. SBS17 mutations are likely caused by oxidative damage.
• We found that IMs from different countries showed different patterns of DNA mutations, possibly contributing to different local rates of GC. These included local environmental conditions such as the strains of Helicobacter pylori present, and specific gene mutations that may accelerate the risk of GC development.
• In many IM samples, we found mutations that activate the KRAS-MAPK pathway. Once this pathway is switched on, IM cells tend to assume a more proliferative state. Because this pathway is druggable, this raises the possibility of targeted intervention using agents such as pyrvinium to delay the transition from IM to gastric cancer.
• We also observed a higher prevalence of clonal haematopoiesis (CH) in the blood of IM patients who eventually develop GC or dysplasia. CH is a genetic condition of the blood that often develops as we age. We found that CH may contribute to GC risk by altering the immune properties of the stomach, leading to overgrowth of oral bacteria.
• Collectively, these data point to molecular features in IM that could help identify higher-risk individuals and inform prevention and surveillance strategies.

 
 
MedicalResearch.com: Does Helicobacter pylori or alcohol play a role in the development of gastric cancer?

Response:  Helicobacter pylori: Yes. Helicobacter pylori (H. pylori) is a WHO class I carcinogen and the strongest known risk factor for gastric cancer. Chronic infection drives atrophic gastritis and IM, setting the stage for dysplasia and cancer. However, eradication reduces—but does not completely eliminate—future cancer risk, particularly if premalignant changes have already occurred.

Alcohol: Heavy alcohol consumption has been associated with a modest increase in gastric cancer risk in several studies. However, not all cohorts show a strong association. Interestingly, the risk seems higher in individuals with ALDH2 deficiency (a genetic variant common in East Asia) due to acetaldehyde accumulation.

MedicalResearch.com: What might account for the increased incidence of gastric cancer in East Asia?

Response:  The higher incidence of gastric cancer in East Asia is likely explained by the consequence of interactions between environmental factors like Helicobacter pylori, genetic profiles of the host (person), and lifestyle factors.

Helicobacter pylori:  In East Asian countries, there is a higher prevalence of H. pylori infection compared to other countries. In our study, we also found that there are specific H. pylori genetic variants in a key gene called CagA, found in East Asian but not in South East Asian countries. These East Asian CagA variants that can bind more strongly to key human proteins and potentially enhance cancer risk.

Host genetic factors: Between countries, differences in the frequency of mutations found in IM, either overall or in specific genes such as ARID1A, may contribute to regional differences in cancer risk. In the current paper, we also found that clonal hematopoiesis (CH), a genetic condition associated with aging and systemic inflammation, was a major factor contributing to gastric cancer development.

Lifestyle factors: Diets high in salt and preservatives are known to increase the risk of GC.  Smoking is a well-established risk factor, while alcohol may increase gastric cancer risk in specific subgroups. In our study, we find that smoking was associated with higher SBS17 mutation levels and expansion of CH levels, demonstrating how these different factors can interact.

MedicalResearch.com: How will your study findings present new opportunities for prevention and screening?

Gastric intestinal metaplasia has emerged as a key pre-cancerous lesion in the development of GC, and an actionable checkpoint for the prevention of GC.

Identifying people with the highest risk for GC: Our findings go beyond traditional histological assessment by identifying key molecular biomarkers for risk stratification. The presence of ARID1A mutations and high-level clonal hematopoiesis (CH) were both independently associated with a higher risk of progression to gastric neoplasia. By integrating these specific genomic markers, along with overall mutational levels and clinical factors such as OLGIM stage, we can develop a robust predictive model. This can help identify a small subset of patients with a higher likelihood of progression to cancer, allowing us to focus on patients with the highest risk, and reducing the burden of screening on those at low risk.

Targeted prevention: Our study suggests potential therapeutic strategies to inhibit IM progression. This includes pyrvinium, which targets the KRAS/MAPK pathway, and antimicrobial therapy, which can address the pro-inflammatory oral bacteria found in high-risk CH carriers. For patients at very high risk of developing gastric cancer, targeted prevention using these approaches may reduce the risk of developing gastric cancer. 

MedicalResearch.com: What should readers take away from your report?

Response: There are distinct patterns of Helicobacter pylori infection status and strains between high-risk and low/intermediate risk countries. Specific CagA gene variants may influence Helicobacter pylori virulence by altering CagA binding affinity to key human proteins involved in cancer.

Key human cancer genes are mutated in IM at different frequences in high-risk vs intermediate-risk regions. Specifically. ARID1A mutations associated with high-risk population represent a risk factor for progression to GC.

Frequent mutation and activation of the KRAS-MAPK pathway in IM suggests therapeutic targeting of this pathway could prevent or delay subsequent cancer development.

SBS17 is a distinctive mutational signature in IM, possibly driven by oxidative stress-induced damage to free nucleotide pools, DNA hypomethylation and tobacco exposure.

CH, a genetic condition of the blood associated with aging, is an independent risk factor for GC progression in IM patients, possibly by modulating host-microbe-immune interactions. This may explain why most gastric cancers occur during advanced age.

MedicalResearch.com: What recommendations do you have for future research as a results of this study?

Validating biomarkers in longitudinal cohorts: Our findings should be validated in independent studies. This will require tracking patients with IM over time to validate the association between our identified biomarkers – such as clonal haematopoiesis or specific driver mutations like ARID1A – and the actual progression risk, enabling the development of validated molecular risk scores to identify high-risk patients.

Multi-omic integration: Combine our genetic findings with other molecular levels, such as epigenetics, transcriptomics, proteomics, and microbiome profiling, will provide a fuller picture of the gastric premalignant ecosystem.

Intervention trials: Test whether interventions beyond standard H. pylori eradication—such as targeted antimicrobial therapies against oral bacteria—can reduce gastric inflammation and lower progression risk. Second, evaluate targeted drugs such as pyrvinium for safety and efficacy in intercepting IM progression and preventing early gastric neoplasia.

Citation: Kie Kyon Huang, Takeshi Hagihara, Benedict Shi Xiang Lian, Zhi Xuan Ong, Shen Kiat Lim, Roxanne Hui Heng Chong, Supriya Srivastava, Jason Xing Kang, May Yin Lee, Angie Lay-Keng Tan, Minghui Lee, Shamaine Wei Ting Ho, Siti Aishah Binte Abdul Ghani, Clara Shi Ya Ng, Ruanyi Liang, Lin Liu, Su Ting Tay, Xuewen Ong, Feng Zhu, Hui Chen, Zhen Li, Tiing Leong Ang, Takuji Gotoda, Robert J. Huang, Christopher J.L. Khor, Hyun-Soo Kim, Louis Ho Shing Lau, Yi-Chia Lee, Ayaka Takasu, Ming Teh, Mann Yie Thian, Wai Leong Tam, Xin Lu, Sunny H. Wong, Jimmy B.Y. So, Hyunsoo Chung, Jonathan Lee, Khay Guan Yeoh, Patrick Tan; for the Singapore Gastric Cancer Consortium, Mutational Signatures and Clonal Hematopoiesis in Intestinal Metaplasia across Countries with Varying Stomach Cancer Incidence. Cancer Discov 2026;
https://doi.org/10.1158/2159-8290.CD-25-0778

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Last Updated on January 31, 2026 by Marie Benz MD FAAD