In a groundbreaking series of studies, researchers from the University of Hong Kong’s Li Ka Shing Faculty of Medicine (HKUMed) have unveiled vital insights into the earliest molecular and cellular alterations that precipitate stomach cancer, one of the most lethal malignancies worldwide. Through sophisticated genome sequencing and innovative three-dimensional organoid modeling, these investigations illuminate the enigmatic initial phases of gastric tumorigenesis, potentially revolutionizing early detection and preventive strategies for this devastating disease.
Stomach cancer remains a significant public health challenge, particularly in East Asia, where incidence rates are among the highest globally. Chronic infection with Helicobacter pylori, affecting roughly 15% of Hong Kong’s population, is a well-established contributor, inducing persistent gastric inflammation that fosters precancerous lesions such as intestinal metaplasia (IM). However, the precise molecular events that drive the progression from normal gastric epithelium to early cancerous changes have remained obscure until now. The HKUMed team’s research significantly narrows this knowledge gap by constructing a detailed mutational atlas of the normal and preneoplastic stomach lining.
Using cutting-edge whole-genome sequencing technologies, the multidisciplinary collaboration, including scientists from the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard, meticulously analyzed 238 normal gastric mucosal samples and conducted targeted sequencing on an additional 829 specimens from patients both with and without stomach cancer across Hong Kong, the USA, and the UK. This extensive dataset provided unprecedented resolution to characterize somatic mutations accumulated over a lifetime in histologically normal stomach tissues.
Their findings reveal that normal gastric glands accrue approximately 28 mutations annually, but this mutational burden more than doubles in patients diagnosed with stomach cancer, especially within areas of intestinal metaplasia. Astonishingly, certain gastric regions exhibit structural chromosome abnormalities, such as trisomy in specific chromosomes, which appear to arise early—between adolescence and young adulthood—suggesting exposure to mutagenic agents possibly linked to inflammatory or infectious processes. This discovery provides compelling evidence of how chronic inflammation reshapes the genomic landscape long before cancer manifests clinically.
Complementing this genomic inquiry, the researchers employed organoid culture systems to generate three-dimensional models of intestinal metaplasia derived from gastric tissues of stomach cancer patients. Organoids replicate key architectural and functional features of the original tissue, enabling detailed study of cellular dynamics in a controlled laboratory environment. The team, led by Professors Helen Yan Hoi-ning and Leung Suet-yi, cultivated over 70 organoids representing various stages along the IM continuum, offering a dynamic platform to interrogate the earliest neoplastic transformations.
Intriguingly, the intestinal metaplasia organoids exhibited ‘hybrid’ cellular phenotypes expressing a blend of gastric and intestinal markers, a departure from the distinctly differentiated identities typical of normal stomach or intestinal cells. These hybrid cells also reactivated gene networks usually confined to fetal development, endowing them with plasticity akin to that observed in malignant tumors. This cellular ambiguity underpins the potential for these premalignant states to evolve aggressive characteristics, such as chromosomal gains (notably of chromosome 20) and anchorage-independent growth, hallmarks associated with malignancy and metastatic potential.
The implications of these discoveries extend beyond basic science, touching upon clinical translational applications in early diagnosis and risk stratification. Given the global IM prevalence of about 25%, accurately identifying high-risk individuals remains paramount. The organoid platform, by faithfully modeling early preneoplastic states, offers a promising avenue to differentiate patients likely to progress to invasive stomach cancer from those with stable disease, fostering personalized surveillance and treatment approaches.
Furthermore, the elucidation of specific mutational patterns and chromosomal aberrations linked to chronic inflammation and early life exposures underscores the necessity to understand environmental and lifestyle factors contributing to stomach carcinogenesis. Known risk enhancers include tobacco use, excessive alcohol consumption, high dietary salt intake, and persistent Helicobacter pylori infection—all of which may amplify genomic instability and accelerate malignant progression.
Beyond the potential for improved early detection, the availability of living organoid models promises to accelerate therapeutic innovation. These systems allow for high-throughput drug screening aimed at reversing or halting the progression of intestinal metaplasia before malignant transformation occurs. Professor Leung highlights that such models could facilitate the development of novel pharmacological interventions capable of modulating pre-cancerous lesions, potentially reducing the global burden of stomach cancer.
This comprehensive research endeavor was co-led by distinguished scientists including Professor Sir Michael R Stratton of the Wellcome Sanger Institute and Professor Leung Suet-yi, who holds multiple prominent positions within HKUMed, including Chairperson of the Department of Pathology and Director roles in pan-omic and oncology research centers. The deep collaboration across international institutions and disciplines underscores the critical nature of tackling stomach cancer through multifaceted scientific approaches.
Funding for these pivotal studies was provided by an array of notable institutions, notably the Centre for Oncology and Immunology under the Health@InnoHK Initiative, supported by the Hong Kong Government’s Innovation and Technology Commission, and the Wellcome Trust. Additional support came through charitable donations and competitive research grants, reflecting broad recognition of the global need to address stomach cancer through innovative research.
In summary, the HKUMed-led research charts a new frontier in understanding stomach cancer initiation by integrating comprehensive genomic analyses with advanced modeling of early pathological states. By capturing the silent, gradual accumulation of mutational changes and the dynamic plasticity of premalignant cells, these studies pave the way for transformative clinical interventions aimed at arresting stomach cancer at its very inception, potentially saving countless lives worldwide.
Subject of Research: Early molecular and cellular changes underlying stomach cancer initiation and progression.
Article Title: The somatic mutation landscape of normal gastric epithelium
News Publication Date: 10-Apr-2025
Web References:
Nature publication: https://www.nature.com/articles/s41586-025-08708-6
Gut publication: https://gut.bmj.com/content/74/4/522
Image Credits: The University of Hong Kong
Keywords: Stomach cancer, discovery research, cancer research, intestinal metaplasia, genomic mutations, organoid models, early cancer detection, gastric epithelium, Helicobacter pylori, chronic inflammation
Tags: chronic gastric inflammationearly detection stomach cancerearly genetic mutations stomach cancerEast Asia cancer incidencegastric tumorigenesis molecular alterationsgenome sequencing gastric cancerHelicobacter pylori infection stomach cancerHKUMed stomach cancer researchintestinal metaplasia risk factorsmultidisciplinary research gastric cancerpre-cancer model stomach cancerpublic health stomach cancer