HKUMed uncovers early mutations and risk factors for stomach cancer, and develops a pre-cancer model for stomach cancer prevention

Researchers from the Department of Pathology, School of Clinical Medicine at the LKS Faculty of Medicine of the University of Hong Kong (HKUMed) have made significant advancements in understanding the earliest stages of stomach cancer, a leading cause of cancer-related deaths worldwide, through two recent innovative studies. With a prevalence rates particularly high in East Asia, including China, this cancer often stems from chronic inflammation caused by Helicobacter pylori infection, which affects approximately 15% of the Hong Kong population. This inflammation can lead to a pre-cancerous stage known as intestinal metaplasia. The innovative studies have uncovered crucial insights into the earliest changes in the stomach that contribute to the development of stomach cancer, laying the foundation for improved prevention and early detection, ultimately saving lives.

While the stomach’s acidic environment aids digestion, it can induce cancer-causing mutations in normal stomach tissues as individuals age. However, the timing and mechanisms of these early changes and how they promote the progression to cancer remain largely unknown. HKUMed researchers provided valuable insights into these processes.

Mapping the origins of stomach cancer
In a collaborative study, researchers from HKUMed, the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard, analysed genetic mutations in normal stomach lining tissue using advanced genome sequencing. For the first time, they sequenced whole genomes from 238 samples and performed targeted sequencing on an additional 829 samples from individuals with and without stomach cancer in Hong Kong, the US and the UK. The study, published in Nature [link to the publication], revealed that despite the stomach's harsh acidic environment, the stomach lining has protective mechanisms that prevent significant mutations.

The study found that the number of mutations increases with age, with normal stomach glands accumulating approximately 28 mutations annually. In stomach cancer patients, the mutation rate is more than double, especially in the metaplastic glands. Professor Leung Suet-yi, co-lead author of the research and Chairperson of the Department of Pathology, School of Clinical Medicine, HKUMed, said, ‘By age 60, nearly 10% of the stomach lining has mutations in known cancer genes, highlighting a gradual accumulation of potential cancer-causing changes over decades. The most surprising finding was that some stomach regions exhibited chromosome abnormalities linked to chronic inflammation. Usually, cells have two copies of each chromosome, but researchers found some patients’ stomach cells had three copies of a chromosome. Shockingly, the extra chromosome was often acquired very early in life (age 12–25), suggesting potential exposure to a causal mutagen such as an infectious pathogen.

Risk factors for stomach cancer include being smoking, excessive alcohol drinking, a high salt diet, and a Helicobacter pylori infection. Professor Leung elaborated, ‘Our multinational team found that individuals with long-term stomach inflammation had significantly more mutations or extra chromosomes, indicating the potential role of inflammation in shaping a pre-cancer environment from an early age.’ Overall, the research contributes to a mutational map of the gastrointestinal tract, revealing early mutations, long before cancer develops, which could be useful for early detection and prevention strategies.

World’s first biobank of ‘intestinal metaplasia’ organoid models to study early cancer development
In a related study, researchers from HKUMed and the InnoHK Centre for Oncology and Immunology investigated intestinal metaplasia (IM) in which stomach cells are transformed to resemble intestine cells. This transformation significantly increases the risk of developing stomach cancer, but the process remains poorly understood. Co-led by Professor Helen Yan Hoi-ning, Assistant Professor in the Department of Pathology at HKUMed, and Professor Suet Yi Leung, the study used organoid culture to make a 3D model of IM. Organoids, tiny versions of organs grown in the lab from a patient's tissue, provide a realistic model for studying the progression of IM to cancer. Professor Yan explained that they grew a collection of 70 organoids from tissue samples of 47 stomach cancer patients at Queen Mary Hospital, spanning a range of stages from normal to advanced IM.

Published in Gut [link to the publication], the study revealed that IM organoids contain ‘hybrid’ cells with a mix of both stomach and intestinal characteristics. Typically, cells have a set identity (stomach cells maintain stomach features), but these hybrid cells display confusion, as they are part stomach and part intestine. They also express genes normally active only in developing foetuses, allowing them to partially transform into different cell types. This flexibility mirrors the adaptive nature of cancer cells, which grow uncontrollably. Understanding this flexibility is key to learning how cancer develops and resists treatment. Another important finding was that IM cells often have chromosome 20 gain and can grow without attaching to a surface—traits typically associated with cancer cells that facilitate tissue spread. Identifying these specific genetic changes linked to IM could detect early warning signs of stomach cancer and reveal potential targets for early intervention.

With a global prevalence of 25%, identifying high-risk groups for targeted intervention in IM is crucial. Professor Yan explained, ‘Using organoid technology, we can identify early changes when stomach cells become pre-cancerous. This can help clinicians assess which patients are at high risk of developing stomach cancer and reassure those with IM who are at lower risk. Our goal is to accelerate the detection of these early signs and introduce this technology to clinics for better risk assessment.’

Harnessing innovation for early detection and prevention
By uncovering the earliest mutations and risk factors associated with stomach cancer and developing a sophisticated pre-cancer model, these studies offer invaluable insights for current prevention and early detection strategies. Professor Leung Suet-yi said, ‘With a living cell model now available, the potential for drug development to reverse IM becomes increasingly achievable. These breakthroughs provide new hope in the fight against stomach cancer, potentially transforming patient outcomes and clinical practices.’

More details about the studies and the research teams:
The research study titled The somatic mutation landscape of normal gastric epithelium published in Nature was co-led by Professor Sir Michael R Stratton from the Wellcome Sanger Institute and Professor Leung Suet-yi. The latter is Chairperson of the Department of Pathology, School of Clinical Medicine; Y W Kan Professor in Natural Sciences and Chair Professor of Gastrointestinal Cancer Genetics and Genomics; Director of the Centre for PanorOmic Sciences and the Jockey Club Centre for Clinical Innovation and Discovery; and Co-director of the InnoHK Centre for Oncology and Immunology, Ltd (COI); all under HKUMed. The first author of the study was Dr Tim Coorens from the Broad Institute of MIT and Harvard.

The research study titled Divergent lineage trajectories and genetic landscapes in human gastric intestinal metaplasia organoids associated with early neoplastic progression published in Gut was co-led by Professor Helen Yan Hoi-ning (Assistant Professor in the Department of Pathology, School of Clinical Medicine; and Principal Investigator at the COI; HKUMed) and Professor Leung Suet-yi. The first authors were Dr Sarah Yue and Dr Yin Tong, both from Professors Yan and Leung’s lab. Another key research team member was Professor Simon Law Ying-kit, Department of Surgery, School of Clinical Medicine, HKUMed.

Acknowledgments
This research was funded by the Centre for Oncology and Immunology under the Health@InnoHK Initiative funded by the Innovation and Technology Commission, The Government of Hong Kong SAR, China, and the Wellcome Trust, along with donations from the Kadoorie Charitable Foundation and The Hong Kong Jockey Club Charities Trust. It also received separate grants under the Theme-based Research Scheme and the General Research Fund from the Research Grants Council, HKSAR, China.

Media enquiries
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