New Insights into Early Mutations Linked to Stomach Cancer Development

Researchers at the University of Hong Kong have made pivotal strides in understanding the initial stages of stomach cancer, which is a major contributor to cancer-related fatalities globally. Their findings, published in notable journals, enhance knowledge about how stomach cancer develops, particularly in regions with high prevalence rates such as East Asia.

The studies reveal that chronic inflammation from Helicobacter pylori infection, which affects about 15% of Hong Kong's population, can lead to a pre-cancerous stage known as intestinal metaplasia. This transformation is crucial as it significantly increases the risk of developing stomach cancer.

The research team, collaborating with prestigious institutions such as the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard, conducted a thorough analysis of genetic mutations in the stomach lining. Utilizing advanced genome sequencing techniques, they sequenced the entire genomes of 238 samples and performed targeted sequencing on an additional 829 samples from individuals with and without stomach cancer across Hong Kong, the United States, and the United Kingdom.

Findings indicate that while the stomach's acidic environment has defensive mechanisms to prevent extensive mutations, the mutation rate escalates with age. Specifically, normal stomach glands accumulate approximately 28 mutations each year. In patients with stomach cancer, this mutation rate is notably higher, particularly within metaplastic glands.

Remarkably, the study revealed that nearly 10% of the stomach lining in individuals around the age of 60 exhibits mutations in known cancer-related genes. A surprising discovery showed that certain stomach regions presented chromosome abnormalities associated with chronic inflammation. Some patients' stomach cells had three copies of a chromosome, a condition often acquired early in life, suggesting exposure to potential mutagens.

Risk factors contributing to stomach cancer include habits like smoking, excessive alcohol consumption, a high-salt diet, and Helicobacter pylori infections. The researchers noted that individuals experiencing long-term stomach inflammation exhibited a higher mutation frequency, highlighting inflammation's role in creating a pre-cancerous environment from a young age.

In a related inquiry, the research team established the world's first biobank of organoid models for intestinal metaplasia, a condition where stomach cells begin to resemble intestinal cells. This transformation heightens cancer risk but remains poorly understood. Using organoid technology, they created a three-dimensional model of this pre-cancerous state, growing 70 organoids from tissue samples of 47 stomach cancer patients.

The study found that these organoids contained "hybrid" cells, displaying characteristics of both stomach and intestinal cells. This cellular flexibility, which involves the expression of genes typically active only during fetal development, mirrors the traits of cancer cells that grow uncontrollably. Understanding these changes is vital for comprehending cancer progression and potential treatment resistance.

Moreover, the intestinal metaplasia cells frequently exhibited chromosome 20 gains and the ability to proliferate without surface attachment, traits associated with invasive cancer cells. Identifying these genetic alterations could help detect early indicators of stomach cancer and suggest possible targets for intervention.

Given that stomach cancer has a global prevalence of 25%, pinpointing high-risk groups for targeted interventions is crucial. The research emphasizes the importance of utilizing organoid technology to identify early changes in stomach cells that signify a transition to a pre-cancerous state.

The insights gained from these studies foster hope for improved early detection and prevention strategies against stomach cancer. The development of a living cell model opens avenues for drug discovery that could potentially reverse intestinal metaplasia, enhancing patient outcomes and clinical practices in the fight against this lethal disease.