"Gene Mutation Identified in 'Gastric Intestinal Metaplasia' with Mucosal Damage Leading to Stomach Cancer"

Seoul National University and Singapore General Hospital Joint Research

A genetic mutation involved in the progression of 'intestinal metaplasia,' a major risk factor for gastric cancer, into gastric cancer has been identified. Combining the genetic characteristics of intestinal metaplasia with individual clinical information of patients is expected to predict high-risk groups for gastric cancer progression.

[Image courtesy of Pixabay]

According to Seoul National University Hospital, a multi-institutional collaborative research team from the National University Hospital of Singapore, Duke-NUS Medical School, including Professor Hyunsoo Jeong from the Department of Gastroenterology, genetically analyzed 1,256 gastric tissue samples to identify the characteristics of intestinal metaplasia cells progressing to gastric cancer. Based on this, the research team proposed a model to screen high-risk groups for gastric cancer progression.

Gastric cancer ranks fifth in incidence and fourth in mortality worldwide. In particular, patients with intestinal metaplasia, where the gastric mucosal tissue is destroyed due to persistent inflammatory responses and transformed to resemble intestinal mucosa, have up to six times higher risk of gastric cancer. However, the mechanisms of occurrence and progression of intestinal metaplasia have not been known until now. Therefore, it has been difficult to predict when and how severely gastric cancer will progress in patients diagnosed with intestinal metaplasia.

Intestinal metaplasia of the gastric mucosa.
[Image courtesy of Seoul National University Hospital]

To molecularly analyze the process of intestinal metaplasia progressing to gastric cancer, the collaborative research team conducted genome profiling based on gastric tissue samples from patients with intestinal metaplasia. As a result, they identified 26 oncogenes related to the development and progression of intestinal metaplasia. While mutations in the tumor-related gene TP53 were relatively rare, suggesting they occur later during gastric cancer formation, mutations in the stem cell behavior regulatory gene 'SOX9' were abundantly observed in intestinal metaplasia tissues. SOX9 mutations can promote the expansion of intestinal stem cell clones (cell populations), and indeed, as intestinal metaplasia progresses to gastric cancer, the number of oncogene mutations increases stepwise and clone size enlarges.

Single-cell sequencing analysis showed that some stem cell lineage clones within intestinal metaplasia gastric tissue appeared similar to early gastric cancer cells. This result, indicating the origin of gastric cancer cells, suggests that intestinal metaplasia cells can easily change due to interactions with surrounding microbiota and microenvironment, explained the research team.

Additionally, the research team discovered a specific subtype of intestinal metaplasia. Although found in the major gastric region, its morphology resembled the lower stomach (antrum), adjacent to the intestine, and it harbored 'oral microbiota' not typically seen in healthy stomachs. At the same time, signs of chronic inflammation were observed, along with mutations in the tumor suppressor gene 'ARID1A,' showing abnormal features distinguishing it from other types of intestinal metaplasia.

Genetic and Clinical Feature-Based Risk Prediction Curve for Progression of Intestinal Metaplasia (ROC). [Image courtesy of Seoul National University Hospital]

Furthermore, to identify high-risk groups for gastric cancer progression early among patients with intestinal metaplasia, the research team developed a gastric cancer progression prediction model combining genetic characteristics identified through genome profiling (such as mutation count and clone size) with clinical variables (age, smoking history, pepsinogen index, etc.). According to the research team, this model could identify high-risk groups more accurately than models using only clinical variables. The sensitivity and specificity of the combined genetic and clinical characteristic model were 88.2% and 87.6%, respectively, significantly higher than the model using only clinical characteristics (70.6% and 68.3%, respectively).

The research team explained that these results present opportunities to improve patient treatment outcomes, such as surveillance of the highest risk groups or the possibility of controlling clones with anti-inflammatory and antimicrobial treatments before intestinal metaplasia progresses to cancer.

Professor Hyunsoo Jeong of the Department of Gastroenterology at Seoul National University Hospital said, "This study shows that genetic profiling technology can relatively accurately stratify the risk among patients with intestinal metaplasia." He added, "Based on these results, it will be possible to distinguish high-risk and low-risk groups among intestinal metaplasia patients for gastric cancer progression and establish different examination and treatment strategies for each."

Professor Jeong Hyun-su, Department of Gastroenterology, Seoul National University Hospital.
[Photo by Seoul National University Hospital]

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