“Gastric cancer is often called a silent killer because it takes hold quietly, long before symptoms appear. What our study shows is that risk does not come from one place—it builds over many years through a complex interplay between ageing, genetic changes, immune shifts and even the bacteria we carry,” said Professor Patrick Tan, Dean at Duke-NUS Medical School and a senior author of the study.
FACTORS SUCH AS smoking and infection by oral bacteria, and genetic and age-related blood mutations, increases the risk for stomach (gastric) cancer.
This was the finding by scientists at Duke-NUS Medical School and the National University Health System (NUHS), and an international team of researchers
Published in Cancer Discovery, the findings provide new insight into the earliest biological changes that precede the development of gastric cancer and could offer more precise approaches for risk stratification and prevention.
“Gastric cancer is often called a silent killer because it takes hold quietly, long before symptoms appear. What our study shows is that risk does not come from one place—it builds over many years through a complex interplay between ageing, genetic changes, immune shifts and even the bacteria we carry,” said Professor Patrick Tan, Dean at Duke-NUS Medical School and a senior author of the study.
Gastric cancer remains one of the world’s deadliest cancers. It is the fifth most common cancer and the fourth leading cause of cancer-related deaths globally, accounting for 769,000 deaths in 2020. In Singapore, it is among the top 10 causes of cancer-related deaths, claiming about 300 lives each year.
Gastric cancer typically develops over many decades, beginning with chronic inflammation in the stomach lining. This can progress to intestinal metaplasia, a condition in which normal stomach cells gradually convert to cells resembling those usually found in the intestines. Over time, these changes may progress to more severe tissue damage and cancer. However, clinicians have limited ability to predict which individuals with intestinal metaplasia are most likely to progress to gastric cancer.
To address this gap, studies were conducted under the Singapore Gastric Cancer Consortium (SGCC), a multidisciplinary national research program comprising clinicians and scientists from various academic medical centers, universities and research institutes working in gastric cancer research and management.
IDENTIFYNG MUTATED GENES
Using advanced genetic analyses, the researchers identified 47 significantly mutated genes in intestinal metaplasia cells. Mutations in one particular gene, ARID1A, were associated with increased risk of gastric cancer and poorer prognosis. The team also uncovered a distinct pattern of DNA damage, known as SBS17, which was absent in healthy stomach tissue but commonly found in intestinal metaplasia. SBS17 is linked to oxidative stress—a type of cellular damage caused by reactive molecules generated by abnormal metabolism. This damage can be worsened by exposure to tobacco smoking. This finding suggests that oxidative stress may play a critical role in the earliest stages of gastric cancer development.
In another exciting development, the team also discovered that pyrvinium, a drug currently used to treat parasites, had the ability to inhibit the growth of intestinal metaplasia cells. Building on this finding, clinical studies under the SGCC are being planned to explore therapeutic strategies for intestinal metaplasia.
“Our findings open the door to exploring new and more effective treatments such as eliminating specific bacteria, and therapies to inhibit or potentially reverse intestinal metaplasia. These findings also provide insights into which intestinal metaplasia patients are at greatest risk of developing gastric cancer. These can serve as valuable biomarkers to identify the most vulnerable long before the disease strikes, guiding more focused screening to identify those who require closer monitoring,” said Professor Yeoh Khay Guan, Chief Executive, NUHS and co-senior author of the study.
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