Breakthrough Study Identifies Key Factors Increasing Gastric Cancer Risk

SINGAPORE: Researchers at Duke-NUS Medical School and the National University Health System (NUHS), alongside an international team, have uncovered a complex network of factors that elevate the risk of developing gastric (stomach) cancer. Their findings, published in Cancer Discovery, shed new light on the earliest biological changes that precede cancer development and could pave the way for more targeted risk assessment and preventative strategies.

 Gastric cancer remains one of the most lethal cancers worldwide, ranking as the fifth most common and the fourth leading cause of cancer-related deaths, with an estimated 769,000 fatalities in 2020. In Singapore, it is among the top ten causes of cancer mortality, claiming roughly 300 lives annually.

 The disease typically develops over decades, beginning with chronic inflammation of the stomach lining, progressing to intestinal metaplasia, a condition where stomach cells gradually transform into intestinal-type cells. This process can advance to severe tissue damage and, ultimately, cancer. Currently, clinicians struggle to predict which individuals with intestinal metaplasia are most at risk of progression.

 To address this challenge, the research was conducted under the auspices of the Singapore Gastric Cancer Consortium (SGCC), a multidisciplinary national initiative involving clinicians, scientists from various universities and research institutes, and partners from Singapore, Hong Kong, Japan, South Korea, Taiwan, and the USA. The team analysed over 1,500 intestinal metaplasia samples from six countries, enabling a comparative study of genetic mutations across diverse populations with varying gastric cancer risks.

Advanced genetic analysis revealed 47 significantly mutated genes in intestinal metaplasia tissues. Notably, mutations in the gene ARID1A were linked to increased cancer risk and poorer prognosis. The researchers also identified a unique pattern of DNA damage, called SBS17, absent in healthy stomach tissue but prevalent in intestinal metaplasia. Linked to oxidative stress—cellular damage caused by reactive molecules often intensified by smoking, this pattern suggests oxidative stress plays a pivotal role in early gastric carcinogenesis.

 An unexpected discovery was the potential therapeutic role of pyrvinium, an anti-parasitic drug, which was shown to inhibit the growth of intestinal metaplasia cells. This promising finding has prompted plans for clinical trials to explore its use in preventing gastric cancer.

The team also identified an association between clonal haemopoiesis, a process where blood stem cells acquire mutations and expand, and increased gastric cancer susceptibility. Since clonal haemopoiesis is common in older adults, this link offers insights into why gastric cancer often appears later in life. Furthermore, individuals with clonal haemopoiesis exhibited higher levels of oral bacteria such as Streptococcus in their stomachs. The combined effect of weakened immunity and increased bacterial presence may foster chronic inflammation, accelerating disease progression.

 Professor Patrick Tan, Dean of Duke-NUS and senior author of the study, commented,"Gastric cancer is often called a silent killer because it develops quietly over many years before symptoms emerge. Our research shows that risk factors are multifaceted, building over time through a complex interplay of ageing, genetic alterations, immune system changes, and bacterial influences. As Singapore’s population ages rapidly, these insights will be vital in advancing our understanding of biological ageing and promoting healthier longevity."

 Professor Yeoh Khay Guan, Chief Executive of NUHS and co-senior author, added, "Our findings open new avenues for treatment, including targeting specific bacteria and potentially reversing intestinal metaplasia. They also enable us to identify individuals at greatest risk long before cancer develops, allowing for more focused screening and early intervention."

Supported by the Singapore Ministry of Health and research grants from the National Medical Research Council and the National Research Foundation, this study marks a significant step forward in gastric cancer research and prevention.