How chronic heartburn can drive esophageal cancer

A new UBC Faculty of Medicine study has revealed how long-term, chronic heartburn can drive the earliest steps toward an aggressive form of esophageal cancer, suggesting new ways to detect the cancer sooner and potentially even prevent it from developing in the first place.

Chronic heartburn, or gastroesophageal reflux disease (GERD), affects up to 20 per cent of the population. While most people with GERD don’t go on to develop cancer, it can lead to Barrett’s esophagus—a condition in which the cells lining the esophagus begin to change due to damage from acid reflux.

Barrett’s esophagus is one of the strongest known risk factors for esophageal adenocarcinoma, an aggressive cancer with poor survival rates that is on the rise in North America and other Western countries.

Led by Drs. Dermot Kelleher and Shane Duggan, the new research identifies a group of key genes that are activated by acid reflux and act as potential “molecular switches”, tipping cells toward a more abnormal, precancerous state.

“Many people don’t realize that chronic acid reflux is a risk factor for the development of esophageal cancer,” said Dr. Duggan, a research associate in the division of gastroenterology at UBC’s Faculty of Medicine. “Our research has shown that reflux doesn’t just irritate the esophagus, it can actually change how genes are expressed in a way that pushes cells toward cancer in some people.”

The findings, published recently in Cellular and Molecular Gastroenterology and Hepatology, offer critical new insight into why some patients with chronic acid reflux go on to develop cancer while the majority do not.

“Identifying the molecular driver of these changes not only helps us understand how cancer develops, it suggests a promising new biomarker to detect high-risk cases earlier,” said Dr. Kelleher, Dean of the Faculty of Medicine and Vice-President, Health at UBC. “This could enhance our ability to prevent cancer from developing or start treatment sooner, which would be transformative for a lot of patients.”

New insights into how cancer begins

While the link between chronic acid reflux and esophageal cancer is well-established at a population level, the new study describes a potential molecular pathway from GERD to Barrett’s esophagus to esophageal adenocarcinoma.

Using advanced tools like spatial transcriptomics and organ-on-a-chip platforms, the researchers were able to model how precancerous changes occur in real tissue.

One such “molecular switch” involves a group of genes known as GATA transcription factors, which can be activated by long-term exposure to refluxed stomach acid. These genes promote changes in esophageal cells, including the expression of a cell surface protein called GPRC5B, that push the cells away from their normal state and toward one that resembles high-grade dysplasia—a serious precancerous condition.

“The research shows a step-by-step cascade that occurs in some people,” said Dr. Duggan. “Reflux activates GATA factors, which triggers expression of the GPRC5B surface protein, which can then drive abnormal cell growth and ultimately move cells toward becoming cancerous.”

The study further revealed that GATA factors are typically kept in check by a protective gene (TRPS1) that helps maintain healthy cells. But in some people, this balance is disrupted—allowing GATA factors to dominate and trigger changes that increase cancer risk.

Hope for early detection and prevention

When the researchers artificially increased GPRC5B in lab-grown esophageal stem cells, the cells began multiplying rapidly, lost their structure and started to resemble cancerous tissue at the molecular level.

With esophageal adenocarcinoma becoming more common—and often diagnosed too late—the researchers hope their findings will lead to new tools to monitor those at risk and detect cancerous changes early.

“This protein could be something we eventually test for to determine when problematic tissue should be removed before it becomes cancerous.”

Dr. Shane Duggan

“Most people with acid reflux will never develop cancer, but we need better ways to monitor those who have warning signs and detect cancer sooner,” said Dr. Duggan. “GPRC5B appears to be one of those warning signs—something we could eventually test for and use to determine when problematic tissue should be removed before it becomes cancerous.”

As a next step, the researchers will investigate how GPRC5B and other factors could be harnessed as biomarkers to guide early diagnosis and as potential targets for new treatments.

By uncovering the molecular changes that precede cancer development, their work opens the door to new strategies for identifying high-risk patients before cancer takes hold. This shift could help clinicians intervene earlier, improving outcomes and survival for a cancer that’s often caught too late.