Saliva could flag one of SA’s deadliest and baffling cancers sooner

Scientists at the Sydney Brenner Institute for Molecular Bioscience (SBIMB) at Wits University are exploring whether bacteria in saliva could offer a low-cost warning signal for oesophageal squamous cell carcinoma, where late diagnosis leaves palliative care as the only option.

Unlike oesophageal adenocarcinoma, which is strongly linked to reflux, obesity, diet and other lifestyle changes and is found across developed nations, the squamous cell subtype common in South Africa follows a far more puzzling pattern.

Indeed, the full picture of what causes oesophageal squamous cell carcinoma has baffled scientists for decades.  Distinguished Professor at the SBIMB, Professor Christopher Mathew, and colleagues in the Wits Faculty of Health Sciences have been trying to answer this question, working with limited etiologic or clinical research devoted to this specific cancer.

“A  feature of the cancer is the young age of many patients, with a mean age of 50,  and 18% of patients presenting before the age of 40”, says Mathew.

Notably, oesophageal squamous cell carcinoma occurs in a high-incidence belt that runs through parts of China and Iran, and down the eastern side of Africa, including South Africa’s Eastern Cape and KwaZulu-Natal.

“This geographical occurrence is also puzzling, and may reflect genetic susceptibility, a specific environmental exposure, or a combination of factors that researchers have still not been able to pin down,” explains Dr Wenlong Carl Chen, a researcher at SBIMB.

Chen and his colleagues have shown from the Johannesburg Cancer Study data that smoking and heavy alcohol use remain important risks, as does living in rural areas, having lower educational attainment, and use of biomass or other household fuels.

“Still, they do not fully explain the number of cases, the geographic clustering, or why some patients develop the disease without these obvious exposures.”

The saliva clue

But a newly published study, a collaboration between Chen and Columbia University in New York, published in Communications Medicine, may open a new line of inquiry.

“We found clear differences between the saliva bacteria of people with oesophageal squamous cell carcinoma and unaffected controls. Using genetic sequencing of bacteria and machine-learning methods, the team identified a distinctive microbial pattern associated with the cancer,” says Chen.

The microbiome-based model performed better than a model based only on clinical and demographic data.

Several bacteria were more abundant in patients with oesophageal squamous cell carcinoma, including Fusobacterium nucleatum, a bacterium implicated in other cancers.

Chen is careful not to overstate what this means. The bacterial changes may not be causing the cancer. They may instead be a consequence of the disease, much like what happens when a kitchen sink becomes blocked, and material begins to accumulate.

“But even that could be useful. A blockage in the oesophagus develops gradually, often before patients arrive at the hospital, unable to swallow properly. If microbial changes in saliva can help flag that something is already changing, they could one day help identify people who need earlier referral for endoscopy.”

From clue to triage tool

A saliva-based, or even cheek-swab-based, test would not replace endoscopy, and it is not yet an early cancer-detection test. But if validated, it could become a low-cost triage tool for high-risk communities. Clinicians could then make better decisions about who should be investigated sooner.  

Globally, oesophageal cancer accounted for more than 600,000 new cases and more than 540,000 deaths in 2020, with a substantial burden in sub-Saharan Africa.

Asking better questions

Oesophageal squamous cell carcinoma remains understudied, and so the next step, argues Chen, is to build a broader research programme that combines epidemiology, genomics, microbiome science, environmental exposure work and community engagement.

Researchers are now asking two related questions. First, could some people inherit genetic differences that make them more vulnerable to this cancer? And second, could the tumours themselves carry clues about what patients were exposed to before they became ill?

One way to look for those clues is by studying mutation signatures in the tumour. These are patterns of DNA changes that can act like molecular fingerprints. If a certain chemical, pollutant, smoke exposure, water contaminant or other local environmental factor has damaged the DNA over time, it may leave a trace in the tumour genome that researchers can use to infer possible causes.

But Chen stresses that this is still early work. The model has been internally validated and still needs to be tested in external cohorts. Microbial patterns can differ by geography, diet, environment and population, so a model developed in one setting may not automatically work in another.

 “This is critical research which has generated important foundational knowledge that will take us to the next step, and hopefully to the clinic in the long run,” says Professor Michèle Ramsay, Director of the SBIMB. 

The next step is enrolling new cohorts, including confirmed ESCC cases, people with benign oesophageal  conditions that may also cause swallowing difficulties , and healthy population controls.

It will help researchers understand whether the saliva signal can distinguish cancer from non-cancerous blockage, or whether it is better understood as a broader warning sign that something abnormal is happening in the oesophagus.