Healthcare (Commonwealth Union) – Researchers have revealed that a genetic mutation long thought to promote oesophageal cancer might actually serve a protective function in the disease’s early stages.
This surprising finding, revealed in research funded by Cancer Research UK and published recently in Nature Cancer, could aid doctors in identifying individuals at higher risk of developing the disease. Such insights might pave the way for more tailored and effective preventive measures.
Researchers of the study indicated that, only 12 percent of oesophageal cancer patients in England survive for 10 years or longer. The UK reports one of the highest global rates of oesophageal adenocarcinoma, a subtype of the cancer, with cases steadily rising. This form of cancer originates from Barrett’s oesophagus, a condition where the cells lining the oesophagus undergo abnormal changes. However, only about 1% of individuals with Barrett’s oesophagus develop cancer annually.
The study aimed to uncover why certain cases of Barrett’s progress to cancer while others do not, providing valuable knowledge for improving the prediction and treatment of oesophageal adenocarcinoma.
The team examined a large gene sequencing dataset comprising over 1,000 individuals with oesophageal adenocarcinoma and more than 350 individuals with Barrett’s oesophagus. They discovered that mutations in a gene called CDKN2A were more prevalent in individuals with Barrett’s oesophagus who did not progress to cancer. This finding was surprising, as CDKN2A is widely recognized as a tumour suppressor gene—a molecular defense mechanism against cancer—and is typically lost in many cancers.
The study revealed that when normal oesophageal cells lose CDKN2A, it facilitates the development of Barrett’s oesophagus. However, this loss also provides a protective effect by safeguarding cells from losing another crucial gene, TP53, which encodes the tumour suppressor p53, often referred to as the “guardian of the genome.” The loss of p53 is a major driver of the progression from Barrett’s oesophagus to cancer. The researchers found that cells missing both CDKN2A and p53 became weaker and were outcompeted by surrounding cells, preventing cancer from taking hold. On the other hand, if cancer cells lose CDKN2A later in the disease’s progression, it leads to a more aggressive form of the disease and poorer outcomes for patients.
The lead researcher, Francesca Ciccarelli, who is Professor of Cancer Genomics at the Queen Mary University of London, Barts Cancer Institute and Principal Group Leader at the Francis Crick Institute, where these experimental studies took place says “We often assume that mutations in cancer genes are bad news, but that’s not the whole story,” said the lead researcher. “The context is crucial. These results support a paradigm shift in how we think about the effect of mutations in cancer.”
“It can be tempting to look at cancer mutations as good or bad, black or white. But like the Roman god, Janus, they can have multiple faces – a dual nature,” she elaborated. “We’re increasingly learning that we all accumulate mutations as an inevitable part of ageing. Our findings challenge the simplistic perception that these mutations are ticking time bombs and show that, in some cases, they can even be protective.”
Researchers of the study pointed out that these findings could reshape how we evaluate cancer risk. The research suggests that in individuals with Barrett’s oesophagus, an early CDKN2A mutation without accompanying p53 mutations may indicate a lower likelihood of progression to cancer. However, at more advanced stages of the disease, CDKN2A mutations might signify a worse prognosis. Further studies are essential to determine how this knowledge can be translated into clinical benefits for patients.
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