Image of Janus heads by Joe Brock
The unexpected discovery of this genetic mechanism, funded by Cancer Research UK and published today in Nature Cancer, could help doctors identify which individuals are at greater risk of developing cancer, potentially leading to more personalised and effective preventive strategies.
Only 12% of patients with oesophageal cancer in England survive their disease for 10 years or more. The UK has one of the world's highest incidences of a subtype called oesophageal adenocarcinoma, and cases continue to increase. This cancer type develops from a condition called Barrett's oesophagus, in which the cells lining the oesophagus become abnormal. However, only around 1% of people with Barrett's go on to develop cancer each year. In the new study, the research team sought to better understand why some cases of Barrett's lead to cancer, while others do not, to support better prediction and treatment of oesophageal adenocarcinoma.
The team analysed a large gene sequencing dataset from more than 1,000 people with oesophageal adenocarcinoma and more than 350 people with Barrett's oesophagus. They found that defects in a gene called CDKN2A were more common in people with Barrett's oesophagus who never progressed to cancer. This finding was unexpected, as CDKN2A is commonly lost in various cancers and is well-known as a tumour suppressor gene – a molecular safeguard that stops cancer from forming.
The research showed that if normal cells in our oesophagus lose CDKN2A, it helps promote the development of Barrett's oesophagus. However, it also protects cells against the loss of another key gene encoding p53 – a critical tumour suppressor often dubbed the 'guardian of the genome'. Loss of p53 strongly drives the progression of disease from Barrett's to cancer. The team found that potentially cancerous cells that lost both CDKN2A and p53 were weakened and unable to compete with other cells around them, preventing cancer from taking root. In contrast, if cancer cells lose CDKN2A after the disease has had time to develop, it promotes a more aggressive disease and worse outcomes for patients.
Lead researcher, Francesca Ciccarelli, Professor of Cancer Genomics at Queen Mary University of London's Barts Cancer Institute and Principal Group Leader at the Francis Crick Institute, where the experimental work in this study took place, said: "We often assume that mutations in cancer genes are bad news, but that's not the whole story," says 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 explained. "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."
The findings could have significant implications for how we assess cancer risk. They suggest that if a person with Barrett's oesophagus has an early CDKN2A mutation but no mutations in p53, it could indicate that their condition is less likely to progress to cancer. On the other hand, later in the disease, CDKN2A mutations may signal a poor prognosis. Further research is needed to determine how to best apply this new knowledge to benefit patients in the clinic.
This paper was funded by Cancer Research UK and the experimental work in this study took place at The Francis Crick Institute.
