Researchers from the Francis Crick Institute and Barts Cancer Institute have shown that a genetic fault long believed to drive the development of oesophageal cancer may in fact play a protective role early in the disease.
The researchers liken the dual role of CDKN2A to the ancient Roman god of transitions Janus, who has two faces.
Published today in Nature Cancer, the unexpected discovery could help doctors identify which individuals are at a greater risk of developing cancer, potentially leading to more personalised and effective preventive strategies.
Just 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, which 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, so the research team sought to better understand why some cases of Barrett’s lead to cancer while others do not.
They analysed a large gene sequencing dataset from more than 1,000 people with oesophageal adenocarcinoma and more than 350 people with Barrett’s oesophagus, including samples from a network of clinical centres called the OCCAMS consortium.
The researchers found that defects in a gene called CDKN2A were more common in people with Barrett’s oesophagus who never progressed to cancer. This 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.
The findings suggest that if a person with Barrett’s oesophagus has an early CDKN2A mutation but no mutations in p53, 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.
Francesca Ciccarelli, Principal Group Leader of the Cancer Systems Biology Laboratory at the Crick, and Professor of Cancer Genomics at Queen Mary University of London’s Barts Cancer Institute, said: “We often assume that mutations in cancer genes are bad news, but that’s not the whole story. The context is crucial. These results support a paradigm shift in how we think about the effect of mutations in cancer.”
The researchers liken the dual role of CDKN2A to the ancient Roman god of transitions Janus, after whom January is named. Janus has two faces – one looking to the past and one to the future.
Francesca said: “It can be tempting to look at cancer mutations as good or bad, black or white. But like Janus, they can have multiple faces – a dual nature. 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.”
This research was funded by Cancer Research UK and Barts Charity and the experimental work in this study took place at the Crick.
Nisharnthi Duggan, Science Engagement Manager at Cancer Research UK, said: “Survival for oesophageal cancer has improved since the 1970s, but it’s still one of the most challenging cancers to treat. This is largely because it’s often diagnosed at advanced stages, when treatments are less likely to be successful.
"Funding research like this is critical to advancing our understanding and improving outcomes for people affected by the disease. It shows the importance of discovery science in unravelling the complexities of cancer, so we can identify new ways to prevent, detect and treat it."
