According to new research published in nature cancer. This unexpected discovery could help doctors identify which people are at highest risk of developing cancer, which could lead to more personalized and effective preventative strategies.
“We often assume that mutations in cancer genes are bad news, but that’s not the whole story,” says lead researcher Francesca Ciccarelli, Professor of Cancer Genomics at the Barts Cancer Institute, Queen Mary University of London. and senior group leader at the Francis Crick Institute. where the experimental work of this study was carried out. “Context is crucial. These results support a paradigm shift in the way we think about the effect of mutations on cancer.”
This research was funded by Cancer Research UK and the experimental work for this study was carried out at the Francis Crick Institute.
A new understanding of esophageal cancer risk
Only 12% of esophageal cancer patients in England survive the 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 rise. This type of cancer develops from a condition called Barrett’s esophagus, in which the cells lining the esophagus become abnormal. However, only about 1% of people with Barrett’s disease develop cancer each year. In the new study, the research team sought to better understand why some cases of Barrett’s cause cancer, while others do not, to support better prediction and treatment of esophageal adenocarcinoma.
The team analyzed a large gene sequencing data set from more than 1,000 people with esophageal adenocarcinoma and more than 350 people with Barrett’s esophagus, including samples from the OCCAMS* consortium. They found that defects in a gene called CDKN2A were more common in people with Barrett’s esophagus who never progressed to cancer. This finding was unexpected, since CDKN2A is commonly lost in several types of cancer and is well known as a tumor suppressor gene, a molecular protection that stops cancer from forming.
Research has shown that if normal cells in our esophagus lose CDKN2A, this helps promote the development of Barrett’s esophagus. However, it also protects cells against the loss of another key gene that encodes p53, a critical tumor suppressor often called the “guardian of the genome.” Loss of p53 strongly drives the progression of Barrett’s disease 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 the cancer from taking root. Conversely, if cancer cells lose CDKN2A after the disease has had time to develop, it promotes more aggressive disease and worse outcomes for patients.
A gene with two faces
Professor Ciccarelli compares the dual role of CDKN2A to the ancient Roman god of transitions Janus, after whom January is named. Janus has two faces: one that looks to the past and another to the future.
“It may be tempting to view cancer mutations as good or bad, black or white. But, like Janus, they can be multifaceted—a dual nature,” he explains. “We are increasingly learning that we all accumulate mutations as an inevitable part of aging. Our findings challenge the simplistic perception that these mutations are ticking time bombs and show that, in some cases, they may even be protective.”
The findings could have significant implications for how we assess cancer risk. They suggest that if a person with Barrett’s esophagus has an early mutation in CDKN2A but no mutation 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 indicate a poor prognosis. More research is needed to determine how to best apply this new knowledge for the benefit of patients in the clinic.
Dr Nisharnthi Duggan, director of scientific engagement at Cancer Research UK, said: “Survival from oesophageal cancer has improved since the 1970s, but it remains one of the most difficult cancers to treat. This is largely due to Because it is often diagnosed in 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 scientific discoveries in unraveling the complexities of cancer, so we can identify new ways to prevent, detect and treat it.”