Unexpected Role for CDKN2A Gene in Esophageal Cancer Progression

Scientists from the Barts Cancer Institute and the Francis Crick Institute have demonstrated that a genetic flaw that has long been thought to cause esophageal cancer may actually protect against the disease in its early stages.

According to a surprising discovery published in Nature Cancer, doctors may be able to determine which people are more likely to develop cancer, which could result in more individualized and successful preventive measures.

A New Understanding of Esophageal Cancer Risk

In England, only 12% of esophageal cancer patients live for 10 years or longer. Esophageal adenocarcinoma, a subtype of the disease that arises from Barrett's esophagus, a condition in which the cells lining the esophagus become abnormal, is one of the most common in the UK.

The research team aimed to better understand why some Barrett's cases result in cancer while others do not, as only about 1% of people with the condition go on to develop cancer each year.

The scientists examined a sizable gene sequencing dataset that included samples from a network of clinical centers known as the OCCAMS consortium, which included over 1,000 patients with esophageal adenocarcinoma and over 350 patients with Barrett's esophagus.

The researchers discovered that those with Barrett's esophagus who never developed cancer had a higher prevalence of abnormalities in a gene called CDKN2A. This was surprising because CDKN2A is known to be a tumor suppressor gene, a molecular defense that prevents cancer from developing, and it is frequently lost in a variety of cancers.

According to the study, the development of Barrett's esophagus is aided by the loss of CDKN2A by healthy esophageal cells. But it also shields cells from losing another important gene that codes for p53, a vital tumor suppressor known as the "guardian of the genome." The progression of Barrett's disease to cancer is significantly influenced by p53 loss.

The researchers discovered that cells that were at risk of developing cancer but lost both p53 and CDKN2A were weaker and less able to compete with nearby cells, which stopped cancer from spreading. In contrast, a more aggressive disease and worse patient outcomes are promoted if cancer cells lose CDKN2A after the disease has progressed.

According to the research, a person with Barrett's esophagus who has an early CDKN2A mutation but no p53 mutations has a lower chance of developing cancer. However, CDKN2A mutations may indicate a poor prognosis later in the disease. To find the best way to use this new information to help patients in the clinic, more research is required.

A Gene with Two Faces

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 dual function of CDKN2A is compared by the researchers to that of Janus, the ancient Roman god of transitions, after whom January is named. Janus has two faces: a forward-facing face and a backward-looking one.

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 aging. 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 experimental work for this study was conducted at the Crick, and it was supported by funding from Barts Charity and Cancer Research UK.

Survival for esophageal 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.”

Nisharnthi Duggan, Science Engagement Manager, Cancer Research UK

“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 unraveling the complexities of cancer, so we can identify new ways to prevent, detect, and treat it,” said Nisharnthi Duggan.