A surprising discovery reveals that a gene previously thought to accelerate esophageal cancer actually helps protect against it initially.

This pivotal study could lead to better prediction and prevention strategies tailored to individual genetic profiles.

Shifting Paradigms in Cancer Genetics

A genetic mutation long thought to drive oesophageal cancer may actually have a protective role in the early stages of the disease, according to new research published today (January 3) in Nature Cancer. This surprising finding could help doctors better assess who is most at risk of developing cancer, paving the way for more targeted and effective prevention strategies.

“We often assume that mutations in cancer genes are bad news, but that’s not the whole story,” explains 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. “The context is crucial. These results support a paradigm shift in how we think about the effect of mutations in cancer.”

Rethinking Esophageal Cancer Risk Factors

Just 12% of patients with esophageal 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 esophageal adenocarcinoma, and cases continue to increase. this cancer type develops from a condition called Barrett’s esophagus, in which the cells lining the esophagus 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 esophageal adenocarcinoma.

The team analyzed a large gene sequencing dataset from more than 1,000 people with esophageal adenocarcinoma and more than 350 people with Barrett’s esophagus, including samples from the Occams Consortium.[1] 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, as CDKN2A is commonly lost in various cancers and is well-known as a tumor suppressor gene – a molecular safeguard that stops cancer from forming.

The Dual Role of CDKN2A in Cancer Progression

The research showed that if normal cells in our esophagus lose CDKN2A, it helps promote the development of Barrett’s esophagus. However, it also protects cells against the loss of another key gene encoding p53 – a critical tumor 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.

A Gene With Two Faces

Professor Ciccarelli likens 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.

“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,” she explains. “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 findings could have significant implications for how we assess cancer risk. They suggest that if a person with Barrett’s esophagus 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.

Advances in Cancer Research and Funding

Science Engagement Manager at Cancer Research UK, Dr Nisharnthi Duggan, said: “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.

“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.”

Notes

  1. OCCAMS consortium = the Oesophageal Cancer Clinical and Molecular Stratification is a network of clinical centers across the UK recruiting patients with esophageal and gastro-esophageal junction (GOJ) adenocarcinoma

Reference: “Context-dependent effects of CDKN2A and other 9p21 gene losses during the evolution of oesophageal cancer” by Piyali Ganguli, et al., 3 January 2025, Nature Cancer.
DOI: 10.1101/2024.01.24.576991

This research was funded by Cancer Research UK and the experimental work in this study took place at the Francis Crick Institute.

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