A genetic mutation that was previously thought to be a major factor in the emergence of esophageal cancer may actually serve a protective function in the initial stages of the disease. This surprising finding could assist healthcare professionals in pinpointing individuals who are at a heightened risk of developing cancer, paving the way for more tailored and effective preventative measures.
Recent research featured in Nature Cancer indicates that a genetic mutation once thought to contribute to the rise of esophageal cancer might instead offer protection in the early stages of the condition. This unexpected insight may aid physicians in recognizing individuals who are more susceptible to developing cancer, potentially resulting in more customized and efficient preventative strategies.
“Typically, we assume that mutations in cancer-related genes are detrimental, but this isn’t the complete picture,” states lead researcher Francesca Ciccarelli, a Professor of Cancer Genomics at Barts Cancer Institute, Queen Mary University of London, and Principal Group Leader at the Francis Crick Institute, where this study’s experimental work was conducted. “The context is key. These findings could change how we perceive the influence of mutations in cancer.”
This study received funding from Cancer Research UK, and the experiments were conducted at the Francis Crick Institute.
New insights into esophageal cancer risk
Only 12% of those diagnosed with esophageal cancer in England survive for a decade or more. The UK has one of the highest rates of a specific subtype known as esophageal adenocarcinoma, and the incidence continues to rise. This cancer originates from Barrett’s esophagus, a condition where the cells lining the esophagus become abnormal. However, only about 1% of people with Barrett’s esophagus develop cancer each year. The research team aimed to gain a clearer understanding of why some Barrett’s cases progress to cancer while others do not, thus enhancing prediction and treatment methods for esophageal adenocarcinoma.
The researchers analyzed an extensive gene sequencing dataset from over 1,000 individuals with esophageal adenocarcinoma and more than 350 with Barrett’s esophagus, including samples from the OCCAMS consortium*. They discovered that defects in a gene known as CDKN2A were more prevalent among individuals with Barrett’s esophagus who did not advance to cancer. This was an unexpected revelation, as CDKN2A is frequently absent in various cancers and recognized as a tumor suppressor gene, which acts as a protective barrier against cancer development.
The study revealed that when normal cells in the esophagus lose CDKN2A, this can encourage the formation of Barrett’s esophagus. However, it simultaneously safeguards cells from losing another crucial gene, which encodes p53, often referred to as the ‘guardian of the genome’. The absence of p53 is a significant factor that promotes the transition from Barrett’s esophagus to cancer.
The research team found that cells which might become cancerous and lose both CDKN2A and p53 are weakened, unable to compete effectively with neighboring cells, thus hindering cancer growth. Conversely, if cancer cells lose CDKN2A after the disease has progressed, it can lead to a more aggressive form of cancer and poorer patient outcomes.
A gene with a dual role
Professor Ciccarelli compares the twofold role of CDKN2A to Janus, the ancient Roman god of transitions, for whom the month of January is named. Janus is depicted with two faces, one looking back and the other forward.
“It’s easy to classify cancer mutations as either beneficial or harmful, black or white. However, like Janus, they can exhibit multiple roles — a dual nature,” she remarks. “We are increasingly finding that as we age, we accumulate mutations as a natural process. Our results challenge the oversimplified view that these mutations are simply harmful, indicating that in certain situations, they may even offer protection.”
This discovery could greatly affect how cancer risk is evaluated. It suggests that a person with Barrett’s esophagus who has an early CDKN2A mutation but lacks p53 mutations may have a lower risk of progressing to cancer. Conversely, if mutations in CDKN2A appear later in the disease, it might indicate a worse prognosis. Further studies are needed to explore how this new information can be effectively utilized in clinical settings to benefit patients.
Dr. Nisharnthi Duggan, Science Engagement Manager at Cancer Research UK, stated, “Survival rates for esophageal cancer have improved since the 1970s, but it remains one of the most difficult cancers to treat. The main challenge arises from late-stage diagnoses, where treatments are less likely to be effective.
“Supporting this type of research is essential for enhancing our understanding and improving outcomes for individuals affected by this disease. It emphasizes the value of discovery science in disentangling the complexities of cancer, enabling the identification of new prevention, detection, and treatment strategies.”
