A genetic mutation long believed to drive the development of esophageal cancer may play a protective role early in the disease, according to a recent study published by Ganguli et al in Nature Cancer. The findings could help physicians identify which patients are at greater risk of developing cancer and lead to more personalized and effective preventive strategies.
Background
Just a small proportion of patients with esophageal cancer may survive for 10 years or more.
“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,” detailed Nisharnthi Duggan, PhD, Science Engagement Manager at Cancer Research UK.
Esophageal adenocarcinoma, a subtype of the disease, develops from a condition called Barrett’s esophagus—in which the cells lining the esophagus become abnormal. However, only about 1% of patients with Barrett’s esophagus may develop cancer per year.
“We often assume that mutations in cancer genes are bad news, but that’s not the whole story,” explained senior study author Francesca Ciccarelli, PhD, Professor of Cancer Genomics at Queen Mary University of London’s Barts Cancer Institute and Principal Group Leader at the Francis Crick Institute. “The context is crucial. These results support a paradigm shift in how we think about the effect of mutations in cancer,” she continued.
Study Methods and Results
In the recent study, researchers sought to better understand why some cases of Barrett’s esophagus develop into cancer, with the goal of enhancing the prediction and treatment of esophageal adenocarcinoma. They analyzed a large gene sequencing data set from over 1,000 patients with esophageal adenocarcinoma and over 350 patients with Barrett’s esophagus—including samples from the OCCAMS consortium.
The researchers found that defects in a gene called CDKN2A were more common in patients with Barrett’s esophagus whose disease never progressed to cancer. They noted that CDKN2A is commonly lost in various cancers and is well known as a tumor suppressor gene that acts as a molecular safeguard and prevents cancer development.
Further, the researchers revealed that if normal cells in the esophagus lost CDKN2A, it helped promote the development of Barrett’s esophagus. Nonetheless, it also protected cells against the loss of another key gene encoding p53, the loss of which can drive the progression of disease from Barrett’s esophagus to cancer.
The researchers discovered that potentially cancerous cells that lost both CDKN2A and p53 were weakened and unable to compete with other cells around them, preventing cancer from forming. In contrast, if cancer cells lost CDKN2A following the development of the disease, the researchers observed more aggressive disease and poorer patient outcomes.
The findings could have significant implications for how physicians assess cancer risk. The researchers suggested that if a patient with Barrett’s esophagus had an early CDKN2A mutation but no mutations in p53, it could indicate that their condition is less likely to progress to cancer. Conversely, later in the disease, CDKN2A mutations may signal a poor prognosis.
Conclusions
“It can be tempting to look at cancer mutations as good or bad, black or white, [b]ut … they can have multiple faces—a dual nature,” Dr. Ciccarelli emphasized. “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,” she added.
Further research may be needed to determine how to best apply the findings to benefit patients in the clinical setting.
“Funding research like this is critical to advancing our understanding and improving outcomes for [patients] affected by [this] 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,” concluded Dr. Duggan.
Disclosure: The research in this study was funded by Cancer Research UK. For full disclosures of the study authors, visit nature.com.
