A genetic mutation previously thought to cause oesophageal cancer may in some contexts be protective against the condition.
CDKN2A, a tumour suppressor gene, was previously understood to contribute to the development of oesophageal cancer in patients diagnosed with Barrett's oesophagus, a condition where cells in the oesophagus develop abnormally. However, newly published research has found that loss-of-function mutations in this gene may actually prevent the loss of another gene, called p53, which protects against the development of oesophageal cancer.
'We now know that Barrett's patients with CDKN2A alterations are less likely to develop cancer', Professor Francesca Ciccarelli, principal group leader at the Francis Crick Institute and lead researcher on the study, told Inside Precision Medicine. Highlighting the significance of the findings, Professor Ciccarelli said that 'these results support a paradigm shift in how we think about the effect of mutations in cancer'.
To assess the role of the gene, the researchers compared genomic data of patients diagnosed with Barrett's oesophagus and oesophageal adenocarcinoma. They found that 44 percent of samples from patients with Barrett's contained mutations in CDKNA2, compared to 25 percent in patients with oesophageal cancer. The higher rate of mutations in patients with Barrett's compared to oesophageal cancer suggests that mutations in the CDKNA2 gene do not always result in the development of cancer.
The researchers also discovered that in Barrett's patients who progress to develop oesophageal cancer, mutations causing CDKNA2 loss of function contribute to the cancer being more aggressive. The authors summarised this finding in the paper published in Nature Cancer by explaining that 'alterations in cancer genes may change during the evolution of disease, from preventing cancer transformation in the premalignant setting to favouring a more aggressive disease at later stages'.
Patients diagnosed with Barrett's oesophagus are currently monitored for progression to oesophageal cancer via endoscopic examinations. This research has identified that patients with CDKNA2 mutations are at lower risk of developing oesophageal cancer, and has the potential to benefit both patients and healthcare providers. The study authors highlight this in the paper, stating that 'identifying [Barrett's oesophagus] cases with a lower risk of progression could substantially improve patient management, decreasing the burden of endoscopy for patients who have low chances to develop cancer'.
More research is needed to understand how this new knowledge can benefit patients diagnosed with Barrett's oesophagus or oesophageal cancer. Professor Ciccarelli's group plans further research to study the relationship between the timing of CDKNA2 mutations in driving the development of Barrett's oesophagus and oesophageal adenocarcinoma.
Sources and References
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Surprising 'two-faced' cancer gene role supports paradigm shift in predicting disease
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Context-dependent effects of CDKN2A and other 9p21 gene losses during the evolution of esophageal cancer
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Study highlights dual role of CDKN2A mutations in oesophageal carcinoma progression
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Unexpected role for CDKN2A gene in oesophageal cancer progression
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