Submitted by Catherine Atkins on Wed, 10/05/2023 - 16:09
In a recent paper published in Nature , the authors sought to understand the role of extrachromosomal DNA in the development of cancer - is ecDNA a later manifestation of genomic instability, or is it an early event in the transition from dysplasia to cancer? The researchers analysed whole-genome sequencing (WGS) data from patients with oesophageal adenocarcinoma (EAC) or Barrett’s oesophagus.
The team summarised their findings:
Extrachromosomal DNA (ecDNA) circles containing oncogenes is increasingly recognised as a common event in human cancer. Because these circles are not constrained by the mitotic spindle, they are inherited by random segregation leading to rapid accumulation of copy number heterogeneity in the daughter cells, with some ecDNA genes surpassing 100 copies.
These ecDNA events can lead to a selective advantage and may contribute to poor outcomes and therapy resistance. What has not been known is how early in the evolution of cancer these events occur. We recently teamed up with a team led by Paul Mischel at Stanford to evaluate the timing of these events in oesophageal cancer, which is known to have one of the highest frequencies of ecDNA events across all cancer types.
Using whole genome sequencing data from over 200 patients with different stages of disease encompassing pre-cancerous Barrett’s oesophagus, as well as early and late stage cancer cases we showed that the frequency of ecDNA events increased with the stage of disease. In a complementary cohort from Seattle 33% of cases who developed oesophageal cancer had ecDNA events at an earlier time point of their Barrett’s.
These ecDNA events were strongly associated with biallelic disruption of TP53 suggesting that prior loss of this tumour suppressor gene enables ecDNA formation. In around one third of cases multiple ecDNA events were found within a given sample, and the copy number was higher in more advanced histological stage, suggesting that multiple and ongoing focal amplification events, including in immunomodulatory genes, may enhance the fitness of a clone during the development of cancer.
These findings shed light on how ecDNA can arise early in the genesis of a cancer and characterisation of these events may impact on treatment strategies.
Rebecca Fitzgerald is one of the corresponding authors
Luebeck, J., Ng, A.W.T., Galipeau, P.C. et al. Extrachromosomal DNA in the cancerous transformation of Barrett’s oesophagus. Nature 616, 798–805 (2023). https://doi.org/10.1038/s41586-023-05937-5