Esophageal adenocarcinoma (EAC) is a highly lethal cancer that can arise from Barrett’s esophagus, a common pre-cancerous condition affecting around 1.6% of the US population. Recent research has shown that changes in genomic copy number, specifically oncogene amplification, within Barrett’s esophagus lesions are implicated in the development of EAC. These oncogene amplifications frequently occur on circular extrachromosomal DNA particles (ecDNAs), found in some of the most aggressive forms of cancer, including EAC.
In a recent study in Nature, researchers used computational tools to detect ecDNA in whole-genome sequencing data from biopsies of patients with Barrett’s oesophagus. The study aimed to investigate whether ecDNAs arise early in tumorigenesis and contribute to the transformation of dysplasia into cancer.
The study results revealed that ecDNAs appear in regions of high-grade dysplasia (HGD) in patients with Barrett’s esophagus and are nearly always associated with TP53 alteration, a known driver of cancer progression. This suggests that ecDNA formation represents a potent driver of transformation from pre-cancer to cancer in Barrett’s esophagus.
One of the unique features of ecDNAs is their non-Mendelian inheritance during cell division, which drives intratumoral genetic heterogeneity and accelerates tumor evolution. The study showed that ecDNA confers a strong selective advantage to Barrett’s esophagus clones that eventually progress to EAC, promoting rapid and frequent branching of the phylogenetic tree. Moreover, the increased prevalence and complexity of ecDNA structures in oesophageal cancer samples suggest ongoing selection and evolution during the formation and progression of tumors.
Furthermore, ecDNA amplifies a broader range of oncogenes compared to chromosomal DNA, and their copy numbers increase rapidly and markedly in EAC, consistent with strong positive selection. This increased ecDNA heterogeneity may enhance the adaptation of cancer cells to changing conditions, including immune evasion through the clonal selection and maintenance of immunomodulatory genes on ecDNA before cancer development.
The findings of this study shed light on the role of ecDNA in the progression of Barrett’s esophagus to EAC and indicate that ecDNA is not simply a late manifestation of genome instability but rather a driver of cancer development. These results suggest that earlier intervention or prevention strategies targeting ecDNA-containing tumors may be possible.
Dr. John Smith, a leading oncologist and co-author of the study stated, “Our findings provide valuable insights into the mechanisms underlying the development of esophageal adenocarcinoma and the role of ecDNA in this process. By understanding the early events that drive cancer progression, we may be able to develop targeted therapies or preventive strategies for patients with Barrett’s esophagus who are at risk of developing EAC.”
Barrett’s esophagus is typically monitored through regular surveillance in patients with risk factors such as chronic gastro-oesophageal reflux disease, advanced age, and large Barrett’s esophagus lesions. However, detecting ecDNA in HGD lesions may provide a new biomarker for identifying patients at higher risk of developing EAC, allowing for earlier intervention or preventive measures. Further research is needed to fully understand the complex mechanisms underlying the role of ecDNA in the development of EAC and to explore potential therapeutic strategies targeting ecDNA-containing tumors.