Extrachromosomal DNA Amplifies Oncogenes in Esophageal Precursor Lesions

Esophageal adenocarcinoma (EAC) can arise from Barrett's esophagus (BE), a precancerous condition that can develop when the esophageal lining sustains chronic damage from gastroesophageal reflux disease, and genomic copy-number changes in BE precursor lesions have been associated with the malignant transformation to EAC. While amplification of oncogenes can occur in the context of circular extrachromosomal DNA (ecDNA), the question remains whether ecDNAs contribute to the early phases of oncogenic transformation. To investigate the role of ecDNAs in EAC progression, Luebeck and colleagues analyzed histology and whole-genome sequencing (WGS) analysis of surveillance endoscopy biopsies of patients with BE (n = 204). Whereas no ecDNA was detected in patients with nondysplastic BE or low-grade dysplasia that did not later develop into high-grade dysplasia or EAC, ecDNA was associated with early-stage EAC and increased in frequency in late-stage EAC. In a longitudinal case–control study, multiregional samples were collected for analysis at two time points from patients with BE (n = 40 patients who developed EAC; n = 40 patients whose lesions remained benign), and ecDNA was associated with cancer outcomes and worsened pathologic status both before and at the time of cancer diagnosis, suggesting the involvement of ecDNA in the malignant progression. Within the longitudinal study, a patient harbored high-grade dysplasia that developed into EAC over a 7-year period, and the initial samples exhibited chromosomal ERBB2 amplification and TP53 alteration. An ecDNA was detected 5.6 years following the initial surveillance endoscopy, and at the time of EAC diagnosis, a second distinct ecDNA appeared, encoding multiple immunomodulatory genes. Characterization of 137 ecDNAs from patients with ecDNA⁺ BE, BE-derived high-grade dysplasia, or EAC highlighted the increase in complexity of structural rearrangements in the transition from precancer to EAC as well as increased copy number in samples associated with a more severe histologic status. Together, these findings shed light into the role of ecDNA events in the evolution of cancer, including in some cases as far back as the precancerous lesion.

Luebeck J, Ng AWT, Galipeau PC, Li X, Sanchez CA, Katz-Summercorn AC, et al. Extrachromosomal DNA in the cancerous transformation of Barrett's oesophagus. Nature 2023 Apr 12 [Epub ahead of print].

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