1. Extrachromosomal DNA in the cancerous transformation of Barrett’s oesophagus
- Author
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Luebeck, Jens, Ng, Alvin Wei Tian, Galipeau, Patricia C, Li, Xiaohong, Sanchez, Carissa A, Katz-Summercorn, Annalise C, Kim, Hoon, Jammula, Sriganesh, He, Yudou, Lippman, Scott M, Verhaak, Roel GW, Maley, Carlo C, Alexandrov, Ludmil B, Reid, Brian J, Fitzgerald, Rebecca C, Paulson, Thomas G, Chang, Howard Y, Wu, Sihan, Bafna, Vineet, and Mischel, Paul S
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Clinical Research ,Prevention ,Human Genome ,Rare Diseases ,Biotechnology ,Genetics ,Infectious Diseases ,Cancer Genomics ,4.2 Evaluation of markers and technologies ,2.1 Biological and endogenous factors ,4.1 Discovery and preclinical testing of markers and technologies ,Humans ,Adenocarcinoma ,Barrett Esophagus ,Case-Control Studies ,DNA ,Esophageal Neoplasms ,Carcinogenesis ,Whole Genome Sequencing ,Cohort Studies ,Biopsy ,Disease Progression ,Oncogenes ,Immunomodulation ,DNA Copy Number Variations ,Gene Amplification ,Early Detection of Cancer ,General Science & Technology - Abstract
Oncogene amplification on extrachromosomal DNA (ecDNA) drives the evolution of tumours and their resistance to treatment, and is associated with poor outcomes for patients with cancer1-6. At present, it is unclear whether ecDNA is a later manifestation of genomic instability, or whether it can be an early event in the transition from dysplasia to cancer. Here, to better understand the development of ecDNA, we analysed whole-genome sequencing (WGS) data from patients with oesophageal adenocarcinoma (EAC) or Barrett's oesophagus. These data included 206 biopsies in Barrett's oesophagus surveillance and EAC cohorts from Cambridge University. We also analysed WGS and histology data from biopsies that were collected across multiple regions at 2 time points from 80 patients in a case-control study at the Fred Hutchinson Cancer Center. In the Cambridge cohorts, the frequency of ecDNA increased between Barrett's-oesophagus-associated early-stage (24%) and late-stage (43%) EAC, suggesting that ecDNA is formed during cancer progression. In the cohort from the Fred Hutchinson Cancer Center, 33% of patients who developed EAC had at least one oesophageal biopsy with ecDNA before or at the diagnosis of EAC. In biopsies that were collected before cancer diagnosis, higher levels of ecDNA were present in samples from patients who later developed EAC than in samples from those who did not. We found that ecDNAs contained diverse collections of oncogenes and immunomodulatory genes. Furthermore, ecDNAs showed increases in copy number and structural complexity at more advanced stages of disease. Our findings show that ecDNA can develop early in the transition from high-grade dysplasia to cancer, and that ecDNAs progressively form and evolve under positive selection.
- Published
- 2023