Extrachromosomal DNA in the cancerous transformation of Barrett's oesophagus. Nature. 2023;616(7958):798-805
JGM, 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
This work was delivered as part of the eDyNAmiC team supported by the Cancer Grand Challenges partnership funded by Cancer Research UK (CRUK) (P.S.M. and H.Y.C., CGCATF-2021/100012; V.B. and J.L., CGCATF-2021/100025; S.W., CGCATF-2021/100023; and R.G.W.V., CGCATF-2021/ 100016) and the National Cancer Institute (P.S.M. and H.Y.C., OT2CA278688; V.B. and J.L., OT2CA278635; S.W., OT2CA278683; and R.G.W.V., OT2CA278649). P.S.M. is the eDyNAmiC team lead and co-authors R.G.W.V., H.Y.C., S.W. and V.B. are members of the eDyNAmiC team. This study was also supported by a grant from the National Brain Tumour Society (P.S.M.) and National Institutes of Health (NIH) R01-CA238379 (P.S.M.). V.B. and J.L. were supported in part by grants U24CA264379 and R01GM114362 from the NIH. S.W. is a scholar of and is supported by the Cancer Prevention and Research Institute of Texas (RR210034). The Cambridge research (R.C.F., A.W.T.N. and S.J.) was funded by a programme grant from the Medical Research Biomedical Research Centre and the CRUK Experimental Cancer Research Centre. A.C.K.-S. was funded by CRUK through a clinical research fellowship. Research at FHCC (T.G.P., B.J.R., C.A.S., P.C.G. and X.L.) was funded by NIH grants P01 CA91955 and P30 CA015704. H.K. is supported by the Brain Korea 21 Four Project, a Korean Ministry of Food and Drug Safety grant (21153MFDS607) and Korean Ministry of Science and ICT grants (NRF-2019R1A5A2027340 and NRF-2022M3C1A309202211). R.G.W.V. acknowledges support from NIH–NCI grants R01 CA237208, R21 CA256575 and R33 CA236681 and a Cancer Center Support grant P30 CA034196, as well as NIH–NINDS grant R21 NS114873. Work in the L.B.A. laboratory (L.B.A. and Y.H.) was supported by NIH grants R01ES030993-01A1 and R01ES032547-01 and a Cancer Grand Challenges Mutographs team award funded by CRUK (C98/A24032). L.B.A. is also personally supported by a Packard Fellowship for Science and Engineering. This work was also supported by the PreCancer Genome Atlas (PCGA) project with core funding from UC San Diego NCI P30 (P30 CA023100; S.M.L.), and in part by the SU2C-AACR-DT25-17 and US NIH grants R01DE026644, P30 CA023100, HHSN261201200031I and UG1CA242596.
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.