Extrachromosomal DNA in the cancerous transformation of Barrett’s esophagus

Abstract

BACKGROUND Oncogenes are commonly amplified on extrachromosomal DNA (ecDNA) contributing to poor outcomes for patients. Currently, the chronology of ecDNA development is not known. We studied the origination and evolution of ecDNA in patients with Barrett's esophagus (BE) who progressed to esophageal adenocarcinoma (EAC). METHODS We analyzed whole-genome sequencing (WGS) data from a BE surveillance cohort and EAC patients at Cambridge University UK (n=206 patients). We also analyzed WGS data from biopsies taken at two time points from multiple sites in the esophagus from 80 patients enrolled in a case-control study at the Fred Hutchinson Cancer Center (FHCC) - 40 BE patients who progressed to EAC and 40 who did not. RESULTS ecDNA was detected in 24% and 43% of BE patients with BE-associated early and late-stage EAC, respectively, in the Cambridge cross-sectional cohort. ecDNA was found in 33% of all FHCC BE patients who developed cancer, either prior to, or at EAC diagnosis. ecDNA was strongly associated with patients who developed cancer, in contrast with FHCC BE patients who did not progress (odds ratio, 18.8, CI - 2.3-152, p=3.3x10-4). ecDNAs were enriched for oncogenes and immunomodulatory genes and could be detected early in the transition from high-grade dysplasia to cancer and increased in copy number and complexity over time. CONCLUSIONS ecDNAs can develop before a diagnosis of cancer in BE patients and are strongly selected for during the evolution to EAC. ecDNAs promote diverse oncogene and immunomodulatory gene amplification during EAC development and progression.

Cell-cycle dependent DNA repair and replication unifies patterns of chromosome instability

“…The slight changes of ecDNA sizes, moderate increases of mean copy numbers, and larger increases of maximum copy numbers over time (Fig. 4c) are consistent with previous discoveries obtained from patients with Barrett's oesophagus, which showed ecDNA sizes were not significantly different whereas ecDNA copy numbers became significantly higher during malignant progression [50].…”

“…Using simulations of larger cell populations under both neutral evolution and selection, our model can help to reveal the evolutionary dynamics of SVs in the long run. The ecDNA-based oncogene amplifications are common and associated with poor outcome across multiple cancer types [48], whose evolutionary dynamics has been recently well studied [49, 50]. To compare with previous results, we continued our simulation of one unrepaired DSB with local fragmentation until 1000, 3000, and 5000 cells to see the long-term effect of selection on ecDNAs.…”

'A distinct circular DNA profile intersects with proteome changes in the genotoxic stress-related hSOD1G93A model of ALS'

“…Accounting for the suggested capability to embed pathophysiologically impactful sequences, in analogy to the recently described regulator and enhancer functions of long ecDNAs in tumors [47], the modes of interaction with the linear genome will greatly broaden our understanding of small eccDNA in the context of neurological disorders. To allow conclusions in humans and to understand whether eccDNA can be an early causal event in ALS, as suggested for cancer [103], future investigations are required.…”

Extrachromosomal Circular DNA Orchestrates Genome Heterogeneity and Outcome in Urothelial Bladder Carcinoma

“…The detected amplicons were annotated with the NCBI RefSeqGene database (GRCh38). AmpliconClassifier (AC) (version 0.4.9, https://github.com/jluebeck/AmpliconClassifier) (Luebeck et al, 2022) was then performed to classify the AA output data into different types of focal amplifications (including BFB, Circular, Heavily-rearranged, and Linear) and to extract coordinates of the genomic regions corresponding to those amplicons. Following previous procedures, amplicons and tumor samples were divided into different groups for further comparative analysis (Kim et al, 2020).…”