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Oncogene expression from extrachromosomal DNA is driven by copy number amplification and does not require spatial clustering in glioblastoma stem cells

ABSTRACT: Oncogene expression from extrachromosomal DNA is driven by copy number amplification and does not require spatial clustering in glioblastoma stem cells

PROVIDER: PRJNA890239 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21894100.fastq.gz	Fastqsanger.gz
	SRR21894095_1.fastq.gz	Fastqsanger.gz
	SRR21894095_2.fastq.gz	Fastqsanger.gz
	SRR21894096_1.fastq.gz	Fastqsanger.gz
	SRR21894096_2.fastq.gz	Fastqsanger.gz

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Oncogene expression from extrachromosomal DNA is driven by copy number amplification and does not require spatial clustering in glioblastoma stem cells

Project description:Extrachromosomal DNA (ecDNA) are frequently observed in human cancers and are responsible for high levels of oncogene expression. In glioblastoma (GBM), ecDNA copy number correlates with poor prognosis. It is hypothesized that their copy number, size and chromatin accessibility facilitate clustering of ecDNA and colocalization with transcriptional hubs, and that this underpins their elevated transcriptional activity. Here, we use super-resolution imaging and quantitative image analysis to evaluate GBM stem cells harboring distinct ecDNA species (EGFR, CDK4, PDGFR). We found no evidence that ecDNA routinely cluster with one another or closely interact with transcriptional hubs. Cells with EGFR-containing ecDNA have increased EGFR transcriptional output, but transcription per gene copy was similar in ecDNA compared to the endogenous chromosomal locus. These data suggest that it is the increased copy number of oncogene-harboring ecDNA that primarily drives high levels of oncogene transcription, rather than specific interactions of ecDNA with each other or with high concentrations of the transcriptional machinery.

2022-11-11 | GSE215420 | GEO

Oncogene expression from extrachromosomal DNA is driven by copy number amplification and does not require spatial clustering in glioblastoma stem cells.

Project description:Extrachromosomal DNA (ecDNA) are frequently observed in human cancers and are responsible for high levels of oncogene expression. In glioblastoma (GBM), ecDNA copy number correlates with poor prognosis. It is hypothesized that their copy number, size, and chromatin accessibility facilitate clustering of ecDNA and colocalization with transcriptional hubs, and that this underpins their elevated transcriptional activity. Here, we use super-resolution imaging and quantitative image analysis to evaluate GBM stem cells harbouring distinct ecDNA species (EGFR, CDK4, PDGFRA). We find no evidence that ecDNA routinely cluster with one another or closely interact with transcriptional hubs. Cells with EGFR-containing ecDNA have increased EGFR transcriptional output, but transcription per gene copy is similar in ecDNA compared to the endogenous chromosomal locus. These data suggest that it is the increased copy number of oncogene-harbouring ecDNA that primarily drives high levels of oncogene transcription, rather than specific interactions of ecDNA with each other or with high concentrations of the transcriptional machinery.

| S-EPMC9728993 | biostudies-literature

Extrachromosomal DNA-driven oncogene dosage heterogeneity promotes rapid adaptation to therapy in MYCN-amplified cancers

Project description:Extrachromosomal DNA (ecDNA) amplification enhances intercellular oncogene dosage variability and accelerates tumor evolution by violating foundational principles of genetic inheritance through its asymmetric mitotic segregation. Spotlighting high-risk neuroblastoma we demonstrate how ecDNA amplification undermines the clinical efficacy of current therapies in cancers with extrachromosomal MYCN amplification. Integrating theoretical models of oncogene copy number-dependent fitness with single-cell ecDNA quantification and phenotype analyses, we reveal that ecDNA copy number heterogeneity drives phenotypic diversity and determines treatment sensitivity through mechanisms unattainable by chromosomal oncogene amplification. We demonstrate that ecDNA copy number directly influences critical cell fate decisions in cancer cell lines, patient-derived xenografts and primary neuroblastomas, illustrating how extrachromosomal oncogene dosage-driven phenotypic diversity offers a strong evolutionary advantage under therapeutic pressure. Furthermore, we identify senescent ecDNA-containing cells with reduced copy numbers in neuroblastomas and other MYC-amplified cancers as a source of treatment resistance and outline a strategy for their targeted elimination to improve the poor outcome of patients with MYCN-amplified cancers.

2025-07-05 | PXD064049 | Pride

Engineered extrachromosomal oncogene amplifications promote tumorigenesis

Project description:Engineered extrachromosomal oncogene amplifications promote tumorigenesis

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Functional enhancers shape extrachromosomal oncogene amplifications

Project description:Functional enhancers shape extrachromosomal oncogene amplifications

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Engineered extrachromosomal oncogene amplifications promote tumorigenesis (RNA-Seq)

Project description:Engineered extrachromosomal oncogene amplifications promote tumorigenesis (RNA-Seq)

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Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity.

Project description:Human cells have twenty-three pairs of chromosomes. In cancer, however, genes can be amplified in chromosomes or in circular extrachromosomal DNA (ecDNA), although the frequency and functional importance of ecDNA are not understood. We performed whole-genome sequencing, structural modelling and cytogenetic analyses of 17 different cancer types, including analysis of the structure and function of chromosomes during metaphase of 2,572 dividing cells, and developed a software package called ECdetect to conduct unbiased, integrated ecDNA detection and analysis. Here we show that ecDNA was found in nearly half of human cancers; its frequency varied by tumour type, but it was almost never found in normal cells. Driver oncogenes were amplified most commonly in ecDNA, thereby increasing transcript level. Mathematical modelling predicted that ecDNA amplification would increase oncogene copy number and intratumoural heterogeneity more effectively than chromosomal amplification. We validated these predictions by quantitative analyses of cancer samples. The results presented here suggest that ecDNA contributes to accelerated evolution in cancer.

| S-EPMC5334176 | biostudies-literature

Engineered extrachromosomal oncogene amplifications promote tumorigenesis [shallow whole genome sequencing and ATACseq]

Project description:Engineered extrachromosomal oncogene amplifications promote tumorigenesis [shallow whole genome sequencing and ATACseq]

| PRJNA1101531 | ENA

Circular extrachromosomal DNA drives massive oncogene expression and chromatin accessibility

Project description:Oncogenes are commonly amplified on extrachromosomal DNA particles (ecDNA) in cancer, but our understanding of the structure of ecDNA and its impact on gene regulation is limited. We integrated ultrastructural imaging, long range-optical mapping, and computational analysis of whole genome sequencing to demonstrate unequivocally that ecDNA is circular. Pan-cancer analyses reveal that the oncogenes encoded on ecDNA are among the most highly expressed genes in the transcriptome of tumours, linking elevated copy with very high levels of transcription. Quantitative assessment of the chromatin state, including ATAC-seq to map the accessible genome and ATAC-see to examine spatial distribution of open chromatin, reveal that while ecDNA is chromatinized, it lacks higher order compaction typical of chromosomes. In fact, ecDNA contains the most accessible DNA in the tumour genome. Using chromosome conformation capture technologies and CRISPR interference, we reveal the differential organization of active chromatin in cancer that is dictated by the circular shape of ecDNA. Lastly, we develop comprehensive maps that provide new insight into how circular ecDNA structure determines oncogene function, bridging ecDNA biology with modern cancer genomics and epigenetics.

2019-12-31 | GSE131956 | GEO

Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers.

Project description:Extrachromosomal DNA (ecDNA) amplification promotes intratumoral genetic heterogeneity and accelerated tumor evolution1-3; however, its frequency and clinical impact are unclear. Using computational analysis of whole-genome sequencing data from 3,212 cancer patients, we show that ecDNA amplification frequently occurs in most cancer types but not in blood or normal tissue. Oncogenes were highly enriched on amplified ecDNA, and the most common recurrent oncogene amplifications arose on ecDNA. EcDNA amplifications resulted in higher levels of oncogene transcription compared to copy number-matched linear DNA, coupled with enhanced chromatin accessibility, and more frequently resulted in transcript fusions. Patients whose cancers carried ecDNA had significantly shorter survival, even when controlled for tissue type, than patients whose cancers were not driven by ecDNA-based oncogene amplification. The results presented here demonstrate that ecDNA-based oncogene amplification is common in cancer, is different from chromosomal amplification and drives poor outcome for patients across many cancer types.

| S-EPMC7484012 | biostudies-literature

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