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

Kim, Hoon; Nguyen, Nam; Turner, Kristen M.; Wu, Sihan; Gujar, Amit D.; Luebeck, Jens; Liu, Jihe; Deshpande, Viraj; Rajkumar, Utkrisht; Namburi, Sandeep; Amin, Samirkumar B.; Yi, Eunhee; Menghi, Francesca; Schulte, Johannes H.; Henssen, Anton; Chang, Howard Y.; Beck, Christine R.; Mischel, Paul S.; Bafna, Vineet; Verhaak, Roel G.W.

doi:10.1038/s41588-020-0678-2

Cited by 369 publications

(578 citation statements)

References 42 publications

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“…To reconstruct ecDNA molecules in COLO320-DM cells, we obtained whole-genome sequencing data and applied AmpliconArchitect, a computational tool which uses both copy number variation and structural variant analysis of short sequencing reads to reconstruct DNA amplicons arising from ecDNAs and other complex rearrangements 5,6,33 . We identified multiple “subspecies” of ecDNA amplicons resulting from the rearrangement of the MYC locus in COLO320-DM cells with a range of copy numbers ( Supplemental Figure 3a,b ).…”

Section: Resultsmentioning

confidence: 99%

“…EcDNAs are covalently closed, double-stranded, and range from ~100 kilobases to several megabases in size 1,8–11 . EcDNAs lack centromeres and are randomly distributed among daughter cells after each cell division allowing for rapid accumulation and selection of ecDNA variants that drug resistance or other fitness advantage 5,12–14 . ecDNAs can evolve over time from submicroscopic episomes to large double minutes, and that these extrachromosomal elements can re-integrate into chromosomes and form tandem repeats termed homogeneously staining regions (HSRs) 15–19 .…”

Section: Introductionmentioning

confidence: 99%

“…The MYC oncogene on human chromosome 8q24 is a hotspot for somatic DNA rearrangements in cancer 25 , and nearly 30% of MYC amplifications in human cancers exist as ecDNA 5 , typically encompassing MYC and 5’ portion of PVT1 (plasmacytoma variant transcript 1) . PVT1 , located 55kb 3’ of MYC , is a recurrent breakpoint in human cancers 26,27 .…”

Section: Introductionmentioning

confidence: 99%

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EcDNA hubs drive cooperative intermolecular oncogene expression

Hung

Yost

Xie

et al. 2020

Preprint

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Extrachromosomal DNAs (ecDNAs) are prevalent in human cancers and mediate high oncogene expression through elevated copy number and altered gene regulation1. Gene expression typically involves distal enhancer DNA elements that contact and activate genes on the same chromosome2,3. Here we show that ecDNA hubs, comprised of ~10-100 ecDNAs clustered in the nucleus of interphase cells, drive intermolecular enhancer input for amplified oncogene expression. Single-molecule sequencing, single-cell multiome, and 3D enhancer connectome reveal subspecies of MYC-PVT1 ecDNAs lacking enhancers that access intermolecular and ectopic enhancer-promoter interactions in ecDNA hubs. ecDNA hubs persist without transcription and are tethered by BET protein BRD4. BET inhibitor JQ1 disperses ecDNA hubs, preferentially inhibits ecDNA oncogene transcription, and kills ecDNA+ cancer cells. Two amplified oncogenes MYC and FGFR2 intermix in ecDNA hubs, engage in intermolecular enhancer-promoter interactions, and transcription is uniformly sensitive to JQ1. Thus, ecDNA hubs are nuclear bodies of many ecDNAs tethered by proteins and platforms for cooperative transcription, leveraging the power of oncogene diversification and combinatorial DNA interactions. We suggest ecDNA hubs, rather than individual ecDNAs, as units of oncogene function, cooperative evolution, and new targets for cancer therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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EcDNA hubs drive cooperative intermolecular oncogene expression

Hung

Yost

Xie

et al. 2020

Preprint

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“…Recent sequencing efforts show that both MYC and MYCN frequently form extrachromosomal amplifications in GBM ( 28 , 29 ). Accumulation of such extrachromosomal DNA is essentially connected to tumor evolution and is associated with overall poor prognosis in cancer ( 30 ).…”

Section: Diagnosis and Molecular Profiling Of Brain Tumors With Myc Fmentioning

confidence: 99%

Targeting MYCN in Molecularly Defined Malignant Brain Tumors

et al. 2021

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Misregulation of MYC genes, causing MYC overexpression or protein stabilization, is frequently found in malignant brain tumors highlighting their important roles as oncogenes. Brain tumors in children are the most lethal of all pediatric malignancies and the most common malignant primary adult brain tumor, glioblastoma, is still practically incurable. MYCN is one of three MYC family members and is crucial for normal brain development. It is associated with poor prognosis in many malignant pediatric brain tumor types and is focally amplified in specific adult brain tumors. Targeting MYCN has proved to be challenging due to its undruggable nature as a transcription factor and for its importance in regulating developmental programs also in healthy cells. In this review, we will discuss efforts made to circumvent the difficulty of targeting MYCN specifically by using direct or indirect measures to treat MYCN-driven brain tumors. We will further consider the mechanism of action of these measures and suggest which molecularly defined brain tumor patients that might benefit from MYCN-directed precision therapies.

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“…What factors determine the genomic loci of the origin of ecDNA? Alternatively, the formation of ecDNA is just a random event, as recently suggested by Kim et al 63 If an antineoplastic strategy specifically targeting ecDNA is to be developed, it is crucial to have a deeper understanding of the process of ecDNA formation and maintenance.…”

Section: Mechanisms Of Ecdna Formationmentioning

confidence: 99%

Progress on the role of extrachromosomal DNA in tumor pathogenesis and evolution

et al. 2020

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The amplification of oncogenes on extrachromosomal DNA (ecDNA) provides a new mechanism for cancer cells to adapt to the changes in the tumor microenvironment and accelerate tumor evolution. These extrachromosomal elements contain oncogenes, and their chromatin structures are more open than linear chromosomes and therefore have stronger oncogene transcriptional activity. ecDNA always contains enhancer elements, and genes on ecDNA can be reintegrated into the linear genome to regulate the selective expression of genes. ecDNA lacks centromeres, and the inheritance from the parent cell to the daughter cell is uneven. This non‐Mendelian genetic mechanism results in the increase of tumor heterogeneity with daughter cells that can gain a competitive advantage through a large number of copies of oncogenes. ecDNA promotes tumor invasiveness and provides a mechanism for drug resistance associated with poorer survival outcomes. Recent studies have demonstrated that the overall proportion of ecDNA in tumors is approximately 40%. In this review, we summarize the current knowledge of ecDNA in the field of tumorigenesis and development.

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

Cited by 369 publications

References 42 publications

EcDNA hubs drive cooperative intermolecular oncogene expression

EcDNA hubs drive cooperative intermolecular oncogene expression

Targeting MYCN in Molecularly Defined Malignant Brain Tumors

Progress on the role of extrachromosomal DNA in tumor pathogenesis and evolution

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