Oncogene Convergence in Extrachromosomal DNA Hubs

Review Pathology

Extrachromosomal DNA: An Emerging Hallmark in Human Cancer

Sihan Wu et al.

Summary: This review discusses the formation and function of circular, extrachromosomal pieces of DNA (ecDNA) found in cancer, as well as their contribution to tumor pathogenesis, drug resistance, and accelerated cancer evolution.

ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE (2022)

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Article Multidisciplinary Sciences

Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA

Erik N. Bergstrom et al.

Summary: This study provides a comprehensive characterization of clustered mutations and small insertions and deletions in cancer genomes. The results show that clustered mutations are enriched in driver genes and associated with differential gene expression and overall survival. Different mutational processes contribute to clustered insertions and deletions, including specific signatures in tobacco smokers and homologous-recombination-deficient cancers. APOBEC3 plays a significant role in clustered substitutions, although only a small percentage matches APOBEC3 patterns. The study also reveals the associations between the activation-induced deaminase (AID) and APOBEC3 family of deaminases with kataegis (longer strand-coordinated events).

NATURE (2022)

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Article Oncology

Live-Cell Imaging Shows Uneven Segregation of Extrachromosomal DNA Elements and Transcriptionally Active Extrachromosomal DNA Hubs in Cancer

Eunhee Yi et al.

Summary: Oncogenic ecDNA plays a crucial role in tumor evolution, but our understanding of its biology is limited. In this study, we investigated the distribution and frequency of ecDNA copy number in patient tissues and cell line models. We discovered uneven segregation of ecDNA during mitosis and the formation of ecDNA hubs that drive oncogene transcription.

CANCER DISCOVERY (2022)

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Article Multidisciplinary Sciences

Chromothripsis drives the evolution of gene amplification in cancer

Ofer Shoshani et al.

Summary: The study reveals that chromothripsis is a major driver of circular extrachromosomal DNA (ecDNA) amplification, mediated by poly(ADP-ribose) polymerases (PARP) and DNA-dependent protein kinase (DNA-PKcs). The structural evolution of ecDNAs further increases drug tolerance, leading to rapid acquisition of tolerance to altered growth conditions. This mechanism accelerates genomic DNA rearrangement and amplification into ecDNA, contributing to cancer therapy resistance.

NATURE (2021)

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Article Multidisciplinary Sciences

ecDNA hubs drive cooperative intermolecular oncogene expression

King L. Hung et al.

Summary: Extrachromosomal DNA (ecDNA) hubs are clusters of ecDNAs within the nucleus that enable intermolecular enhancer-gene interactions, promoting oncogene overexpression. The protein-tethered ecDNA hubs facilitate intermolecular transcriptional regulation, serving as units of oncogene function and potential targets for cancer therapy.

NATURE (2021)

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Article Genetics & Heredity

Chromothripsis followed by circular recombination drives oncogene amplification in human cancer

Carolina Rosswog et al.

Summary: Seismic amplifications are a type of amplification caused by chromothripsis, resulting in circular recombination of circular extrachromosomal DNA, providing a mechanism for oncogene amplification in various human tumor types. In pediatric neuroblastoma data, seismic amplification was characterized by multiple rearrangements and discontinuous copy number levels.

NATURE GENETICS (2021)

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Article Oncology

Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription

Yanfen Zhu et al.

Summary: The study reveals that extrachromosomal, circular DNA (ecDNA) is a common and oncogenic alteration in cancer genomes, impacting transcriptional programs through chromatin interactions. ecDNAs in neurosphere and prostate cancer cell cultures show widespread intra-ecDNA and genome-wide chromosomal interactions, potentially leading to high-level expression of chromosomal genes.

CANCER CELL (2021)

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Article Oncology