Defining the Role of Extrachromosomal DNA Amplifications in Medulloblastoma

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Abstract

Circular extrachromosomal DNA (ecDNA), a common mechanism of oncogene amplification, has been identified as a major contributor to intratumoral heterogeneity and patient outcomes. In a recent publication in Nature Genetics, Chapman and colleagues further explored the role of ecDNA in the context of medulloblastoma. Using whole-genome sequencing, they found that 18% of the patients carry ecDNA amplification across a 468 medulloblastoma patient cohort. The presence of ecDNA was associated with worse survival. Single-cell FISH imaging and multiomic sequencing revealed that ecDNA copy number displayed a cell-to-cell variability within the sample, contributing to tumor heterogeneity. Furthermore, through sequencing and CRISPRi experiments, the authors uncovered frequent enhancer rewiring events on ecDNA that drive proliferation.

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Most cited references 10

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Circular ecDNA promotes accessible chromatin and high oncogene expression

Sihan Wu, Kristen M Turner, Nam H. Nguyen … (2019)

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

Hoon Min Kim, Nam-Phuong D Nguyen, Kristen Turner … (2020)

Extrachromosomal DNA (ecDNA) amplification promotes intratumoral genetic heterogeneity and accelerated tumor evolution 1–3 , but its frequency and clinical impact are unclear. Here we show, using computational analysis of whole-genome sequencing data from 3,212 cancer patients, 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 arise 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 carry ecDNAs have significantly shorter survival, even when controlled for tissue type, than do patients whose cancers are 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.

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Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma

Richard P Koche, Elias Rodríguez-Fos, Konstantin Helmsauer … (2019)

Extrachromosomal circularization of DNA is an important genomic feature in cancer. However, the structure, composition and genome-wide frequency of extrachromosomal circular DNA have not yet been profiled extensively. Here, we combine genomic and transcriptomic approaches to describe the landscape of extrachromosomal circular DNA in neuroblastoma, a tumor arising in childhood from primitive cells of the sympathetic nervous system. Our analysis identifies and characterizes a wide catalog of somatically acquired and undescribed extrachromosomal circular DNAs. Moreover, we find that extrachromosomal circular DNAs are an unanticipated major source of somatic rearrangements, contributing to oncogenic remodeling through chimeric circularization and reintegration of circular DNA into the linear genome. Cancer-causing lesions can emerge out of circle-derived rearrangements and are associated with adverse clinical outcome. It is highly probable that circle-derived rearrangements represent an ongoing mutagenic process. Thus, extrachromosomal circular DNAs represent a multihit mutagenic process, with important functional and clinical implications for the origins of genomic remodeling in cancer.

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Author and article information

Contributors

Dacheng Zhao: (View ORCID Profile)

Roel G.W. Verhaak: (View ORCID Profile)

Journal

Title: Cancer Research

Publisher: American Association for Cancer Research (AACR)

ISSN (Print): 0008-5472

ISSN (Electronic): 1538-7445

Publication date Created: February 15 2024

Publication date Created: January 04 2024

Publication date (Print): February 15 2024

Publication date (Electronic): January 04 2024

Volume: 84

Issue: 4

Pages: 515-516

Article

DOI: 10.1158/0008-5472.CAN-23-4025

PubMed ID: 38175761

SO-VID: 419dda4f-aab3-48d9-83f9-ec6fe6218e88

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