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Genome-wide Purification of Extrachromosomal Circular DNA from Eukaryotic Cells
Published on: April 4, 2016
Origins and impact of extrachromosomal DNA
Chris Bailey1, Oriol Pich1, Kerstin Thol2,3
1Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.
Abstract:
Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer1,2. Here we examine the diversity of ecDNA elements across cancer, revealing the associated tissue, genetic and mutational contexts. By analysing data from 14,778 patients with 39 tumour types from the 100,000 Genomes Project, we demonstrate that 17.1% of tumour samples contain ecDNA. We reveal a pattern highly indicative of tissue-context-based selection for ecDNAs, linking their genomic content to their tissue of origin. We show that not only is ecDNA a mechanism for amplification of driver oncogenes, but it also a mechanism that frequently amplifies immunomodulatory and inflammatory genes, such as those that modulate lymphocyte-mediated immunity and immune effector processes. Moreover, ecDNAs carrying immunomodulatory genes are associated with reduced tumour T cell infiltration. We identify ecDNAs bearing only enhancers, promoters and lncRNA elements, suggesting the combinatorial power of interactions between ecDNAs in trans. We also identify intrinsic and environmental mutational processes linked to ecDNA, including those linked to its formation, such as tobacco exposure, and progression, such as homologous recombination repair deficiency. Clinically, ecDNA detection was associated with tumour stage, more prevalent after targeted therapy and cytotoxic treatments, and associated with metastases and shorter overall survival. These results shed light on why ecDNA is a substantial clinical problem that can cooperatively drive tumour growth signals, alter transcriptional landscapes and suppress the immune system.
Insights
Extrachromosomal DNA (ecDNA) drives cancer treatment resistance. This study reveals ecDNA amplifies oncogenes and immune genes, impacting patient survival and T cell infiltration.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- Extrachromosomal DNA (ecDNA) is implicated in cancer treatment resistance and poor patient outcomes.
- Understanding the diversity and context of ecDNA is crucial for developing effective cancer therapies.
Purpose of the Study:
- To investigate the diversity of ecDNA elements across various cancer types.
- To identify the genetic, mutational, and tissue-specific contexts associated with ecDNA.
- To explore the clinical implications of ecDNA in cancer progression and patient survival.
Main Methods:
- Analysis of 14,778 tumor samples from 39 tumor types using data from the 100,000 Genomes Project.
- Examination of genomic content, mutational processes, and clinical data associated with ecDNA presence.
- Assessment of the relationship between ecDNA and tumor-infiltrating lymphocytes, treatment history, and patient survival.
Main Results:
- 17.1% of analyzed tumor samples contained ecDNA, with patterns linked to tissue of origin.
- ecDNA frequently amplifies oncogenes, immunomodulatory, and inflammatory genes, potentially suppressing T cell infiltration.
- ecDNA presence correlates with tumor stage, metastases, shorter survival, and is more prevalent after certain cancer treatments.
- Intrinsic and environmental mutational processes, including tobacco exposure and homologous recombination repair deficiency, are linked to ecDNA.
Conclusions:
- ecDNA is a significant driver of cancer progression, treatment resistance, and poor prognosis.
- ecDNA's amplification of oncogenes and immune-related genes contributes to tumor growth and immune evasion.
- Further research into ecDNA's role is essential for improving cancer patient outcomes and therapeutic strategies.
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