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Genome-wide Purification of Extrachromosomal Circular DNA from Eukaryotic Cells
Published on: April 4, 2016
Extrachromosomal Circular DNA from TCGA Tumors Is Generated from Common Genomic Loci, Is Characterized by
Philip D Tatman1, Joshua C Black1
1Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
Abstract:
Extrachromosomal circular DNA has emerged as a frequent genomic alteration in tumors. High numbers of circular DNAs correspond to poor prognosis suggesting an important function in tumor biology. However, despite mounting evidence supporting the importance of circular DNA, little is known about their production, maintenance, or selection. To provide insight into these processes, we analyzed circular DNA elements computationally identified in 355 TCGA tumors spanning 22 tumor types. Circular DNAs originated from common genomic loci irrespective of cancer type. Genes found in circularized genomic regions were more likely to be expressed and were enriched in cancer-related pathways. Finally, in support of a model for circle generation through either a homology or microhomology-mediated process, circles exhibit homology near their breakpoint. These breakpoints are also enriched in specific DNA motifs. Our analysis supports a model where gene-containing circles emerge from common, highly transcribed regions through a homology-mediated process.
Insights
Extrachromosomal circular DNA (ecDNA) is common in tumors and linked to poor prognosis. This study reveals ecDNA originates from expressed genes via homology-mediated processes, offering insights into tumor development.
Area of Science:
- Genomics
- Cancer Biology
- Molecular Oncology
Background:
- Extrachromosomal circular DNA (ecDNA) represents a frequent genomic alteration in various cancers.
- Elevated ecDNA levels correlate with poor patient prognosis, indicating a significant role in tumor progression.
- The precise mechanisms of ecDNA production, maintenance, and selection remain largely unelucidated.
Purpose of the Study:
- To computationally analyze ecDNA elements across a diverse range of tumor types.
- To investigate the genomic origins, characteristics, and potential formation mechanisms of ecDNA.
- To understand the functional implications of ecDNA in cancer biology.
Main Methods:
- Computational analysis of ecDNA in 355 tumors from 22 cancer types using TCGA data.
- Identification of common genomic loci and gene expression patterns associated with ecDNA.
- Analysis of breakpoint homology and DNA motifs to infer formation mechanisms.
Main Results:
- ecDNA frequently arises from common genomic loci, independent of cancer type.
- Genes within circularized regions show higher expression and are enriched in cancer-related pathways.
- Analysis revealed homology near ecDNA breakpoints, supporting homology-mediated formation, and identified specific DNA motifs at these sites.
Conclusions:
- Gene-containing ecDNA likely originates from highly transcribed genomic regions.
- Homology-mediated processes are implicated in the generation of ecDNA.
- Understanding ecDNA formation provides crucial insights into tumor evolution and potential therapeutic targets.
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