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Extrachromosomal DNA associates with poor survival across a broad spectrum of childhood solid tumors
Owen S Chapman1,2,3, Sunita Sridhar4,5, Eugene Yui-Ching Chow2
1Department of Neuro-oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Abstract:
Circular extrachromosomal DNA (ecDNA) is a common form of oncogene amplification in aggressive cancers. The frequency and diversity of ecDNA has been catalogued in adult and some childhood cancers; however, its role in most pediatric cancers is not well-understood. To address this gap, we accessed large pediatric cancer genomics data repositories and identified ecDNA from whole genome sequencing data using cloud computing. This retrospective cohort comprises 3,631 solid tumor biopsies from 2,968 patients covering all major childhood solid tumor types. Aggressive tumor types had particularly high incidences of ecDNA. Pediatric patients whose tumors harbored extrachromosomal DNA had significantly poorer five-year overall survival than children whose tumors contained only chromosomal amplifications. We catalogue known and potentially novel oncogenes recurrently amplified on ecDNA and show that ecDNA often evolves during disease progression. These results highlight patient populations that could potentially benefit from future ecDNA-directed therapies. To facilitate discovery, we developed an interactive catalogue of ecDNA in childhood cancer at https://ccdi-ecdna.org/.
Insights
Circular extrachromosomal DNA (ecDNA) is prevalent in aggressive childhood cancers and linked to poorer survival. This study catalogues ecDNA in pediatric tumors, identifying potential targets for new therapies.
Area of Science:
- Genomics
- Oncology
- Molecular Biology
Background:
- Circular extrachromosomal DNA (ecDNA) is a key driver of oncogene amplification in aggressive cancers.
- The role and prevalence of ecDNA in most pediatric cancers remain largely uncharacterized.
Purpose of the Study:
- To investigate the frequency and impact of ecDNA in a large cohort of childhood solid tumors.
- To catalogue oncogenes amplified on ecDNA and understand its evolution in pediatric cancers.
Main Methods:
- Utilized whole genome sequencing data from 3,631 pediatric solid tumor biopsies.
- Employed cloud computing for ecDNA identification and analysis.
- Conducted a retrospective cohort study of 2,968 pediatric patients.
Main Results:
- Identified high incidences of ecDNA, particularly in aggressive pediatric tumor types.
- Found significantly poorer five-year overall survival in pediatric patients with ecDNA-harboring tumors.
- Catalogued known and novel oncogenes amplified on ecDNA, observing its evolution during disease progression.
Conclusions:
- ecDNA is a significant factor in pediatric solid tumors, associated with worse outcomes.
- The findings highlight potential patient populations for future ecDNA-directed therapies.
- An interactive catalogue of ecDNA in childhood cancer was developed to aid further research.
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