Extrachromosomal DNA associates with poor survival across a broad spectrum of childhood solid tumors

Circular extrachromosomal DNA (ecDNA) is a powerful driver of oncogene amplification and tumor evolution, yet its prevalence, composition, and clinical significance across pediatric cancers remains incompletely understood. Leveraging two major cloud-based genomic data repositories, we analyzed whole genome sequencing data from 3,630 tumor biosamples representing 2,967 children across 39 solid tumor types. ecDNA was identified in 9% of cases and was enriched in high-grade and clinically aggressive malignancies including ETMR, pediatric high-grade glioma, medulloblastoma, neuroblastoma, osteosarcoma and rhabdomyosarcoma. We catalogued 392 ecDNA sequences, revealing recurrent amplification of known oncogenes, diverse gene fusions, and oncogenic loci where recurrent ecDNA involvement underscores their emerging importance in pediatric tumors. Oncogenes amplified on ecDNA reached significantly higher copy number than chromosomal amplifications, and ecDNA was associated with significantly poorer 5-year survival independent of tumor type, age and sex. Longitudinal analyses demonstrated that ecDNA frequently arises, is lost, or undergoes structural remodeling during progression and recurrence, including acquisition or loss of oncogenes on the same circular element. Together, these findings define the landscape, clinical relevance, and evolutionary behavior of ecDNA across childhood cancers, highlight candidate drivers, and identify patient populations that may benefit from emerging ecDNA-targeted therapeutic strategies. An interactive resource is available at https://ccdi-ecdna.org/.