10186-CO-2 The genomic landscape of extrachromosomal DNA amplification across pediatric brain tumors

Abstract Extrachromosomal DNA (ecDNA) has been linked to oncogene amplification, evolution of drug resistance, and poor outcomes in various adult cancers. However, the extent to which ecDNA contributes to oncogenesis of pediatric solid tumors has heretofore remained understudied. In addition, the relative importance of intra- versus extrachromosomal amplification remains an open question. We have therefore reanalyzed whole genome sequencing data to identify ecDNA sequences in a large retrospective cohort of 3,000 pediatric solid tumors. ecDNA was most frequent in aggressive tumor types and rare in low-grade or benign histologies. Among pediatric CNS tumors, we find ecDNA most frequently in embryonal tumors with multilayered rosettes (ETMR), pediatric high-grade gliomas (pHGG) and medulloblastomas, and examples of ecDNA+ tumors belonging to ultra-rare subtypes of pineoblastoma and ependymoma. Recurrently ecDNA-amplified genomic regions included well-established oncogenes as well as genes with emerging evidence of possible oncogenic roles. Notably, multivariate Cox regression identifies additive effects of amplification and extrachromosomal amplification which contributed independently to poor patient outcomes. These results constitute a comprehensive map of the genetic and phenotypic diversity of extrachromosomal amplification in pediatric tumors, and underscore the utility of large genomic data resources to drive clinically relevant discoveries.