Metb-08. Circular Extrachromosomal Dna Is Associated With Poor Survival in Childhood Cancer Types

Abstract BACKGROUND Circular extrachromosomal DNA (ecDNA) is a common form of oncogene amplification in aggressive cancers and a promising target for improved cancer therapy. The frequency and diversity of ecDNA has been described in different types of adult cancers and in selected childhood cancer types such as neuroblastoma and medulloblastoma. However, the frequency of ecDNA and its association with survival has not been comprehensively analyzed across the spectrum of pediatric cancers. METHODS We performed a pediatric pan-cancer study of ecDNA in which we mined large pediatric cancer genomics repositories and reconstructed ecDNA sequence structures from whole genome sequencing data. RESULTS We analyzed a retrospective cohort of 1684 tumor biopsies from 1506 different patients, covering all major childhood cancers, many of which occur exclusively in children, including rare embryonal tumor types. The fraction of patients with ecDNA-positive tumors was 10%, varying significantly by tumor type. Aggressive tumor types had particularly high incidences of ecDNA, including embryonal tumors with multilayered rosettes (n = 6, 67%), osteosarcoma (n = 55, 47%), rhabdomyosarcoma (n = 38, 39%), and neuroblastoma (n = 111, 30%). Survival analysis revealed that ecDNA amplifications are significantly associated with poor outcome. Furthermore, we catalogued known and potentially novel oncogenes that are recurrently amplified on ecDNA in pediatric cancers and showed that ecDNA often evolves during disease progression. CONCLUSIONS These results reveal childhood tumor types in which ecDNA is widely prevalent and highlight patient populations that could potentially benefit from future therapies targeting mechanisms of ecDNA biogenesis and function.