Abstract 2541: The landscape of circular extrachromosomal amplification in pediatric cancers

Abstract Circular extrachromosomal DNA (ecDNA, also known as double minutes, dm) has emerged as a driver of oncogenic copy number amplification, intratumoral heterogeneity, tumor evolution and therapy resistance. We recently screened the whole genomes of 481 medulloblatomas for ecDNA and concluded that medulloblastoma tumors harboring ecDNA are more than twice as likely to progress within 5 years of diagnosis. To evaluate the frequency and clincical impact of ecDNA across the spectrum of childhood cancers, we performed a retrospective analysis of 1671 tumors from 1482 patients across 47 pediatric tumor types from two large cloud pediatric cancer genomics resources, the Children’s Brain Tumor Network and St. Jude Cloud. ecDNA was detected in 15 pediatric tumor types, including ETMR (100%, n=4), osteosarcoma (47%, n=57), rhabdomyosarcoma (40%, n=35), neuroblastoma (30%, n=106), high-grade glioma (20%, n=157), and retinoblastoma (19%, n=32). Patients with tumors containing ecDNA had significantly poorer 5-year overall survival. In sequential samples from the same tumor at diagnosis and relapse, we observe evidence of ecDNA evolution including sequence instability and generation of new high-copy ecDNA amplification not detected at initial diagnosis. These results comprise the most detailed survey to date of the landscape of extrachromosomal amplifications across childhood cancers. Citation Format: Sunita Sridhar, Owen S. Chapman, Shanqing Wang, Aditi Dutta, Jill P. Mesirov, Lukas Chavez. The landscape of circular extrachromosomal amplification in pediatric cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2541.