2359 - Extrachromosomal and Complex Amplicons are Independent Prognostic Markers inPediatric Medulloblastoma

Purpose/Objective(s):

Extrachromosomal DNA (ecDNA) and other complex amplicon structures are increasingly recognized as key drivers of oncogene amplification and therapeutic resistance. Their role in pediatric brain tumors treated with radiotherapy (RT), particularly medulloblastoma, is not well defined.

Materials/Methods:

Structural amplicon data were obtained from the Pediatric Pancancer Project, including samples from St. Jude and the Pediatric Brain Tumor Atlas (PBTA). Only patients who received RT were included in subsequent analysis. Amplicon classifications (ecDNA, linear, complex-non-cyclic) were derived from ampliconrepository.org/project/PedPanCan. These data were integrated with clinical annotations. Cox models assessed associations with survival, and concordance indices evaluated model performance.

Results:

ecDNA was observed in multiple pediatric tumors, including high-grade gliomas, diffuse midline gliomas, ETMR, ependymomas, and medulloblastomas. Common oncogenes on ecDNA included PDGFRA, EGFR, MYCN, CDK6, and MET. In medulloblastoma, molecular subtype strongly predicted outcome: Group 3 had the worst prognosis (HR = 2.35, p < 0.01), Group 4 the best, SHH intermediate (HR = 1.34, not significant), and WNT showed no events. Amplicon structure provided independent prognostic value: complex-non-cyclic (HR = 5.82), linear (HR = 9.82), and ecDNA (HR = 2.30) were all associated with worse survival (p < 0.05). ecDNA was most frequent in SHH tumors. Incorporating amplicon architecture improved concordance from 0.643 to 0.686.

Conclusion:

Both molecular subtype and amplicon architecture are independent predictors of outcome in medulloblastoma. Structural amplicon profiling, particularly identification of ecDNA and complex amplicons, adds prognostic value and may improve risk stratification in pediatric brain tumors.