Genetic ancestry superpopulations show distinct prevalence and outcomes across pediatric central nervous system tumors from the Pediatric Brain Tumor Atlas and Pediatric Neuro-Oncology Consortium

Background Central nervous system (CNS) tumors lead to cancer-related mortality in children. Genetic ancestry-associated cancer prevalence and outcomes have been studied but are limited. Methods We performed genetic ancestry prediction in 1,452 pediatric patients with paired normal and tumor whole genome sequencing from the Open Pediatric Cancer (OpenPedCan) project to evaluate the influence of reported race and ethnicity and ancestry-based genetic superpopulations on tumor histology, molecular subtype, survival, and treatment. Results Predicted superpopulations included African (AFR, N = 153), Admixed American (AMR, N = 222), East Asian (EAS, N = 67), European (EUR, N = 968), and South Asian (SAS, N = 42). Reported race and ethnicity and ancestry-based genetic superpopulations were non-randomly associated (P < .001). Patients with an atypical teratoid rhabdoid tumor or meningioma were enriched for AFR ancestry (OR = 2.6, FDR = 0.01; OR = 2.9, FDR = 0.01, respectively). Among KIAA1549::BRAF fusion-positive low-grade glioma (LGG) diagnoses, EAS and SAS patients disproportionately harbored exon 15:09 breakpoints (FDR < 0.05), and AMR patients demonstrated rare breakpoints, which were associated with lesser degree of surgical resection and worse event-free survival (EFS) versus other breakpoints (hazard ratio (HR) = 4.6, P = .03). Non-EUR and AMR patients with germ cell tumors and SHH-activated medulloblastoma, respectively, exhibited worse EFS relative to EUR patients (HR = 12.1, P < .01; HR = 5.2, P = .03) and AFR patients with LGG (HR = 16.4, P < .01) or ependymoma (HR = 5.5, P = .02) had worse overall survival compared to EUR patients. We observed a higher frequency of clinical trial enrollment among AMR patients across tumor histologies (OR = 2.0, P <= .01), but increased utilization of photon versus proton radiation relative to other superpopulations (OR = 0.55, P= .04). Conclusions Genetic ancestry-associated differences exist across pediatric CNS tumor histological and molecular subtypes from PBTA and PNOC. Further investigation into genetic and socioeconomic factors contributing to these observed inequities is needed.