Background: Central nervous system (CNS) tumors lead to cancer-related mortality in children. Genetic ancestry-associated cancer prevalence and outcomes have been studied, but is limited. Methods: We performed genetic ancestry prediction in 1,484 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=155), Admixed American (AMR, N=224), East Asian (EAS, N=67), European (EUR, N=995), and South Asian (SAS, N=43). Reported race and ethnicity and ancestry-based genetic superpopulations were non-randomly associated. Patients with an atypical teratoid rhabdoid tumor (ATRT), MYC subtype or meningioma were enriched for AFR ancestry. Patients of AMR ancestry with KIAA1549::BRAF fusion-positive low-grade glioma (LGG) had tumors enriched for rare fusion breakpoints, lesser extent of surgical resection, and worse event-free survival (EFS). Non-EUR and AMR patients with germ cell tumors or SHH-activated medulloblastoma exhibited worse EFS relative to EUR patients, and patients of AFR ancestry with LGG or ependymoma had worse overall survival compared to EUR patients. We observed higher frequency of clinical trial enrollment among AMR patients across tumor histologies, but increased utilization of photon versus proton radiation relative to other superpopulations. Conclusions: Genetic ancestry-associated disparities exist across pediatric CNS tumor histological and molecular subtypes. Further investigation into genetic and socioeconomic factors contributing to these observed inequities is needed.

Angela J. Waanders is a consultant for Alexion and for DayOne Biopharmaceuticals.

C.K. is the recipient of the Robert A. Winn Diversity in Clinical Trials Career Development Award, established by Bristol Myers Squibb Foundation. This work was also supported in part by the CBTN, the Chad Tough Foundation, and the Division of Neurosurgery at Children's Hospital of Philadelphia.

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This study used only openly available human data that were originally made available as part of the Open Pediatric Cancer project (https://github.com/d3b-center/OpenPedCan-analysis).

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Raw sequencing data can be accessed at dbGaP accession number phs002517 or data access request to CBTN. All data and code used to perform analyses and generate figures for this manuscript can be found at https://github.com/d3b-center/pbta-ancestry.