Genetic ancestry superpopulations show distinct prevalence and outcomes across pediatric central nervous system tumors

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. ### Competing Interest Statement Angela J. Waanders is a consultant for Alexion and for DayOne Biopharmaceuticals. ### Funding Statement 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. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: 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). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes 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.