Genetic ancestry superpopulations show distinct prevalence and outcomes across pediatric central nervous system tumors from the PBTA and PNOC

Authors

Ryan J. Corbett, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Cricket C. Gullickson, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Zhuangzhuang Geng, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Miguel A. Brown, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Bo Zhang, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Chuwei Zhong, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Nicholas Van Kuren, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Antonia Chroni, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Christopher Blackden, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Ammar S. Naqvi, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Alexa Plisiewicz, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Sean McHugh, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Emmett Drake, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Kaitlin Lehmann, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Tom B. Davidson, Keck School of Medicine of University of Southern California, Children's Hospital of Los Angeles, Los Angeles, CA, USA.
Michael Prados, Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
Phillip B. Storm, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Adam C. Resnick, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Angela J. Waanders, Division of Hematology, Oncology, Neuro-Oncology, and Stem Cell Transplant, Ann & Robert H Lurie Children's Hospital of Chicago, USA.
Sebastian M. Waszak, Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
Sabine Mueller, Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
Jo Lynne Rokita, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Cassie Kline, Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Document Type

Journal Article

Publication Date

1-23-2025

Journal

Neuro-oncology

DOI

10.1093/neuonc/noaf017

Keywords

Clinical Outcomes; Genetic Ancestry; Health equity; Pediatric neuro-oncology

Abstract

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 1,452 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<0.001). 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 (HR=4.6, p=0.03). 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<0.01; HR=5.2, p=0.03) and AFR patients with LGG (HR=16.4, p<0.01) or ependymoma (HR=5.5, p=0.02) had worse overall survival compared to EUR patients. We observed higher frequency of clinical trial enrollment among AMR patients across tumor histologies (OR=2.0, p=<0.01), but increased utilization of photon versus proton radiation relative to other superpopulations (OR=0.55, p=0.04). 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.

APA Citation

Corbett, Ryan J.; Gullickson, Cricket C.; Geng, Zhuangzhuang; Brown, Miguel A.; Zhang, Bo; Zhong, Chuwei; Van Kuren, Nicholas; Chroni, Antonia; Blackden, Christopher; Naqvi, Ammar S.; Plisiewicz, Alexa; McHugh, Sean; Drake, Emmett; Lehmann, Kaitlin; Davidson, Tom B.; Prados, Michael; Storm, Phillip B.; Resnick, Adam C.; Waanders, Angela J.; Waszak, Sebastian M.; Mueller, Sabine; Rokita, Jo Lynne; and Kline, Cassie, "Genetic ancestry superpopulations show distinct prevalence and outcomes across pediatric central nervous system tumors from the PBTA and PNOC" (2025). GW Authored Works. Paper 6330.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/6330

Department

Pediatrics