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Germline pathogenic variation impacts somatic alterations and patient outcomes in pediatric central nervous system tumors

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  • Ryan J. Corbett

    (Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
    Children’s Hospital of Philadelphia, Division of Neurosurgery
    Children’s Hospital of Philadelphia, Center for Childhood Cancer Research
    Children’s National Hospital, Center for Cancer and Immunology Research)

  • Rebecca S. Kaufman

    (Children’s Hospital of Philadelphia, Center for Childhood Cancer Research
    Children’s Hospital of Philadelphia, Department of Biomedical and Health Informatics)

  • Shelly W. McQuaid

    (Ann & Robert H. Lurie Children’s Hospital of Chicago
    Northwestern University Feinberg School of Medicine, Division of Hematology, Oncology, Neuro-Oncology, and Stem Cell Transplantation, Department of Pediatrics)

  • Zalman Vaksman

    (Children’s Hospital of Philadelphia, Center for Childhood Cancer Research
    Children’s Hospital of Philadelphia, Department of Biomedical and Health Informatics)

  • Saksham Phul

    (Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
    Children’s Hospital of Philadelphia, Division of Neurosurgery)

  • Miguel A. Brown

    (Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
    Children’s Hospital of Philadelphia, Division of Neurosurgery)

  • Jennifer L. Mason

    (Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
    Children’s Hospital of Philadelphia, Division of Neurosurgery)

  • Sebastian M. Waszak

    (École Polytechnique Fédérale de Lausanne, Laboratory of Computational Neuro-Oncology, Swiss Institute for Experimental Cancer Research, School of Life Sciences)

  • Bo Zhang

    (Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
    Children’s Hospital of Philadelphia, Division of Neurosurgery)

  • Chuwei Zhong

    (Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
    Children’s Hospital of Philadelphia, Division of Neurosurgery)

  • Emily Blauel

    (Children’s Hospital of Philadelphia, Center for Childhood Cancer Research)

  • Heena Desai

    (University of Pennsylvania, Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine
    University of Pennsylvania, Abramson Family Cancer Research Institute, Perelman School of Medicine)

  • Ryan Hausler

    (University of Pennsylvania, Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine
    University of Pennsylvania, Abramson Family Cancer Research Institute, Perelman School of Medicine)

  • Ammar S. Naqvi

    (Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
    Children’s Hospital of Philadelphia, Division of Neurosurgery)

  • Jessica M. Daggett

    (Children’s National Hospital, Center for Cancer and Immunology Research)

  • Alex Sickler

    (Children’s National Hospital, Center for Cancer and Immunology Research)

  • Evan C. Cresswell-Clay

    (Children’s Hospital of Philadelphia, Center for Childhood Cancer Research
    Children’s Hospital of Philadelphia, Department of Biomedical and Health Informatics)

  • Patricia J. Sullivan

    (Children’s National Hospital, Center for Cancer and Immunology Research)

  • Antonia Chroni

    (Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
    Children’s Hospital of Philadelphia, Division of Neurosurgery)

  • Zhuangzhuang Geng

    (Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
    Children’s Hospital of Philadelphia, Division of Neurosurgery)

  • Elizabeth M. Gonzalez

    (Children’s Hospital of Philadelphia, Center for Childhood Cancer Research)

  • Yuankun Zhu

    (Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
    Children’s Hospital of Philadelphia, Division of Neurosurgery)

  • Allison P. Heath

    (Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
    Children’s Hospital of Philadelphia, Division of Neurosurgery)

  • Marilyn Li

    (Children’s Hospital of Philadelphia, Department of Pathology and Laboratory Medicine)

  • Phillip B. Storm

    (Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
    Children’s Hospital of Philadelphia, Division of Neurosurgery)

  • Adam C. Resnick

    (Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
    Children’s Hospital of Philadelphia, Division of Neurosurgery)

  • Kara N. Maxwell

    (University of Pennsylvania, Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine
    University of Pennsylvania, Abramson Family Cancer Research Institute, Perelman School of Medicine)

  • Kristina A. Cole

    (Children’s Hospital of Philadelphia, Center for Childhood Cancer Research
    University of Pennsylvania, Division of Oncology, Department of Pediatrics, Perelman School of Medicine)

  • Angela J. Waanders

    (Ann & Robert H. Lurie Children’s Hospital of Chicago
    Northwestern University Feinberg School of Medicine, Division of Hematology, Oncology, Neuro-Oncology, and Stem Cell Transplantation, Department of Pediatrics)

  • Miriam Bornhorst

    (Ann & Robert H. Lurie Children’s Hospital of Chicago
    Northwestern University Feinberg School of Medicine, Division of Hematology, Oncology, Neuro-Oncology, and Stem Cell Transplantation, Department of Pediatrics)

  • Suzanne P. MacFarland

    (Children’s Hospital of Philadelphia, Center for Childhood Cancer Research
    University of Pennsylvania, Division of Oncology, Department of Pediatrics, Perelman School of Medicine)

  • Jo Lynne Rokita

    (Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
    Children’s Hospital of Philadelphia, Division of Neurosurgery
    Children’s National Hospital, Center for Cancer and Immunology Research
    Children’s Hospital of Philadelphia, Department of Biomedical and Health Informatics)

  • Sharon J. Diskin

    (Children’s Hospital of Philadelphia, Center for Childhood Cancer Research
    Children’s Hospital of Philadelphia, Department of Biomedical and Health Informatics
    University of Pennsylvania, Abramson Family Cancer Research Institute, Perelman School of Medicine
    University of Pennsylvania, Division of Oncology, Department of Pediatrics, Perelman School of Medicine)

Abstract

The contribution of rare pathogenic/likely pathogenic (P/LP) germline variants to pediatric central nervous system (CNS) tumor development remains understudied. Here, we characterize the prevalence and biological significance of germline P/LP variants in cancer predisposition genes across 830 CNS tumor patients from the Pediatric Brain Tumor Atlas (PBTA). We identify germline P/LP variants in 23.3% (193/830) of patients and the majority (137/193) lack clinical reporting of genetic tumor syndromes. Among P/LP carriers, 34.6% have putative somatic second hits or loss of function tumor alterations. Finally, we link pathogenic germline variation with somatic events and patient survival to highlight the impact of germline variation on tumorigenesis and patient outcomes.

Suggested Citation

  • Ryan J. Corbett & Rebecca S. Kaufman & Shelly W. McQuaid & Zalman Vaksman & Saksham Phul & Miguel A. Brown & Jennifer L. Mason & Sebastian M. Waszak & Bo Zhang & Chuwei Zhong & Emily Blauel & Heena De, 2025. "Germline pathogenic variation impacts somatic alterations and patient outcomes in pediatric central nervous system tumors," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65190-4
    DOI: 10.1038/s41467-025-65190-4
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