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

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 Desai, Ryan Hausler, Ammar S. Naqvi, Jessica M. Daggett, Alex Sickler, Evan C. Cresswell-Clay, Patricia J. Sullivan, Antonia Chroni, Zhuangzhuang Geng, Elizabeth M. Gonzalez, Yuankun Zhu, Allison P. Heath, Marilyn Li, Phillip B. Storm, Adam C. Resnick, Kara N. Maxwell, Kristina A. Cole, Angela J. Waanders, Miriam Bornhorst, Suzanne P. MacFarland, Jo Lynne Rokita () and Sharon J. Diskin ()
Additional contact information
Ryan J. Corbett: Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
Rebecca S. Kaufman: Children’s Hospital of Philadelphia, Center for Childhood Cancer Research
Shelly W. McQuaid: Ann & Robert H. Lurie Children’s Hospital of Chicago
Zalman Vaksman: Children’s Hospital of Philadelphia, Center for Childhood Cancer Research
Saksham Phul: Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
Miguel A. Brown: Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
Jennifer L. Mason: Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
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
Chuwei Zhong: Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
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
Ryan Hausler: University of Pennsylvania, Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine
Ammar S. Naqvi: Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
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
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
Zhuangzhuang Geng: Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
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
Allison P. Heath: Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
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
Adam C. Resnick: Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
Kara N. Maxwell: University of Pennsylvania, Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine
Kristina A. Cole: Children’s Hospital of Philadelphia, Center for Childhood Cancer Research
Angela J. Waanders: Ann & Robert H. Lurie Children’s Hospital of Chicago
Miriam Bornhorst: Ann & Robert H. Lurie Children’s Hospital of Chicago
Suzanne P. MacFarland: Children’s Hospital of Philadelphia, Center for Childhood Cancer Research
Jo Lynne Rokita: Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine
Sharon J. Diskin: Children’s Hospital of Philadelphia, Center for Childhood Cancer Research

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65190-4

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