Germline pathogenic variation impacts somatic alterations and patient outcomes in pediatric CNS tumors

Ryan J. Corbett, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Rebecca S. Kaufman, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Shelly W. McQuaid, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
Zalman Vaksman, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Saksham Phul, 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.
Jennifer L. Mason, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Sebastian M. Waszak, Laboratory of Computational Neuro-Oncology, Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
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.
Heena Desai, Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Ryan Hausler, Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Ammar S. Naqvi, 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.
Zhuangzhuang Geng, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Elizabeth M. Gonzalez, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Yuankun Zhu, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Allison P. Heath, Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Marilyn Li, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Document Type

Journal Article

Publication Date

2-6-2025

Journal

medRxiv : the preprint server for health sciences

DOI

10.1101/2025.02.04.25321499

Keywords

Pediatric brain tumors; aberrant splicing; loss of heterozygosity; pathogenic germline variants

Abstract

The contribution of rare pathogenic/likely pathogenic (P/LP) germline variants to pediatric central nervous system (CNS) tumor development remains understudied. Here, we characterized the prevalence and clinical significance of germline P/LP variants in cancer predisposition genes across 830 CNS tumor patients from the Pediatric Brain Tumor Atlas (PBTA). We identified germline P/LP variants in 24.2% (201/830) of patients and the majority (154/201) lacked clinical reporting of genetic tumor syndromes. Among P/LP carriers, 30.7% had putative somatic second hits or loss of function tumor alterations. Finally, we linked pathogenic germline variation with novel somatic events and patient survival to highlight the impact of germline variation on tumorigenesis and patient outcomes.

Department

Pediatrics

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