Germline pathogenic variation impacts somatic alterations and patient outcomes in pediatric CNS 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; Heena Desai; Ryan Hausler; Ammar S Naqvi; Antonia Chroni; Zhuangzhuang Geng; Elizabeth M Gonzalez; Yuankun Zhu; Allison P Heath; Marilyn Li; Penn Medicine BioBank; Regeneron Genetics Center; Phillip B Storm; Adam C Resnick; Kara N Maxwell; Kristina A Cole; Angela J Waanders; Miriam Bornhorst; Suzanne P MacFarland; Jo Lynne Rokita; Sharon J Diskin

doi:10.1101/2025.02.04.25321499

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

medRxiv [Preprint]. 2025 Feb 6:2025.02.04.25321499. doi: 10.1101/2025.02.04.25321499.

Authors

Ryan J Corbett^{1

2

3}, Rebecca S Kaufman^{3

4}, Shelly W McQuaid^{5

6}, Zalman Vaksman^{3

4}, Saksham Phul^{1

2}, Miguel A Brown^{1

2}, Jennifer L Mason^{1

2}, Sebastian M Waszak⁷, Bo Zhang^{1

2}, Chuwei Zhong^{1

2}, Heena Desai^{8

9}, Ryan Hausler^{8

9}, Ammar S Naqvi^{1

2}, Antonia Chroni^{1

2}, Zhuangzhuang Geng^{1

2}, Elizabeth M Gonzalez³, Yuankun Zhu^{1

2}, Allison P Heath^{1

2}, Marilyn Li¹⁰; Penn Medicine BioBank; Regeneron Genetics Center; Phillip B Storm^{1

2}, Adam C Resnick^{1

2}, Kara N Maxwell^{8

9}, Kristina A Cole^{3

11}, Angela J Waanders^{5

6}, Miriam Bornhorst^{5

6}, Suzanne P MacFarland^{3

11}, Jo Lynne Rokita^{1

2

4

12

13}, Sharon J Diskin^{3

4

9

11}

Affiliations

¹ Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
² Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
³ Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁴ Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁵ Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
⁶ Division of Hematology, Oncology, Neuro-Oncology, and Stem Cell Transplantation, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
⁷ Laboratory of Computational Neuro-Oncology, Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
⁸ Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹¹ Division of Oncology, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹² Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
¹³ Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.

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.

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

Publication types

Preprint

Abstract

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