Germline pathogenic variation impacts somatic alterations and patient outcomes in pediatric central nervous system tumors
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.
Authors
- Jo Lynne Rokita (ORCID: https://orcid.org/0000-0003-2171-3627)
- Kristina A. Cole (ORCID: https://orcid.org/0000-0003-0064-2882)
- Miriam Bornhorst (ORCID: https://orcid.org/0000-0002-7595-7726)
- Angela J. Waanders (ORCID: https://orcid.org/0000-0002-0571-2889)
- Patricia A. Sullivan (ORCID: https://orcid.org/0000-0002-4886-8883)
- Rebecca Kaufman (ORCID: https://orcid.org/0000-0001-8535-9730)
- Zhuangzhuang Geng (ORCID: https://orcid.org/0009-0007-6883-0691)
- Ryan J. Corbett (ORCID: https://orcid.org/0000-0002-3478-0784)
- Evan Cresswell-Clay (ORCID: https://orcid.org/0000-0003-0015-1901)
- Yuankun Zhu (ORCID: https://orcid.org/0000-0002-2455-9525)
- Elizabeth M. Gonzalez (ORCID: https://orcid.org/0000-0001-6424-1522)
- Saksham Phul (ORCID: https://orcid.org/0000-0002-2771-2572)
- Zalman Vaksman (ORCID: https://orcid.org/0000-0001-5121-8657)
- Ammar S. Naqvi (ORCID: https://orcid.org/0000-0002-0625-666X)
- Emily Blauel
- Sebastian M. Waszak (ORCID: https://orcid.org/0000-0003-3042-9521)
- Jennifer L. Mason
- Phillip B. Storm (ORCID: https://orcid.org/0000-0002-7964-2449)
- Allison P. Heath (ORCID: https://orcid.org/0000-0002-2583-9668)
- Shelly W. McQuaid
- Kara N. Maxwell (ORCID: https://orcid.org/0000-0001-8192-4202)
- Sharon J. Diskin (ORCID: https://orcid.org/0000-0002-7200-8939)
- Chuwei Zhong (ORCID: https://orcid.org/0000-0003-2406-2735)
- Ryan Hausler
- Miguel Brown (ORCID: https://orcid.org/0000-0001-6782-1442)
- Marilyn M. Li (ORCID: https://orcid.org/0000-0002-4253-2369)
- Suzanne P. MacFarland (ORCID: https://orcid.org/0000-0001-5894-6403)
- Alex Sickler (ORCID: https://orcid.org/0000-0001-7830-7537)
- Antonia Chroni (ORCID: https://orcid.org/0000-0003-3655-8252)
- Adam Resnick (ORCID: https://orcid.org/0000-0003-0436-4189)
- Bo Zhang (ORCID: https://orcid.org/0000-0003-2962-5314)
- Heena Desai (ORCID: https://orcid.org/0000-0002-9710-4468)
- Jessica M. Daggett (ORCID: https://orcid.org/0000-0002-9404-7939)
Institutions
- Northwestern University (US)
- Lurie Children's Hospital (US)
- Children's Hospital of Philadelphia (US)
- Children's National (US)
- Cancer Research Institute (US)
- George Washington University (US)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-21
- DOI
- https://doi.org/10.1038/s41467-025-65190-4
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00