Summary
A study of 830 children with pediatric central nervous system tumors found that 23.3% carried germline pathogenic variants in cancer predisposition genes, impacting tumor development and outcomes. These findings support routine germline testing and highlight the importance of integrating inherited and somatic genomic data in pediatric neuro-oncology. Another study identified pathogenic variants in 13.2% of infertile women experiencing IVF/ICSI failures, with TUBB8 being the most frequently mutated gene.
Editors: Donna E. Hansel, MD, PhD, division head of pathology and laboratory medicine, MD Anderson Cancer Center, Houston; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, Oregon Health and Science University, Portland; Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh; Alicia Dillard, MD, molecular pathologist, Sonic Healthcare USA, Rye Brook, NY; and Richard Wong, MD, PhD, assistant professor of pathology, University of California San Diego.
How inherited gene changes shape childhood brain tumors and their outcomes
February 2026—Pediatric central nervous system tumors are a biologically diverse group of malignancies, and the role of inherited cancer susceptibility in their development is not fully characterized. The authors conducted a study to provide a comprehensive evaluation of germline pathogenic and likely pathogenic (P/LP) variants in cancer predisposition genes (CPGs) among 830 children enrolled in the Pediatric Brain Tumor Atlas (PBTA). Using whole genome or whole exome sequencing of paired tumor–normal samples, integrated with RNA sequencing, proteomics, DNA methylation profiling, and detailed clinical annotation, the authors systematically assessed the prevalence, functional impact, and clinical significance of germline P/LP variants across major pediatric central nervous system (CNS) tumor types. Germline P/LP variants were identified in 23.3 percent of patients, which is a higher rate than previously seen in other pediatric oncology cohorts. Strikingly, more than two-thirds of affected children did not have a clinically recognized tumor-predisposition syndrome, showing that a substantial inherited risk had not been previously recognized. Variants spanned 71 CPGs, including such established drivers as NF1, TP53, TSC1/2, mismatch repair (MMR) genes, and PTCH1, as well as genes not classically associated with CNS tumors, such as ATM alterations in pineoblastoma. Comparisons with two cancer-free populations confirmed significant enrichment of CPG P/LP variants within the PBTA cohort. Tumor-integrated analyses showed that 34.6 percent of germline P/LP variants underwent functional somatic second-hit events, including loss of heterozygosity, inactivating mutations, or epigenetic silencing. Transcriptomic and proteomic profiling demonstrated concordant decreases in gene expression consistent with biallelic inactivation, while methylation analyses revealed promoter hypermethylation as another mechanism of pathogenic gene loss. Splicing assessments further demonstrated that both splice-site and non–splice-site germline variants triggered aberrant alternative splicing events that disrupted conserved protein domains, reinforcing their functional relevance in tumorigenesis. In high-grade gliomas, germline defects in DNA repair genes, particularly the MMR pathway, were associated with hypermutation, characteristic COSMIC (Catalogue of Somatic Mutations in Cancer) mutational signatures, and profound global hypomethylation. Germline status also influenced clinical outcomes in a subtype-specific manner: Children with KIAA1549::BRAF fusion-positive low-grade gliomas harboring P/LP variants experienced poorer event-free survival, whereas P/LP carriers with medulloblastoma demonstrated significantly improved outcomes, including lower metastasis rates and reduced tumor mutational burden. Further molecular stratification revealed enrichment of P/LP variants in favorable medulloblastoma subgroups, including infant-type SHH tumors and group four subgroups seven and eight, whereas noncarriers were more frequently represented in higher-risk subgroups. The authors showed that germline pathogenic variation is common and biologically impactful in pediatric CNS tumors. These findings strongly support routine germline testing at diagnosis and highlight the importance of integrating inherited and somatic genomic data to refine risk stratification and therapeutic strategies in pediatric neuro-oncology.
Corbett RJ, Kaufman RS, McQuaid SW, et al. Germline pathogenic variation impacts somatic alterations and patient outcomes in pediatric central nervous system tumors. Nat Commun. 2025. doi.org/10.1038/s41467-025-65190-4
Correspondence: Dr. Jo Lynne Rokita at jrokita@childrensnational.org or Dr. Sharon J. Diskin at diskin@chop.edu