Abstract
BACKGROUND: Medulloblastoma (MB) is a heterogeneous pediatric brain tumor characterized by distinct molecular subtypes. Although genomics and transcriptomics have improved subtype classification and informed targeted therapies, the clinical utility of integrated molecular profiling in real-world settings remains incompletely defined. METHODS: We conducted a retrospective analysis of 131 patients with MB from a Chinese cohort. All cases underwent both targeted genomic sequencing and NanoString-based transcriptomic profiling. We evaluated the impact of integrated molecular profiling on diagnostic refinement, identification of germline predisposition, and detection of actionable alterations. RESULTS: Incorporation of genomic data led to optimized or revised molecular classification in 67.2% of patients. Germline variants in Fanconi anemia pathway genes (FANCL, FANCC, NBN) were significantly enriched among patients with Group 3 and Group 4 MB, suggesting a potentially inherited susceptibility component. Furthermore, 52.7% of patients harbored potentially actionable somatic mutations, supporting the feasibility of precision-targeted therapeutic approaches. Notably, we identified one case of WNT-subtype MB harboring a homozygous deletion of CDKN2A, which was associated with unusually poor clinical outcome. CONCLUSIONS: Integrated genomic and transcriptomic profiling substantially improves molecular subtyping of MB and reveals inherited risk factors relevant to specific subgroups. Our findings support the implementation of combined molecular diagnostics in routine clinical management of MB and underscore their potential in guiding individualized treatment strategies.