Early-life exposure to ionizing radiation is a recognized risk factor for pediatric brain tumors, including medulloblastoma (MB), but the dose-dependent mechanisms linking radiation to tumor initiation remain poorly understood. Using the Ptch1⁺/⁻ mouse model of Sonic Hedgehog (SHH)-driven MB, mice were exposed at postnatal day 2 to 0.1 or 2 Gy γ-rays and monitored longitudinally, combined with multi-omics analyses to characterize early cerebellar responses and tumor-associated transcriptional programs. Radiation increased MB incidence in a dose-dependent manner, with 2 Gy significantly increasing tumor burden and reducing latency, whereas 0.1 Gy elevated tumor risk without affecting onset. Genome-wide methylation profiling revealed progressive dose-dependent epigenetic remodeling, with broader developmental and transcriptional regulatory changes after high-dose irradiation and limited signaling-associated alterations after low-dose exposure. Proteomic analyses identified common proliferative programs together with distinct dose-specific biological contexts, with low-dose irradiation preferentially associated with regulatory, transport, and selected immune-related pathways and high-dose exposure with chromatin organization, DNA replication, nucleotide metabolism, and RNA-associated processes. Radiation-induced MBs exhibited transcriptional architectures distinct from spontaneous tumors and differed according to radiation dose. Although involving largely distinct genes and pathways, independent methylomic, proteomic, and transcriptomic analyses converged on the identification of qualitatively distinct dose-associated biological programs. Notably, cross-omics functional concordance increased with radiation dose, revealing greater integration of molecular responses following high-dose irradiation. Together, these findings define dose-specific molecular states associated with radiation-induced MB and provide a biological framework linking early cerebellar remodeling to tumor heterogeneity, with implications for pediatric radiation risk assessment and therapeutic stratification. © 2026

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