Medulloblastoma is the most common brain tumor in children. Although the current treatments help improve the survival rates, patients will suffer severe side effects and will relapse with tumors carrying resistance mutations. This underscores the urgent need for alternative medications. Recently, we identified the GNAS gene, which produces an enzyme called Gαs, is a potent tumor suppressor gene in medulloblastoma. Medulloblastomas carrying mutations in the GNAS gene define a specific group of high-risk tumors and are resistant to therapies. The proposed study will survey the genomic landscape of the high-risk medulloblastomas to identify their genomic rearrangements or mutations that are causing drug resistance and the recurrence of medulloblastomas. Our studies will provide the genomic profile information on molecular drivers for tumor growth and progression in recurrent medulloblastomas, and will help physicians make treatment decisions with genetically matched therapeutic options.