The role of Hedgehog signaling in medulloblastoma

Medulloblastoma, a tumor of the cerebellar granule neuron progenitor cells, is the most common malignant brain tumor in children.^21,22 Current treatment options include surgery, craniospinal irradiation, and chemotherapy, which report 5-year survival rates of approximately 60%.^21,22 Infrequently, current treatment regimens have been associated with permanent side effects, such as cognitive and endocrine deficiencies, as well as psychiatric disorders.²¹

Mutations in the Hedgehog pathway have been linked to medulloblastoma. PTCH loss-of-function mutations are found in 10% to 20% of sporadic medulloblastomas. Mutations in SMO or in the downstream tumor suppressor gene SUFU also occur, albeit much less frequently.^{11-13,17,23-26} Analysis of the expression of Hedgehog target genes in medulloblastomas has demonstrated that more medulloblastomas display active Hedgehog signaling than medulloblastomas with detectable mutations in key Hedgehog pathway components, suggesting that there are additional ways of activating the Hedgehog pathway.²⁶ In summary, after BCC, medulloblastoma is the tumor type that demonstrates the highest frequency of dysregulated Hedgehog signaling, mostly driven by mutations.