Genetic Mutations Predict SMO Inhibitor Response in SHH Medulloblastoma

Medulloblastoma can be classified into multiple subtypes that differ in cell histology, biology, and clinical phenotype. Although surgery, radiation, and chemotherapy can be curative, long-term side effects are common, necessitating the development of less toxic targeted therapies. Inhibitors of Smoothened (SMO), a regulator of the sonic hedgehog (SHH) pathway, are of particular interest given that one medulloblastoma subgroup is distinguished by SHH pathway activation. However, clinical responses to SMO inhibitors have been varied, potentially due to mutations in SHH genes that act downstream of SMO. To determine whether the genetic landscape of SHH-subgroup medulloblastoma might suggest predictors of SMO inhibitor sensitivity, Kool and colleagues performed genomic profiling of 50 adult, 33 childhood, and 50 infant SHH medulloblastomas and observed that DNA methylation and gene expression profiles and the number of somatic mutations largely clustered according to age. Surprisingly, although SHH pathway genes were mutated in 116 of 133 (87%) tumors, mutations other than PTCH1 were associated with certain age groups. SUFU mutations were almost exclusively found in infants, whereas SMO mutations were most common in adults. Children with SHH medulloblastoma rarely had SUFU or SMO mutations, but often harbored TP53 germline mutations accompanied by chromothripsis-associated GLI2 and MYCN amplification. TERT promoter mutations were also almost exclusively found in adult SHH medulloblastomas, and the PI3K–AKT–mTOR pathway was more frequently activated in adult tumors. Cells harboring mutations in PTCH1, which acts upstream of SMO, but not TP53, MYCN, or SUFU, which act downstream of SMO, were sensitive to NVP-LDE225, a SMO inhibitor currently being tested in phase III clinical trials, suggesting that some infant and childhood SHH medulloblastomas may be intrinsically resistant to SMO inhibition. The finding that SHH medulloblastoma is genomically distinct in different age groups emphasizes the importance of using underlying SHH mutations to stratify patients for therapy.

Kool M, Jones DT, Jäger N, Northcott PA, Pugh TJ, Hovestadt V, et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to Smoothened inhibition. Cancer Cell 2014;25:393–405.

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