Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition

By M. Kool, David T. W. Jones, N. Jäger, P. Northcott, Trevor J Pugh, V. Hovestadt, R. Piro, L. Esparza, S. Markant, M. Remke and 66 more. Cancer Cell, 2014

693 citations recorded by the source corpus.

Summary Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant.

View Paper: https://www.semanticscholar.org/paper/60ea96508b95e1d95e2a9029227f8227a3cfb815

Citations in the corpus

• The whole-genome landscape of medulloblastoma subtypes (2017, unknown): “Building on our previous work 6 , we reliably assigned at least one driver gene to more than 95% of patients with SHH MB, and revealed several insights that extend beyond genetic events that target the canonical SHH signalling pathway (Extended Data Fig.”