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Cell Press, Cancer Cell, 3(25), p. 393-405, 2014

DOI: 10.1016/j.ccr.2014.02.004

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

Journal article published in 2014 by Marcel Kool, David T. W. Jones, Natalie Jäger, Paul A. Northcott ORCID, Trevor J. Pugh, Volker Hovestadt ORCID, Rosario M. Piro, L. Adriana Esparza, L. Adriana Esparza, Shirley L. Markant, Marc Remke, Till Milde, Franck Bourdeaut, Marina Ryzhova, Dominik Sturm ORCID and other authors.
This paper is available in a repository.
This paper is available in a repository.

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Abstract

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.