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Cancer Cell DOI:10.1016/j.ccr.2014.02.004

Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition.

Publication TypeJournal Article
Year of Publication2014
AuthorsKool, M, Jones, DTW, Jäger, N, Northcott, PA, Pugh, TJ, Hovestadt, V, Piro, RM, L Esparza, A, Markant, SL, Remke, M, Milde, T, Bourdeaut, F, Ryzhova, M, Sturm, D, Pfaff, E, Stark, S, Hutter, S, Seker-Cin, H, Johann, P, Bender, S, Schmidt, C, Rausch, T, Shih, D, Reimand, J, Sieber, L, Wittmann, A, Linke, L, Witt, H, Weber, UD, Zapatka, M, König, R, Beroukhim, R, Bergthold, G, van Sluis, P, Volckmann, R, Koster, J, Versteeg, R, Schmidt, S, Wolf, S, Lawerenz, C, Bartholomae, CC, von Kalle, C, Unterberg, A, Herold-Mende, C, Hofer, S, Kulozik, AE, von Deimling, A, Scheurlen, W, Felsberg, J, Reifenberger, G, Hasselblatt, M, Crawford, JR, Grant, GA, Jabado, N, Perry, A, Cowdrey, C, Croul, S, Zadeh, G, Korbel, JO, Doz, F, Delattre, O, Bader, GD, McCabe, MG, V Collins, P, Kieran, MW, Cho, Y-J, Pomeroy, SL, Witt, O, Brors, B, Taylor, MD, Schüller, U, Korshunov, A, Eils, R, Wechsler-Reya, RJ, Lichter, P, Pfister, SM
Corporate AuthorsICGC PedBrain Tumor Project
JournalCancer Cell
Volume25
Issue3
Pages393-405
Date Published2014 Mar 17
ISSN1878-3686
KeywordsAdolescent, Adult, Animals, Base Sequence, Biphenyl Compounds, Cerebellar Neoplasms, Child, Child, Preschool, DEAD-box RNA Helicases, DNA Copy Number Variations, Drug Resistance, Neoplasm, Female, Gene Expression Profiling, Hedgehog Proteins, High-Throughput Nucleotide Sequencing, Humans, Infant, Kruppel-Like Transcription Factors, Male, Medulloblastoma, Mice, Mice, Inbred NOD, Mice, SCID, Molecular Sequence Data, N-Myc Proto-Oncogene Protein, Neoplasm Transplantation, Nuclear Proteins, Oncogene Proteins, Patched Receptors, Patched-1 Receptor, Phosphatidylinositol 3-Kinases, Promoter Regions, Genetic, Proto-Oncogene Proteins c-akt, Pyridines, Receptors, Cell Surface, Receptors, G-Protein-Coupled, Repressor Proteins, Signal Transduction, Smoothened Receptor, Telomerase, Tumor Suppressor Protein p53, Young Adult
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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S1535-6108(14)00073-7
DOI10.1016/j.ccr.2014.02.004
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24651015?dopt=Abstract

Alternate JournalCancer Cell
PubMed ID24651015
PubMed Central IDPMC4493053
Grant ListK08 NS075144 / NS / NINDS NIH HHS / United States