%0 Journal Article
%A Kool, Marcel
%A Jones, David
%A Jäger, Natalie
%A Northcott, Paul A
%A Pugh, Trevor J
%A Hovestadt, Volker
%A Piro, Rosario M
%A Esparza, L Adriana
%A Markant, Shirley L
%A Remke, Marc
%A Milde, Till
%A Bourdeaut, Franck
%A Ryzhova, Marina
%A Sturm, Dominik
%A Pfaff, Elke
%A Stark, Sebastian
%A Hutter, Sonja
%A Seker-Cin, Huriye
%A Johann, Pascal
%A Bender, Sebastian
%A Schmidt, Christin
%A Rausch, Tobias
%A Shih, David
%A Reimand, Jüri
%A Sieber, Laura
%A Wittmann, Andrea
%A Linke, Linda
%A Witt, Hendrik
%A Weber, Ursula
%A Zapatka, Marc
%A König, Rainer
%A Beroukhim, Rameen
%A Bergthold, Guillaume
%A van Sluis, Peter
%A Volckmann, Richard
%A Koster, Jan
%A Versteeg, Rogier
%A Schmidt, Sabine
%A Wolf, Stephan
%A Lawerenz, Christian
%A Bartholomae, Cynthia C
%A von Kalle, Christof
%A Unterberg, Andreas
%A Herold-Mende, Christel
%A Hofer, Silvia
%A Kulozik, Andreas E
%A von Deimling, Andreas
%A Scheurlen, Wolfram
%A Felsberg, Jörg
%A Reifenberger, Guido
%A Hasselblatt, Martin
%A Crawford, John R
%A Grant, Gerald A
%A Jabado, Nada
%A Perry, Arie
%A Cowdrey, Cynthia
%A Croul, Sydney
%A Zadeh, Gelareh
%A Korbel, Jan O
%A Doz, Francois
%A Delattre, Olivier
%A Bader, Gary D
%A McCabe, Martin G
%A Collins, V Peter
%A Kieran, Mark W
%A Cho, Yoon-Jae
%A Pomeroy, Scott L
%A Witt, Olaf
%A Brors, Benedikt
%A Taylor, Michael D
%A Schüller, Ulrich
%A Korshunov, Andrey
%A Eils, Roland
%A Wechsler-Reya, Robert J
%A Lichter, Peter
%A Pfister, Stefan
%T Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition.
%J Cancer cell
%V 25
%N 3
%@ 1535-6108
%C Cambridge, Mass.
%I Cell Press
%M DKFZ-2017-03664
%P 393 - 405
%D 2014
%X 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.
%K Biphenyl Compounds (NLM Chemicals)
%K GLI2 protein, human (NLM Chemicals)
%K Hedgehog Proteins (NLM Chemicals)
%K Kruppel-Like Transcription Factors (NLM Chemicals)
%K LDE225 (NLM Chemicals)
%K MYCN protein, human (NLM Chemicals)
%K N-Myc Proto-Oncogene Protein (NLM Chemicals)
%K Nuclear Proteins (NLM Chemicals)
%K Oncogene Proteins (NLM Chemicals)
%K PTCH protein, human (NLM Chemicals)
%K Patched Receptors (NLM Chemicals)
%K Patched-1 Receptor (NLM Chemicals)
%K Ptch1 protein, mouse (NLM Chemicals)
%K Pyridines (NLM Chemicals)
%K Receptors, Cell Surface (NLM Chemicals)
%K Receptors, G-Protein-Coupled (NLM Chemicals)
%K Repressor Proteins (NLM Chemicals)
%K SHH protein, human (NLM Chemicals)
%K SMO protein, human (NLM Chemicals)
%K SUFU protein, human (NLM Chemicals)
%K Smoothened Receptor (NLM Chemicals)
%K TP53 protein, human (NLM Chemicals)
%K Tumor Suppressor Protein p53 (NLM Chemicals)
%K Phosphatidylinositol 3-Kinases (NLM Chemicals)
%K Proto-Oncogene Proteins c-akt (NLM Chemicals)
%K TERT protein, human (NLM Chemicals)
%K Telomerase (NLM Chemicals)
%K DDX3X protein, human (NLM Chemicals)
%K DEAD-box RNA Helicases (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:24651015
%2 pmc:PMC4493053
%R 10.1016/j.ccr.2014.02.004
%U https://inrepo02.dkfz.de/record/127641