%0 Journal Article %1 Kool2014 %A Kool, Marcel %A Jones, David T W. %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 D. %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, Chris %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 M. %A ICGC PedBrain Tumor Project, %D 2014 %J Cancer Cell %K /&/ 3-Kinases, Adolescent; Adult Adult; Animals; Base Biphenyl Cell Cerebellar Child, Child; Compounds, Copy DEAD-box DNA Data; Drug Expression Factors, Female; G-Protein-Coupled, Gene Genetic, Hedgehog Helicases, High-Throughput Humans; Inbred Infant; Kruppel-Like Male; Medulloblastoma, Mice, Mice; Molecular NOD; Neoplasm Neoplasm, Neoplasms, Nuclear Nucleotide Number Oncogene Phosphatidylinositol Preschool; Profiling; Promoter Protein Proteins Proteins, Proto-Oncogene Pyridines, RNA Receptors, Regions, Repressor Resistance, SCID; Sequence Sequence; Sequencing; Signal Suppressor Surface, Telomerase, Transcription Transduction, Transplantation; Tumor Variations, Young antagonists c-akt, drug genetics/metabolism; genetics; inhibitors/genetics; p53, therapeutic therapy/genetics; use; %N 3 %P 393--405 %T Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. %V 25 %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.

@article{Kool2014, __markedentry = {[bbrors:6]}, 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.}, added-at = {2015-04-09T12:36:21.000+0200}, author = {Kool, Marcel and Jones, David T W. and J{\"{a}}ger, Natalie and Northcott, Paul A. and Pugh, Trevor J. and Hovestadt, Volker and Piro, Rosario M. and Esparza, L Adriana and Markant, Shirley L. and Remke, Marc and Milde, Till and Bourdeaut, Franck and Ryzhova, Marina and Sturm, Dominik and Pfaff, Elke and Stark, Sebastian and Hutter, Sonja and Seker-Cin, Huriye and Johann, Pascal and Bender, Sebastian and Schmidt, Christin and Rausch, Tobias and Shih, David and Reimand, J{\"{u}}ri and Sieber, Laura and Wittmann, Andrea and Linke, Linda and Witt, Hendrik and Weber, Ursula D. and Zapatka, Marc and K{\"{o}}nig, Rainer and Beroukhim, Rameen and Bergthold, Guillaume and {van Sluis}, Peter and Volckmann, Richard and Koster, Jan and Versteeg, Rogier and Schmidt, Sabine and Wolf, Stephan and Lawerenz, Chris and Bartholomae, Cynthia C. and {von Kalle}, Christof and Unterberg, Andreas and Herold-Mende, Christel and Hofer, Silvia and Kulozik, Andreas E. and {von Deimling}, Andreas and Scheurlen, Wolfram and Felsberg, J{\"{o}}rg and Reifenberger, Guido and Hasselblatt, Martin and Crawford, John R. and Grant, Gerald A. and Jabado, Nada and Perry, Arie and Cowdrey, Cynthia and Croul, Sydney and Zadeh, Gelareh and Korbel, Jan O. and Doz, Francois and Delattre, Olivier and Bader, Gary D. and McCabe, Martin G. and Collins, V Peter and Kieran, Mark W. and Cho, Yoon-Jae and Pomeroy, Scott L. and Witt, Olaf and Brors, Benedikt and Taylor, Michael D. and Sch{\"{u}}ller, Ulrich and Korshunov, Andrey and Eils, Roland and Wechsler-Reya, Robert J. and Lichter, Peter and Pfister, Stefan M. and {ICGC PedBrain Tumor Project}}, biburl = {https://www.bibsonomy.org/bibtex/2a8997229c4202af3b89e3aeaa2872137/bbrors}, institution = {Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany; Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, 69120 Heidelberg, Germany.}, interhash = {9d916a0ccff876ddab746c5cce8fc480}, intrahash = {a8997229c4202af3b89e3aeaa2872137}, journal = {Cancer Cell}, keywords = {/&/ 3-Kinases, Adolescent; Adult Adult; Animals; Base Biphenyl Cell Cerebellar Child, Child; Compounds, Copy DEAD-box DNA Data; Drug Expression Factors, Female; G-Protein-Coupled, Gene Genetic, Hedgehog Helicases, High-Throughput Humans; Inbred Infant; Kruppel-Like Male; Medulloblastoma, Mice, Mice; Molecular NOD; Neoplasm Neoplasm, Neoplasms, Nuclear Nucleotide Number Oncogene Phosphatidylinositol Preschool; Profiling; Promoter Protein Proteins Proteins, Proto-Oncogene Pyridines, RNA Receptors, Regions, Repressor Resistance, SCID; Sequence Sequence; Sequencing; Signal Suppressor Surface, Telomerase, Transcription Transduction, Transplantation; Tumor Variations, Young antagonists c-akt, drug genetics/metabolism; genetics; inhibitors/genetics; p53, therapeutic therapy/genetics; use;}, language = {eng}, medline-pst = {ppublish}, month = Mar, number = 3, owner = {bbrors}, pages = {393--405}, pmid = {24651015}, timestamp = {2015-04-09T12:36:21.000+0200}, title = {Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition.}, volume = 25, year = 2014 }