title: Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition.
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.
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany. Electronic address: m.kool@dkfz.de.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Jäger
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Pugh
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Hovestadt
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Rosario M
authors.initials: RM
authors.lastname: Piro
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: L Adriana
authors.initials: LA
authors.lastname: Esparza
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Shirley L
authors.initials: SL
authors.lastname: Markant
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Milde
authors.affiliation: Institut Curie, 75005 Paris, France; Institut Curie/INSERM U830, 75248 Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Bourdeaut
authors.affiliation: Department of Neuropathology, NN Burdenko Neurosurgical Institute, Moscow 125047, Russia.
authors.forename: Marina
authors.initials: M
authors.lastname: Ryzhova
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Sturm
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Pfaff
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stark
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hutter
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Huriye
authors.initials: H
authors.lastname: Seker-Cin
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Pascal
authors.initials: P
authors.lastname: Johann
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bender
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Schmidt
authors.affiliation: European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Rausch
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Shih
authors.affiliation: The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Jüri
authors.initials: J
authors.lastname: Reimand
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Sieber
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wittmann
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Linke
authors.affiliation: 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.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Witt
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Ursula D
authors.initials: UD
authors.lastname: Weber
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Zapatka
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany; Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany; Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute (HKI), 07745 Jena, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: König
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA; UMR 8203, CNRS Vectorology and Anticancer Therapeutics, Gustave Roussy Cancer Institute, University Paris XI, 94805 Villejuif Cedex, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bergthold
authors.affiliation: Department of Oncogenomics, Academic Medical Center, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: van Sluis
authors.affiliation: Department of Oncogenomics, Academic Medical Center, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Richard
authors.initials: R
authors.lastname: Volckmann
authors.affiliation: Department of Oncogenomics, Academic Medical Center, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.affiliation: Department of Oncogenomics, Academic Medical Center, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wolf
authors.affiliation: Data Management Facility, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Lawerenz
authors.affiliation: Division of Translational Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69121 Heidelberg, Germany.
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Bartholomae
authors.affiliation: Division of Translational Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69121 Heidelberg, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.affiliation: Division of Translational Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69121 Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Unterberg
authors.affiliation: Division of Translational Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69121 Heidelberg, Germany.
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.affiliation: Department of Oncology, University Hospital Zürich, 8006 Zürich, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Hofer
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
authors.affiliation: Department of Neuropathology, University of Heidelberg, 69120 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: Cnopf'sche Kinderklinik, Nürnberg Children's Hospital, 90419 Nürnberg, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Scheurlen
authors.affiliation: Department of Neuropathology, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Felsberg
authors.affiliation: Department of Neuropathology, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.affiliation: Institute for Neuropathology, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hasselblatt
authors.affiliation: Departments of Pediatrics and Neurosciences, University of California San Diego, La Jolla, CA 92093; Rady Children's Hospital, San Diego, CA 92123, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Crawford
authors.affiliation: Division of Pediatric Hematology/Oncology, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA; Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Grant
authors.affiliation: Departments of Pediatrics and Human Genetics, McGill University Health Centre Research Institute, Montreal, QC H3H 1P3, Canada.
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.affiliation: Departments of Pathology and Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Arie
authors.initials: A
authors.lastname: Perry
authors.affiliation: Departments of Pathology and Neurological Surgery, Brain Tumor Research Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Cowdrey
authors.affiliation: Department of Neuropathology, The Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, ON M5G 1L7, Canada.
authors.forename: Sydney
authors.initials: S
authors.lastname: Croul
authors.affiliation: Department of Neuropathology, The Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, ON M5G 1L7, Canada.
authors.forename: Gelareh
authors.initials: G
authors.lastname: Zadeh
authors.affiliation: European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.
authors.forename: Jan O
authors.initials: JO
authors.lastname: Korbel
authors.affiliation: Institut Curie, 75005 Paris, France; Université Paris Descartes, 75006 Paris, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Doz
authors.affiliation: Institut Curie, 75005 Paris, France; Institut Curie/INSERM U830, 75248 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.affiliation: The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.affiliation: Manchester Academic Health Science Centre, Manchester M13 9NT, UK.
authors.forename: Martin G
authors.initials: MG
authors.lastname: McCabe
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: V Peter
authors.initials: VP
authors.lastname: Collins
authors.affiliation: Pediatric Medical Neuro-Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02215, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
authors.affiliation: Department of Neurology and Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Pomeroy
authors.affiliation: CCU Pediatric Oncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität, 81377 München, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schüller
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany; Department of Neuropathology, University of Heidelberg, 69120 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wechsler-Reya
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.affiliation: 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.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001483:Base Sequence; D001713:Biphenyl Compounds / Q000627:therapeutic use; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D053487:DEAD-box RNA Helicases / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008969:Molecular Sequence Data; D000071447:N-Myc Proto-Oncogene Protein; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use; D011956:Receptors, Cell Surface / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D000072086:Smoothened Receptor; D019098:Telomerase / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D055815:Young Adult; D000075746:Zinc Finger Protein Gli2
chemical_list: D001713:Biphenyl Compounds; D053487:DEAD-box RNA Helicases; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012097:Repressor Proteins; D000072086:Smoothened Receptor; D019098:Telomerase; D016159:Tumor Suppressor Protein p53; D000075746:Zinc Finger Protein Gli2; C082593:GLI2 protein, human; C459801:MYCN protein, human; C000606236:PTCH1 protein, human; C000606240:Ptch1 protein, mouse; C509239:SHH protein, human; C491023:SMO protein, human; C490764:SUFU protein, human; C495901:TP53 protein, human; C561435:sonidegib; C509186:TERT protein, human; C119332:DDX3X protein, human