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

• DOI: 10.1016/j.ccr.2014.02.004
• Publication Date: 2014-03-20T21:17:05Z
• Authors: Marcel Kool; David T.W. Jones; Natalie Jäger; Paul A. Northcott; Trevor J. Pugh; Volker Hovestadt; Rosario M. Piro; L. Adriana Esparza; Shirley L. Markant; Marc Remke; Till Milde; Franck Bourdeaut; Marina Ryzhova; Dominik Sturm; Elke Pfaff; Sebastian Stark; Sonja Hutter; Huriye Şeker-Cin; Pascal Johann; Sebastian Bender; Christin Schmidt; Tobias Rausch; David Shih; Jüri Reimand; Laura Sieber; Andrea Wittmann; Linda Linke; Hendrik Witt; Ursula D. Weber; Marc Zapatka; Rainer König; Rameen Beroukhim; Guillaume Bergthold; Peter van Sluis; Richard Volckmann; Jan Koster; Rogier Versteeg; Sabine Schmidt; Stephan Wolf; Chris Lawerenz; Cynthia C. Bartho...; Christof von Kalle; Andreas Unterberg; Christel Herold-M...; Silvia Hofer; Andreas E. Kulozik; Andreas von Deimling; Wolfram Scheurlen; Jörg Felsberg; Guido Reifenberger; Martin Hasselblatt; John R. Crawford; Gerald A. Grant; Nada Jabado; Arie Perry; Cynthia Cowdrey; Sydney Croul; Gelareh Zadeh; Jan O. Korbel; Francois Doz; Olivier Delattre; Gary D. Bader; Martin G. McCabe; V. Peter Collins; Mark W. Kieran; Yoon-Jae Cho; Scott L. Pomeroy; Olaf Witt; Benedikt Brors; Michael D. Taylor; Ulrich Schüller; Andrey Korshunov; Roland Eils; Robert J. Wechsle...; Peter Lichter; Stefan M. Pfister
• Keywords: Male; Cancer Research; Pyridines; Drug Resistance; DEAD-box RNA Helicases; Mice; Phosphatidylinositol 3-Kinases; Receptors; Child; Telomerase; Cancer; Pediatric; Oncogene Proteins; N-Myc Proto-Oncogene Protein; Nuclear Proteins; High-Throughput Nucleotide Sequencing; Biological Sciences; Smoothened Receptor; Patched-1 Receptor; Oncology; Child, Preschool; Cell Surface; Female; Signal Transduction; Patched Receptors; Adult; Pediatric Research Initiative; Adolescent; DNA Copy Number Variations; Pediatric Cancer; Clinical Sciences; Molecular Sequence Data; Oncology and Carcinogenesis; Kruppel-Like Transcription Factors; Zinc Finger Protein Gli2; SCID; ICGC PedBrain Tumor Project; Promoter Regions; G-Protein-Coupled; Young Adult; Rare Diseases; Genetic; Genetics; Animals; Humans; Hedgehog Proteins; Oncology & Carcinogenesis; Preschool; Cerebellar Neoplasms; Biomedical and Clinical Sciences; Base Sequence; Gene Expression Profiling; Biphenyl Compounds; Neurosciences; Infant; Oncology and carcinogenesis; Cell Biology; Brain Disorders; Brain Cancer; Repressor Proteins; Drug Resistance, Neoplasm; Biochemistry and cell biology; Neoplasm; Inbred NOD; Tumor Suppressor Protein p53; Proto-Oncogene Proteins c-akt; Neoplasm Transplantation; Medulloblastoma

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.