Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition
Standard
Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. / Kool, Marcel; Jones, David T W; Jäger, Natalie; Northcott, Paul A; Pugh, Trevor J; Hovestadt, Volker; Piro, Rosario M; Esparza, Lourdes Adriana; Markant, Shirley L; Remke, Marc; Milde, Till; Bourdeaut, Franck; Ryzhova, Marina; Sturm, Dominik; Pfaff, Elke; Stark, Sebastian; Hutter, Sonja; Seker-Cin, Huriye; Johann, Pascal-David; Bender, Sebastian; Schmidt, Christin; Rausch, Tobias; Shih, David; Reimand, Jüri; Sieber, Laura; Wittmann, Andrea; Linke, Linda; Witt, Hendrik; Weber, Ursula D; Zapatka, Marc; König, Rainer; Beroukhim, Rameen; Bergthold, Guillaume; van Sluis, Peter; Volckmann, Richard; Koster, Jan; Versteeg, Rogier; Schmidt, Sabine; Wolf, Stephan; Lawerenz, Chris; Bartholomae, Cynthia C; von Kalle, Christof; Unterberg, Andreas; Herold-Mende, Christel; Hofer, Silvia; Kulozik, Andreas E; Deimling, Andreas; Scheurlen, Wolfram; Felsberg, Jörg; Reifenberger, Guido; Hasselblatt, Martin; Crawford, John R; Grant, Gerald A; Jabado, Nada; Perry, Arie; Cowdrey, Cynthia J; Croul, Sydney; Zadeh, Gelareh; Korbel, Jan O; Doz, Francois; Delattre, Olivier; Bader, Gary D; McCabe, Martin G; Collins, V Peter; Kieran, Mark W; Cho, Yoon-Jae; Pomeroy, Scott L; Witt, Olaf; Brors, Benedikt; Taylor, Michael D; Schüller, Ulrich; Korshunov, Andrey; Eils, Roland; Wechsler-Reya, Robert J; Lichter, Peter; Pfister, Stefan M; ICGC PedBrain Tumor Project.
In: CANCER CELL, Vol. 25, No. 3, 17.03.2014, p. 393-405.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition
AU - Kool, Marcel
AU - Jones, David T W
AU - Jäger, Natalie
AU - Northcott, Paul A
AU - Pugh, Trevor J
AU - Hovestadt, Volker
AU - Piro, Rosario M
AU - Esparza, Lourdes Adriana
AU - Markant, Shirley L
AU - Remke, Marc
AU - Milde, Till
AU - Bourdeaut, Franck
AU - Ryzhova, Marina
AU - Sturm, Dominik
AU - Pfaff, Elke
AU - Stark, Sebastian
AU - Hutter, Sonja
AU - Seker-Cin, Huriye
AU - Johann, Pascal-David
AU - Bender, Sebastian
AU - Schmidt, Christin
AU - Rausch, Tobias
AU - Shih, David
AU - Reimand, Jüri
AU - Sieber, Laura
AU - Wittmann, Andrea
AU - Linke, Linda
AU - Witt, Hendrik
AU - Weber, Ursula D
AU - Zapatka, Marc
AU - König, Rainer
AU - Beroukhim, Rameen
AU - Bergthold, Guillaume
AU - van Sluis, Peter
AU - Volckmann, Richard
AU - Koster, Jan
AU - Versteeg, Rogier
AU - Schmidt, Sabine
AU - Wolf, Stephan
AU - Lawerenz, Chris
AU - Bartholomae, Cynthia C
AU - von Kalle, Christof
AU - Unterberg, Andreas
AU - Herold-Mende, Christel
AU - Hofer, Silvia
AU - Kulozik, Andreas E
AU - Deimling, Andreas
AU - Scheurlen, Wolfram
AU - Felsberg, Jörg
AU - Reifenberger, Guido
AU - Hasselblatt, Martin
AU - Crawford, John R
AU - Grant, Gerald A
AU - Jabado, Nada
AU - Perry, Arie
AU - Cowdrey, Cynthia J
AU - Croul, Sydney
AU - Zadeh, Gelareh
AU - Korbel, Jan O
AU - Doz, Francois
AU - Delattre, Olivier
AU - Bader, Gary D
AU - McCabe, Martin G
AU - Collins, V Peter
AU - Kieran, Mark W
AU - Cho, Yoon-Jae
AU - Pomeroy, Scott L
AU - Witt, Olaf
AU - Brors, Benedikt
AU - Taylor, Michael D
AU - Schüller, Ulrich
AU - Korshunov, Andrey
AU - Eils, Roland
AU - Wechsler-Reya, Robert J
AU - Lichter, Peter
AU - Pfister, Stefan M
AU - ICGC PedBrain Tumor Project
N1 - Copyright © 2014 Elsevier Inc. All rights reserved.
PY - 2014/3/17
Y1 - 2014/3/17
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Animals
KW - Base Sequence
KW - Biphenyl Compounds
KW - Cerebellar Neoplasms
KW - Child
KW - Child, Preschool
KW - DEAD-box RNA Helicases
KW - DNA Copy Number Variations
KW - Drug Resistance, Neoplasm
KW - Female
KW - Gene Expression Profiling
KW - Hedgehog Proteins
KW - High-Throughput Nucleotide Sequencing
KW - Humans
KW - Infant
KW - Kruppel-Like Transcription Factors
KW - Male
KW - Medulloblastoma
KW - Mice
KW - Mice, Inbred NOD
KW - Mice, SCID
KW - Molecular Sequence Data
KW - N-Myc Proto-Oncogene Protein
KW - Neoplasm Transplantation
KW - Nuclear Proteins
KW - Oncogene Proteins
KW - Patched Receptors
KW - Patched-1 Receptor
KW - Phosphatidylinositol 3-Kinases
KW - Promoter Regions, Genetic
KW - Proto-Oncogene Proteins c-akt
KW - Pyridines
KW - Receptors, Cell Surface
KW - Receptors, G-Protein-Coupled
KW - Repressor Proteins
KW - Signal Transduction
KW - Smoothened Receptor
KW - Telomerase
KW - Tumor Suppressor Protein p53
KW - Young Adult
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1016/j.ccr.2014.02.004
DO - 10.1016/j.ccr.2014.02.004
M3 - SCORING: Journal article
C2 - 24651015
VL - 25
SP - 393
EP - 405
JO - CANCER CELL
JF - CANCER CELL
SN - 1535-6108
IS - 3
ER -