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Cancer Cell. 2014 Mar 17;25(3):393-405. doi: 10.1016/j.ccr.2014.02.004.

Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition.

Author information

1
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany. Electronic address: m.kool@dkfz.de.
2
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
3
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
4
Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
5
Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
6
Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
7
The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
8
Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
9
Institut Curie, 75005 Paris, France; Institut Curie/INSERM U830, 75248 Paris, France.
10
Department of Neuropathology, NN Burdenko Neurosurgical Institute, Moscow 125047, Russia.
11
European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.
12
The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
13
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.
14
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.
15
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.
16
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.
17
Department of Oncogenomics, Academic Medical Center, Amsterdam 1105 AZ, the Netherlands.
18
Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
19
Data Management Facility, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
20
Division of Translational Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69121 Heidelberg, Germany.
21
Department of Oncology, University Hospital Zürich, 8006 Zürich, Switzerland.
22
Department of Neuropathology, University of Heidelberg, 69120 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
23
Cnopf'sche Kinderklinik, Nürnberg Children's Hospital, 90419 Nürnberg, Germany.
24
Department of Neuropathology, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.
25
Institute for Neuropathology, University Hospital Münster, 48149 Münster, Germany.
26
Departments of Pediatrics and Neurosciences, University of California San Diego, La Jolla, CA 92093; Rady Children's Hospital, San Diego, CA 92123, USA.
27
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.
28
Departments of Pediatrics and Human Genetics, McGill University Health Centre Research Institute, Montreal, QC H3H 1P3, Canada.
29
Departments of Pathology and Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
30
Departments of Pathology and Neurological Surgery, Brain Tumor Research Center, University of California, San Francisco, San Francisco, CA 94143, USA.
31
Department of Neuropathology, The Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, ON M5G 1L7, Canada.
32
Institut Curie, 75005 Paris, France; Université Paris Descartes, 75006 Paris, France.
33
Manchester Academic Health Science Centre, Manchester M13 9NT, UK.
34
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
35
Pediatric Medical Neuro-Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02215, USA.
36
Department of Neurology and Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
37
Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
38
CCU Pediatric Oncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
39
Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität, 81377 München, Germany.
40
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.

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.

PMID:
24651015
PMCID:
PMC4493053
DOI:
10.1016/j.ccr.2014.02.004
[Indexed for MEDLINE]
Free PMC Article

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