Original Paper

Acta Neuropathologica

, Volume 123, Issue 4, pp 515-527

Biological and clinical heterogeneity of MYCN-amplified medulloblastoma

  • Andrey KorshunovAffiliated withDepartment of Neuropathology, University of HeidelbergClinical Cooperation Unit Neuropathology, German Cancer Research Center
  • , Marc RemkeAffiliated withDivision Molecular Genetics, German Cancer Research CenterDepartment of Pediatric Oncology, Hematology and Immunology, University of Heidelberg
  • , Marcel KoolAffiliated withDivision Molecular Genetics, German Cancer Research Center
  • , Thomas HielscherAffiliated withDivision Biostatistics, German Cancer Research Center
  • , Paul A. NorthcottAffiliated withProgram in Developmental and Stem Cell Biology, Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto
  • , Dan WilliamsonAffiliated withNorthern Institute for Cancer Research, Newcastle University
  • , Elke PfaffAffiliated withDivision Molecular Genetics, German Cancer Research Center
  • , Hendrik WittAffiliated withDivision Molecular Genetics, German Cancer Research CenterDepartment of Pediatric Oncology, Hematology and Immunology, University of Heidelberg
  • , David T. W. JonesAffiliated withDivision Molecular Genetics, German Cancer Research Center
    • , Marina RyzhovaAffiliated withNN Burdenko Neurosurgical Institute
    • , Yoon-Jae ChoAffiliated withChildren’s Hospital Boston
    • , Andrea WittmannAffiliated withDivision Molecular Genetics, German Cancer Research Center
    • , Axel BennerAffiliated withDivision Biostatistics, German Cancer Research Center
    • , William A. WeissAffiliated withDepartment of Neuropathology, University of HeidelbergDepartments of Neurology, Pediatrics, and Neurological Surgery, UCSF
    • , Andreas von DeimlingAffiliated withDepartment of Neuropathology, University of HeidelbergClinical Cooperation Unit Neuropathology, German Cancer Research Center
    • , Wolfram ScheurlenAffiliated withDepartment of Neuropathology, University of HeidelbergCnopf’sche Kinderklinik, Nürnberg Children’s Hospital
    • , Andreas E. KulozikAffiliated withDepartment of Pediatric Oncology, Hematology and Immunology, University of Heidelberg
    • , Steven C. CliffordAffiliated withNorthern Institute for Cancer Research, Newcastle University
    • , V. Peter CollinsAffiliated withDepartment of Neuropathology, University of HeidelbergDivision of Molecular Histopathology, Department of Pathology, University of Cambridge
    • , Frank WestermannAffiliated withDepartment of Neuropathology, University of HeidelbergDivision Tumor Genetics, German Cancer Research Center
    • , Michael D. TaylorAffiliated withProgram in Developmental and Stem Cell Biology, Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto
    • , Peter LichterAffiliated withDivision Molecular Genetics, German Cancer Research Center
    • , Stefan M. PfisterAffiliated withDepartment of Neuropathology, University of HeidelbergDivision Molecular Genetics, German Cancer Research CenterDepartment of Pediatric Oncology, Hematology and Immunology, University of Heidelberg Email author 

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Abstract

Focal high-level amplifications of MYC (or MYCC) define a subset of high-risk medulloblastoma patients. However, the prognostic role of MYCN oncogene amplification remains unresolved. We aimed to evaluate the prognostic value of this alteration alone and in combination with biological modifiers in 67 pediatric medulloblastomas with MYCN amplification (MYCN-MB). Twenty-one MYCN-MB were examined using gene expression profiling and array-CGH, whereas for 46 tumors immunohistochemical analysis and FISH were performed. All 67 tumors were further subjected to mutational analyses. We compared molecular, clinical, and prognostic characteristics both within biological MYCN-MB groups and with non-amplified tumors. Transcriptomic analysis revealed SHH-driven tumorigenesis in a subset of MYCN-MBs indicating a biological dichotomy of MYCN-MB. Activation of SHH was accompanied by variant-specific cytogenetic aberrations including deletion of 9q in SHH tumors. Non-SHH MB were associated with gain of 7q and isochromosome 17q/17q gain. Among clinically relevant variables, SHH subtype and 10q loss for non-SHH tumors comprised the most powerful markers of favorable prognosis in MYCN-MB. In conclusion, we demonstrate considerable heterogeneity within MYCN-MB in terms of genetics, tumor biology, and clinical outcome. Thus, assessment of disease group and 10q copy-number status may improve risk stratification of this group and may delineate MYCN-MB with the same dismal prognosis as MYC amplified tumors. Furthermore, based on the enrichment of MYCN and GLI2 amplifications in SHH-driven medulloblastoma, amplification of these downstream signaling intermediates should be taken into account before a patient is enrolled into a clinical trial using a smoothened inhibitor.

Keywords

MYCN SHH pathway 10q loss Medulloblastoma