• Open Access

Integrative genomic analyses of neurofibromatosis tumours identify SOX9 as a biomarker and survival gene

Authors

  • Shyra J. Miller,

    1. Divisions of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH, USA
    Search for more papers by this author
    • Contributed equally to this work.

  • Walter J. Jessen,

    1. Divisions of Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH, USA
    Search for more papers by this author
    • Contributed equally to this work.

  • Tapan Mehta,

    1. Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
    Search for more papers by this author
  • Atira Hardiman,

    1. Divisions of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH, USA
    Search for more papers by this author
  • Emily Sites,

    1. Divisions of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH, USA
    Search for more papers by this author
  • Sergio Kaiser,

    1. Divisions of Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH, USA
    2. Present address: Novartis Pharma AG, Basel, Switzerland
    Search for more papers by this author
  • Anil G. Jegga,

    1. Divisions of Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH, USA
    Search for more papers by this author
  • Hua Li,

    1. Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA
    Search for more papers by this author
  • Meena Upadhyaya,

    1. Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF, UK
    Search for more papers by this author
  • Marco Giovannini,

    1. INSERM U434, Foundation Jean Dausset-CEPH, Paris, France
    2. Present address: House Ear Institute, Department of Neural Tumor Research, Los Angeles, CA, USA
    Search for more papers by this author
  • David Muir,

    1. Departments of Pediatrics and Neuroscience, University of Florida, Gainesville, FL, USA
    Search for more papers by this author
  • Margaret R. Wallace,

    1. Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA
    Search for more papers by this author
  • Eva Lopez,

    1. Centre de Genètica Mèdica i Molecular (EL and ES), Laboratori de Recerca Translacional, Institut Català d'Oncologia (CL); Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
    Search for more papers by this author
  • Eduard Serra,

    1. Centre de Genètica Mèdica i Molecular (EL and ES), Laboratori de Recerca Translacional, Institut Català d'Oncologia (CL); Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
    Search for more papers by this author
  • G. Petur Nielsen,

    1. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
    Search for more papers by this author
  • Conxi Lazaro,

    1. Centre de Genètica Mèdica i Molecular (EL and ES), Laboratori de Recerca Translacional, Institut Català d'Oncologia (CL); Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
    Search for more papers by this author
  • Anat Stemmer-Rachamimov,

    1. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
    Search for more papers by this author
  • Grier Page,

    1. Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
    Search for more papers by this author
  • Bruce J. Aronow,

    1. Divisions of Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH, USA
    Search for more papers by this author
  • Nancy Ratner

    Corresponding author
    1. Divisions of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH, USA
    • Tel: +1 513 636 9469; Fax: +1 513 636 3549
    Search for more papers by this author

Abstract

Understanding the biological pathways critical for common neurofibromatosis type 1 (NF1) peripheral nerve tumours is essential, as there is a lack of tumour biomarkers, prognostic factors and therapeutics. We used gene expression profiling to define transcriptional changes between primary normal Schwann cells (n = 10), NF1-derived primary benign neurofibroma Schwann cells (NFSCs) (n = 22), malignant peripheral nerve sheath tumour (MPNST) cell lines (n = 13), benign neurofibromas (NF) (n = 26) and MPNST (n = 6). Dermal and plexiform NFs were indistinguishable. A prominent theme in the analysis was aberrant differentiation. NFs repressed gene programs normally active in Schwann cell precursors and immature Schwann cells. MPNST signatures strongly differed; genes up-regulated in sarcomas were significantly enriched for genes activated in neural crest cells. We validated the differential expression of 82 genes including the neural crest transcription factor SOX9 and SOX9 predicted targets. SOX9 immunoreactivity was robust in NF and MPSNT tissue sections and targeting SOX9 – strongly expressed in NF1-related tumours – caused MPNST cell death. SOX9 is a biomarker of NF and MPNST, and possibly a therapeutic target in NF1.