title: Integrative genomic analyses of neurofibromatosis tumours identify SOX9 as a biomarker and survival gene.
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.
authors.affiliation: Division of Experimental Hematology, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Shyra J
authors.initials: SJ
authors.lastname: Miller
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Jessen
authors.forename: Tapan
authors.initials: T
authors.lastname: Mehta
authors.forename: Atira
authors.initials: A
authors.lastname: Hardiman
authors.forename: Emily
authors.initials: E
authors.lastname: Sites
authors.forename: Sergio
authors.initials: S
authors.lastname: Kaiser
authors.forename: Anil G
authors.initials: AG
authors.lastname: Jegga
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Meena
authors.initials: M
authors.lastname: Upadhyaya
authors.forename: Marco
authors.initials: M
authors.lastname: Giovannini
authors.forename: David
authors.initials: D
authors.lastname: Muir
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wallace
authors.forename: Eva
authors.initials: E
authors.lastname: Lopez
authors.forename: Eduard
authors.initials: E
authors.lastname: Serra
authors.forename: G Petur
authors.initials: GP
authors.lastname: Nielsen
authors.forename: Conxi
authors.initials: C
authors.lastname: Lazaro
authors.forename: Anat
authors.initials: A
authors.lastname: Stemmer-Rachamimov
authors.forename: Grier
authors.initials: G
authors.lastname: Page
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Aronow
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009456:Neurofibromatosis 1 / Q000175:diagnosis / Q000235:genetics*; D010524:Peripheral Nervous System Neoplasms / Q000175:diagnosis / Q000235:genetics*; D055758:SOX9 Transcription Factor / Q000235:genetics*; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human