Integrative genomic analyses of neurofibromatosis tumours identify SOX9 as a biomarker and survival gene.
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.
Miller
Shyra J
SJ
Division of Experimental Hematology, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Jessen
Walter J
WJ
Mehta
Tapan
T
Hardiman
Atira
A
Sites
Emily
E
Kaiser
Sergio
S
Jegga
Anil G
AG
Li
Hua
H
Upadhyaya
Meena
M
Giovannini
Marco
M
Muir
David
D
Wallace
Margaret R
MR
Lopez
Eva
E
Serra
Eduard
E
Nielsen
G Petur
GP
Lazaro
Conxi
C
Stemmer-Rachamimov
Anat
A
Page
Grier
G
Aronow
Bruce J
BJ
Ratner
Nancy
N
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
D014408:Biomarkers, Tumor; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human