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

Grier P. Page ,Anil G. Jegga,Marco Giovannini,G. Petur Nielsen,Eva López ,Walter J. Jessen,Atira Hardiman,Margaret R. Wallace,Emily Sites,Nancy Ratner,Bruce J. Aronow,Tapan Mehta,Shyra J. Miller,Sérgio Kaiser ,Meena Upadhyaya,Eduard Serra,Hua Li,Conxi Lázaro ,Anat Stemmer‐Rachamimov,David Muir

doi:10.1002/emmm.200900027

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.

Highlights

A genetic defect underlies neurofibromatosis type 1 (NF1), which is inherited as an autosomal dominant trait affecting 1:3,000 humans (Rasmussen& Friedman, 2000)
We provide a wealth of high-quality, comprehensive data for the NF1 research community
Comparing gene expression profiles of NF1 tumour samples to cultured primary Schwann cells resulted in a 1,108 unique gene signature distinguishing NF1 tumour samples from normal Schwann cells

Summary

Introduction

A genetic defect underlies NF1, which is inherited as an autosomal dominant trait affecting 1:3,000 humans (Rasmussen& Friedman, 2000). Analysis of progressive changes downstream of NF1 mutation has been complicated by the spectrum (1) Divisions of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital, University of Cincinnati College of Medicine, Cincinnati, OH, USA. (2) Divisions of Biomedical Informatics, Cincinnati Children’s Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH, USA. (4) Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA. (5) Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF, UK. (7) Departments of Pediatrics and Neuroscience, University of Florida, Gainesville, FL, USA. At least 95% of NF1 patients have multiple dermal NFs, benign tumours that typically appear in adolescence (Rasmussen & Friedman, 2000). Questions as fundamental as whether there are molecular differences between dermal and plexiform NF are to date unanswered. Differences between the types of NF are implied as a plexiform NF may transform to an MPNST, a life threatening sarcoma (Evans et al, 2002)

Methods

Results

Conclusion