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PMID: 20049725 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

EMBO molecular medicine ·Vol. 1 ·No. 4 ·2009-07-00 ·Pages 236-48

Miller SJ, Jessen WJ, Mehta T, Hardiman A, Sites E, Kaiser S, Jegga AG, Li H, Upadhyaya M, Giovannini M, Muir D, Wallace MR, Lopez E, Serra E, Nielsen GP, Lazaro C, Stemmer-Rachamimov A, Page G, Aronow BJ, Ratner N

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.

MeSH Terms
Biomarkers, Tumor/genetics Cell Line, Tumor Cells, Cultured Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Neurofibromatosis 1/diagnosis,genetics Peripheral Nervous System Neoplasms/diagnosis,genetics SOX9 Transcription Factor/genetics Schwann Cells/metabolism,pathology
Chemicals
Biomarkers, Tumor SOX9 Transcription Factor SOX9 protein, human
Authors & Affiliations
20 authors, click to expand affiliations / ORCID
Miller Shyra J
Division of Experimental Hematology, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Jessen Walter J
Mehta Tapan
Hardiman Atira
Sites Emily
Kaiser Sergio
Jegga Anil G
Li Hua
Upadhyaya Meena
Giovannini Marco
Muir David
Wallace Margaret R
Lopez Eva
Serra Eduard
Nielsen G Petur
Lazaro Conxi
Stemmer-Rachamimov Anat
Page Grier
Aronow Bruce J
Ratner Nancy
References (52)
52 references, click to expand
  1. Single cell Ras-GTP analysis reveals altered Ras activity in a subpopulation of neurofibroma Schwann cells but not fibroblasts.
    J Biol Chem. 2000 Sep 29;275(39):30740-5 PMID: 10900196
  2. GenomeTrafac: a whole genome resource for the detection of transcription factor binding site clusters associated with conventional and microRNA encoding genes conserved between mouse and human gene orthologs.
    Nucleic Acids Res. 2007 Jan;35(Database issue):D116-21 PMID: 17178752
  3. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2.
    JAMA. 1997 Jul 2;278(1):51-7 PMID: 9207339
  4. Identification of genes required for cellulose synthesis by regression analysis of public microarray data sets.
    Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8633-8 PMID: 15932943
  5. Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in desert hedgehog-expressing cells.
    Cancer Cell. 2008 Feb;13(2):105-16 PMID: 18242511
  6. Differential NF1, p16, and EGFR patterns by interphase cytogenetics (FISH) in malignant peripheral nerve sheath tumor (MPNST) and morphologically similar spindle cell neoplasms.
    J Neuropathol Exp Neurol. 2002 Aug;61(8):702-9 PMID: 12152785
  7. Angiogenic and invasive properties of neurofibroma Schwann cells.
    J Cell Biol. 1990 Aug;111(2):645-53 PMID: 1696266
  8. The transcriptional control of trunk neural crest induction, survival, and delamination.
    Dev Cell. 2005 Feb;8(2):179-92 PMID: 15691760
  9. Lineage dependency and lineage-survival oncogenes in human cancer.
    Nat Rev Cancer. 2006 Aug;6(8):593-602 PMID: 16862190
  10. The heterogeneous nature of germline mutations in NF1 patients with malignant peripheral serve sheath tumours (MPNSTs).
    Hum Mutat. 2006 Jul;27(7):716 PMID: 16786508
  11. Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1.
    Hum Mol Genet. 2000 Jan 22;9(2):237-47 PMID: 10607834
  12. Hypomorphic Sox10 alleles reveal novel protein functions and unravel developmental differences in glial lineages.
    Development. 2007 Sep;134(18):3271-81 PMID: 17699610
  13. NF1 tumor suppressor gene function: narrowing the GAP.
    Cell. 2001 Feb 23;104(4):593-604 PMID: 11239415
  14. Large-scale molecular comparison of human schwann cells to malignant peripheral nerve sheath tumor cell lines and tissues.
    Cancer Res. 2006 Mar 1;66(5):2584-91 PMID: 16510576
  15. Neurofibromas in NF1: Schwann cell origin and role of tumor environment.
    Science. 2002 May 3;296(5569):920-2 PMID: 11988578
  16. Exploration, normalization, and summaries of high density oligonucleotide array probe level data.
    Biostatistics. 2003 Apr;4(2):249-64 PMID: 12925520
  17. Cell of origin and microenvironment contribution for NF1-associated dermal neurofibromas.
    Cell Stem Cell. 2009 May 8;4(5):453-63 PMID: 19427294
  18. Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data.
    Nucleic Acids Res. 2005 Nov 10;33(20):e175 PMID: 16284200
  19. Tumor microenvironment and neurofibromatosis type I: connecting the GAPs.
    Oncogene. 2007 Jul 12;26(32):4609-16 PMID: 17297459
  20. Culture of cytogenetically abnormal schwann cells from benign and malignant NF1 tumors.
    Genes Chromosomes Cancer. 2000 Feb;27(2):117-23 PMID: 10612798
  21. The PowerAtlas: a power and sample size atlas for microarray experimental design and research.
    BMC Bioinformatics. 2006 Feb 22;7:84 PMID: 16504070
  22. High-resolution DNA copy number profiling of malignant peripheral nerve sheath tumors using targeted microarray-based comparative genomic hybridization.
    Clin Cancer Res. 2008 Feb 15;14(4):1015-24 PMID: 18281533
  23. Potential use of Sox9 gene therapy for intervertebral degenerative disc disease.
    Spine (Phila Pa 1976). 2003 Apr 15;28(8):755-63 PMID: 12698117
  24. How does the Schwann cell lineage form tumors in NF1?
    Glia. 2008 Nov 1;56(14):1590-605 PMID: 18803326
  25. Pheochromocytomas in Nf1 knockout mice express a neural progenitor gene expression profile.
    Neuroscience. 2007 Jul 29;147(4):928-37 PMID: 17582688
  26. cDNA microarray analysis of cancer associated gene expression profiles in malignant peripheral nerve sheath tumours.
    J Clin Pathol. 2006 Feb;59(2):160-5 PMID: 16443732
  27. Protein zero gene expression is regulated by the glial transcription factor Sox10.
    Mol Cell Biol. 2000 May;20(9):3198-209 PMID: 10757804
  28. The transcription factor Sox10 is a key regulator of peripheral glial development.
    Genes Dev. 2001 Jan 1;15(1):66-78 PMID: 11156606
  29. Microarray-based identification of tenascin C and tenascin XB, genes possibly involved in tumorigenesis associated with neurofibromatosis type 1.
    Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):398-407 PMID: 17202312
  30. Efficient isolation and gene expression profiling of small numbers of neural crest stem cells and developing Schwann cells.
    J Neurosci. 2004 Mar 10;24(10):2357-65 PMID: 15014110
  31. The origin and development of glial cells in peripheral nerves.
    Nat Rev Neurosci. 2005 Sep;6(9):671-82 PMID: 16136171
  32. Controlling the false discovery rate in behavior genetics research.
    Behav Brain Res. 2001 Nov 1;125(1-2):279-84 PMID: 11682119
  33. Sox10, a novel transcriptional modulator in glial cells.
    J Neurosci. 1998 Jan 1;18(1):237-50 PMID: 9412504
  34. Molecular profiles of neurofibromatosis type 1-associated plexiform neurofibromas: identification of a gene expression signature of poor prognosis.
    Clin Cancer Res. 2004 Jun 1;10(11):3763-71 PMID: 15173083
  35. The loss of Nf1 transiently promotes self-renewal but not tumorigenesis by neural crest stem cells.
    Cancer Cell. 2008 Feb;13(2):129-40 PMID: 18242513
  36. Brain lipid binding protein in axon-Schwann cell interactions and peripheral nerve tumorigenesis.
    Mol Cell Biol. 2003 Mar;23(6):2213-24 PMID: 12612091
  37. Malignant peripheral nerve sheath tumours in neurofibromatosis 1.
    J Med Genet. 2002 May;39(5):311-4 PMID: 12011145
  38. Improved method for harvesting human Schwann cells from mature peripheral nerve and expansion in vitro.
    Glia. 1996 Aug;17(4):327-38 PMID: 8856329
  39. A proposed metric for assessing the measurement quality of individual microarrays.
    BMC Bioinformatics. 2006 Jan 23;7:35 PMID: 16430768
  40. The DNA-binding specificity of SOX9 and other SOX proteins.
    Nucleic Acids Res. 1999 Mar 1;27(5):1359-64 PMID: 9973626
  41. Nf1 mutation expands an EGFR-dependent peripheral nerve progenitor that confers neurofibroma tumorigenic potential.
    Cell Stem Cell. 2008 Dec 4;3(6):658-69 PMID: 19041782
  42. NF1 gene and neurofibromatosis 1.
    Am J Epidemiol. 2000 Jan 1;151(1):33-40 PMID: 10625171
  43. The transcription factor SOX9 regulates cell cycle and differentiation genes in chondrocytic CFK2 cells.
    J Biol Chem. 2001 Nov 2;276(44):41229-36 PMID: 11514554
  44. Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations.
    Hum Mol Genet. 2000 Dec 12;9(20):3055-64 PMID: 11115850
  45. Epidermal growth factor receptor expression in neurofibromatosis type 1-related tumors and NF1 animal models.
    J Clin Invest. 2000 May;105(9):1233-41 PMID: 10791998
  46. The DAVID Gene Functional Classification Tool: a novel biological module-centric algorithm to functionally analyze large gene lists.
    Genome Biol. 2007;8(9):R183 PMID: 17784955
  47. Mitotic recombination effects homozygosity for NF1 germline mutations in neurofibromas.
    Nat Genet. 2001 Jul;28(3):294-6 PMID: 11431704
  48. Hair follicle stem cells are specified and function in early skin morphogenesis.
    Cell Stem Cell. 2008 Jul 3;3(1):33-43 PMID: 18593557
  49. Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients.
    Genes Chromosomes Cancer. 2006 Mar;45(3):265-76 PMID: 16283621
  50. Sox10 acts as a tissue-specific transcription factor enhancing activation of the myelin basic protein gene promoter by p27Kip1 and Sp1.
    J Neurosci Res. 2004 Dec 15;78(6):796-802 PMID: 15523643
  51. Replacement of the Sox10 transcription factor by Sox8 reveals incomplete functional equivalence.
    Development. 2006 Aug;133(15):2875-86 PMID: 16790476
  52. Subclassification of nerve sheath tumors by gene expression profiling.
    Brain Pathol. 2004 Jul;14(3):258-64 PMID: 15446580
Article Info
Journal
EMBO molecular medicine
Abbr.
EMBO Mol Med
ISSN
1757-4684
DOI
10.1002/emmm.200900027
Published
2009-07-00
Pages
236-48
Language
English
Region
England
NLM ID
101487380
PMCID
PMC3378132
Subset
IM
Grants
NINDS NIH HHS · K01 NS049191 · United States
NCI NIH HHS · T32 CA059268 · United States
NINDS NIH HHS · K01-NS049191 · United States
NCI NIH HHS · T32 CA 59268 · United States
Corrections
CommentIn
PMID: 20049721
External Links
PubMed source DOI: 10.1002/emmm.200900027 PMC Full Text View journal details
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