title: Molecular profiling of malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1, based on large-scale real-time RT-PCR.
abstract: BACKGROUND
  Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a complex range of clinical symptoms. The hallmark of NF1 is the onset of heterogeneous (dermal or plexiform) benign neurofibromas. Plexiform neurofibromas can give rise to malignant peripheral nerve sheath tumors (MPNSTs), and the underlying molecular mechanisms are largely unknown.
  
  
  RESULTS
  To obtain further insight into the molecular pathogenesis of MPNSTs, we used real-time quantitative RT-PCR to quantify the mRNA expression of 489 selected genes in MPNSTs, in comparison with plexiform neurofibromas. The expression of 28 (5.7%) of the 489 genes was significantly different between MPNSTs and plexiform neurofibromas; 16 genes were upregulated and 12 were downregulated in MPNSTs. The altered genes were mainly involved in cell proliferation (MKI67, TOP2A, CCNE2), senescence (TERT, TERC), apoptosis (BIRC5/Survivin, TP73) and extracellular matrix remodeling (MMP13, MMP9, TIMP4, ITGB4). More interestingly, other genes were involved in the Ras signaling pathway (RASSF2, HMMR/RHAMM) and the Hedgehog-Gli signaling pathway (DHH, PTCH2). Several of the down-regulated genes were Schwann cell-specific (L1CAM, MPZ, S100B, SOX10, ERBB3) or mast cell-specific (CMA1, TPSB), pointing to a depletion and/or dedifferentiation of Schwann cells and mast cells during malignant transformation of plexiform neurofibromas.
  
  
  CONCLUSIONS
  These data suggest that a limited number of signaling pathways, and particularly the Hedgehog-Gli signaling pathway, may be involved in malignant transformation of plexiform neurofibromas. Some of the relevant genes or their products warrant further investigation as potential therapeutic targets in NF1.
authors.affiliation: Laboratoire de Génétique Moléculaire-UPRES EA 3618, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris V, Paris, France. pascale.levy@etu.univ-paris5.fr
authors.forename: Pascale
authors.initials: P
authors.lastname: Lévy
authors.forename: Dominique
authors.initials: D
authors.lastname: Vidaud
authors.forename: Karen
authors.initials: K
authors.lastname: Leroy
authors.forename: Ingrid
authors.initials: I
authors.lastname: Laurendeau
authors.forename: Janine
authors.initials: J
authors.lastname: Wechsler
authors.forename: Giulia
authors.initials: G
authors.lastname: Bolasco
authors.forename: Béatrice
authors.initials: B
authors.lastname: Parfait
authors.forename: Pierre
authors.initials: P
authors.lastname: Wolkenstein
authors.forename: Michel
authors.initials: M
authors.lastname: Vidaud
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D003199:Computer Systems; D015536:Down-Regulation / Q000235:genetics; D005109:Extracellular Matrix / Q000235:genetics / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D018317:Nerve Sheath Neoplasms / Q000235:genetics*; D018318:Neurofibroma, Plexiform / Q000235:genetics; D009456:Neurofibromatosis 1 / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods*; D012583:Schwann Cells / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D012334:RNA, Neoplasm