title: Evidence of ambiguous differentiation and mTOR pathway dysregulation in subependymal giant cell astrocytoma.
abstract: OBJECTIVE
  The exact cell of origin of subependymal giant cell astrocytoma is debated but most currently consider the tumor in the astrocytic category. Mutations and subsequent biallelic inactivation of TSC1 encoding hamartin, or TSC2 encoding tuberin appear to be the underlying genetic aberrations. Inactivation leads to loss of proteins that inhibit mammalian target of rapamycin (mTOR ) disrupting tightly regulated cell functions.
  
  
  METHODS
  We analyzed the expression of tuberin and hamartin along with an array of neuroepithelial markers in 9 subependymal giant cell astrocytomas. In addition, RPS6 and 4EBP1 regulatory proteins that are downstream in the mTOR pathway were also evaluated.
  
  
  RESULTS
  While hamartin and tuberin expression levels were relatively decreased compared to control tissue, this was not of particular practical use to detect the mutated gene since low levels of positivity could be detected throughout the central nervous system. As expected, the levels of RPS6 and 4EBP1 were increased, further confirming the activation of the mTOR pathway. GFAP was positive in 5 cases, while Synaptophysin positivity was found in all tumors. CD34 (a marker often observed in well differentiated glio-neuronal tumors), Olig2 (a nuclear marker present in most gliomas), IDH1 and IDH2 were entirely negative in all tumor cells. Ki67 (MIB-1) showed a low proliferation rate ranging from 2% to 8%.
  
  
  CONCLUSIONS
  Staining with neuroepithelial markers supports the suggestion of ambiguous differentiation. Subependymal giant cell astrocytomas do not appear to have the typical expression profiles of astrocytic tumors, under which they have been classified.
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, USA.
authors.forename: Brad D
authors.initials: BD
authors.lastname: Barrows
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Rutkowski
authors.forename: Sakir Humayun
authors.initials: SH
authors.lastname: Gültekın
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Parsa
authors.forename: Tarık
authors.initials: T
authors.lastname: Tıhan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis; D000293:Adolescent; D000328:Adult; D018952:Antigens, CD34 / Q000032:analysis; D001254:Astrocytoma / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000473:pathology*; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D001932:Brain Neoplasms / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000473:pathology*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D019394:Ki-67 Antigen / Q000032:analysis; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000032:analysis; D000076104:Oligodendrocyte Transcription Factor 2; D010750:Phosphoproteins / Q000032:analysis; D010766:Phosphorylation; D038601:Ribosomal Protein S6 / Q000032:analysis; D015398:Signal Transduction; D016708:Synaptophysin; D058570:TOR Serine-Threonine Kinases / Q000032:analysis*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000032:analysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018952:Antigens, CD34; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D007521:Isocitrate Dehydrogenase; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D010750:Phosphoproteins; D038601:Ribosomal Protein S6; D016708:Synaptophysin; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D033921:Vesicular Transport Proteins; C087000:EIF4EBP1 protein, human; C405708:OLIG2 protein, human; C569014:SYP protein, human; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C538784:IDH2 protein, human; C543588:IDH1 protein, human; C546842:MTOR protein, human