title: The transcription factor evi-1 is overexpressed, promotes proliferation, and is prognostically unfavorable in infratentorial ependymomas.
abstract: OBJECTIVE
  Ependymomas are glial tumors of presumably radial glial origin that share morphologic similarities with ependymal cells. The molecular genetics of ependymomas of supratentorial, infratentorial, and spinal location is heterogeneous. We aimed at identifying pathways operative in the development of infratentorial ependymomas.
  
  
  METHODS
  To do so, gene expression profiles of tumor cells laser microdissected from infratentorial ependymomas (n = 15) were compared with that of nonneoplastic ependymal cells laser microdissected from autopsy tissue (n = 7).
  
  
  RESULTS
  Among 31 genes significantly overexpressed (>5-fold) in ependymomas, transcription factor EVI1 (ecotropic viral integration site 1) showed the highest overexpression (35-fold). Evi-1 protein expression could be confirmed in formalin-fixed, paraffin-embedded samples of 26 of 28 infratentorial ependymomas but only in 7 of 47 nonependymal glial tumors (P < 0.001). Furthermore, MDS1/EVI1 fusion transcripts were detectable in 17 of 28 infratentorial ependymomas and significantly correlated with MGMT (O6-methylguanine-DNA-methyltransferase) promoter hypermethylation (P < 0.05). In primary infratentorial ependymoma cells, transfection with EVI1-specific siRNAs resulted in significant growth inhibition [48 hours: 87% ± 2% and 74% ± 10% as compared with control (mean ± SD; P < 0.001)]. The prognostic role of EVI1 could further be validated in an independent cohort of 39 infratentorial and 26 supratentorial ependymomas on the basis of mRNA expression profiling. Although in supratentorial ependymomas EVI1 expression status had no prognostic impact, in infratentorial ependymomas, high EVI1 expression was associated with shorter overall survival and progression-free survival.
  
  
  CONCLUSIONS
  To conclude, the transcription factor Evi-1 is overexpressed in infratentorial ependymomas, promotes proliferation of ependymal tumor cells, and is prognostically unfavorable.
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Koos
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bender
authors.forename: Hendrik
authors.initials: H
authors.lastname: Witt
authors.forename: Sonja
authors.initials: S
authors.lastname: Mertsch
authors.forename: Jörg
authors.initials: J
authors.lastname: Felsberg
authors.forename: Rudi
authors.initials: R
authors.lastname: Beschorner
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Barbara
authors.initials: B
authors.lastname: Riesmeier
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfister
authors.forename: Werner
authors.initials: W
authors.lastname: Paulus
authors.forename: Martin
authors.initials: M
authors.lastname: Hasselblatt
mesh_terms: D049109:Cell Proliferation; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004806:Ependymoma / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015192:Infratentorial Neoplasms / Q000378:metabolism* / Q000473:pathology; D000074008:MDS1 and EVI1 Complex Locus Protein; D008297:Male; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011519:Proto-Oncogenes / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C098704:MDS1-EVI1 fusion protein, human; C063575:MECOM protein, human; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D019853:O(6)-Methylguanine-DNA Methyltransferase