title: HDM2 overexpression and focal loss of p14/ARF expression may deregulate the p53 tumour suppressor pathway in meningeal haemangiopericytomas. Study by double immunofluorescence and laser scanning confocal microscopy.
abstract: OBJECTIVE
  To investigate the p53 pathway in meningeal haemangiopericytomas (MHPCs), p14/ARF, p53 protein expression and two wild-type (wt) p53-induced proteins (HDM2 and p21/WAF1) were studied in 18 MHPCs, 11 primary, four of them recurrent on one, one, two and four occasions.
  
  
  METHODS
  Immunohistochemical detection of p14/ARF, p53, p21/WAF1, HDM2 and Ki67 proliferative index (PI) protein expression.
  
  
  RESULTS
  Ki67 index was > 5% in eight out 18 cases (44.4%). The PI in recurrent cases increased with neoplastic progression. Simultaneous p53 and wt p53 transactivated gene (p21/WAF, HDM2) expression occurred in all cases. This argues against p53 mutation. HDM2 overexpression was observed in 10 cases (55.5%). Double-immunofluorescence staining and laser scanning confocal microscopy (LSCM) displayed HDM2 and p53 colocalization. This strongly suggests that HDM2 binds and inactivates p53 that could be pathogenic for MHPCs, by a different mechanism than point mutation. p14/ARF expression > 5% was observed in 12 cases (66.6%). A normal (diffuse) pattern of expression was seen in 13 cases (72.2%). Focal loss of expression was observed in five patients (27.7%): three primary cases and two recurrences. Therefore, p14/ARF down-regulation may also contribute to the development of MHPC.
  
  
  CONCLUSIONS
  HDM2 overexpression, sometimes combined with focal loss of p14/ARF expression, may play a pathogenic role in MHPCs.
authors.affiliation: Department of Pathology (Neuropathology), University Hospital 12 de Octubre, Madrid, Spain.
authors.forename: J-C
authors.initials: JC
authors.lastname: Martínez
authors.forename: J-C
authors.initials: JC
authors.lastname: Palomino
authors.forename: A
authors.initials: A
authors.lastname: Cabello
authors.forename: J M
authors.initials: JM
authors.lastname: Sepúlveda
authors.forename: A G
authors.initials: AG
authors.lastname: de la Cámara
authors.forename: J-R
authors.initials: JR
authors.lastname: Ricoy
mesh_terms: D018797:Cell Cycle Proteins / Q000032:analysis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005455:Fluorescent Antibody Technique / Q000379:methods; D006393:Hemangiopericytoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008577:Meningeal Neoplasms / Q000378:metabolism / Q000473:pathology*; D018613:Microscopy, Confocal; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009687:Nuclear Proteins / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D051736:Proto-Oncogene Proteins c-mdm2; D025803:Tumor Suppressor Protein p14ARF / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2