title: Biological and clinical significance of the intratumour heterogeneity of PTEN protein expression and the corresponding molecular abnormalities of the PTEN gene in glioblastomas.
abstract: OBJECTIVE
  Glioblastomas display marked phenotypic and molecular heterogeneity. The expression of the PTEN protein in glioblastomas also shows great intratumour heterogeneity, but the significance of this heterogeneity has so far received little attention.
  
  
  METHODS
  We conducted a comparative study on paraffin and frozen samples from 60 glioblastomas. Based on PTEN immunostaining, paraffin glioblastomas were divided into positive (homogeneous staining) and both positive and negative (heterogeneous staining) tumours. DNA was extracted from manually microdissected samples from representative areas, and from frozen samples taken randomly from the same tumours. Loss of heterozygosity (LOH) of 10q23 and hypermethylation status of the PTEN promoter were studied, and the molecular findings were correlated with overall survival.
  
  
  RESULTS
  PTEN protein was present heterogeneously in 42 cases and homogeneously in 18 cases. In homogeneous glioblastomas, no correlation was found between PTEN protein expression and the LOH of the gene. Surprisingly, in the heterogeneous glioblastomas, LOH was found significantly more frequently (P < 0.001) in PTEN-positive areas (81%) than in PTEN-negative ones (35.7%). In general, molecular results of frozen tissue were representative of the tumour. Only two cases of methylation of the PTEN promoter were identified. A significant difference was found for overall survival for LOH10q23 status (P = 0.005) and for homogeneous vs. heterogeneous tumours (P = 0.014).
  
  
  CONCLUSIONS
  The expression of PTEN protein does not correlate with the abnormalities of the LOH of the gene. Interestingly, patients with glioblastomas presenting either LOH of 10q23 or heterogeneous PTEN expression have a poorer prognosis.
authors.affiliation: Pathology, University Hospital and Faculty of Medicine, University of Navarra, Pamplona, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Idoate
authors.forename: Jose
authors.initials: J
authors.lastname: Echeveste
authors.forename: Ricardo
authors.initials: R
authors.lastname: Diez-Valle
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Lozano
authors.forename: José
authors.initials: J
authors.lastname: Aristu
mesh_terms: D000368:Aged; D005260:Female; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: LOH10q23; PTEN; glioblastoma; intratumour heterogeneity; microdissection