title: Identification of survival-related genes of the phosphatidylinositol 3'-kinase signaling pathway in glioblastoma multiforme.
abstract: BACKGROUND
  Knowledge of the molecular mechanisms involved in the biology of glioblastoma multiforme (GBM) is essential for the identification of candidate prognostic markers, new putative therapeutic targets, and early detection strategies predictive of survival.
  
  
  METHODS
  The authors performed expression-profiling analyses in a series of primary GBMs by using complementary DNA microarrays. Validation of putative targets was performed in large series of GBMs by immunohistochemistry on tissue microarrays, real-time quantitative reverse transcription-polymerase chain reaction analysis, and Western blot analysis.
  
  
  RESULTS
  The expression signature consisted of 159 up-regulated genes and 186 down-regulated genes. Most of these genes were involved in cell adhesion, signal transduction, cell cycle, apoptosis, and angiogenesis. Among the genes from the molecular signature, annexin 1 (ANXA1) and ubiquitin-specific protease 7 (USP7) were evaluated in wider series of GBMs. ANXA1 analysis carried out in different types of gliomas revealed exclusive overexpression in astrocytomas. Furthermore, survival analysis by using functional clusters of genes related with cancer and glioma biology revealed 7 genes involved in the PI3K-signaling pathway that presented a significant association with clinical outcome. Among these genes, positive expression of BCL2-associated X protein (BAX) was associated significantly with better survival in a larger series of tumors. In addition, activation of the PI3K/Akt pathway was demonstrated in this set of GBMs.
  
  
  CONCLUSIONS
  The authors concluded that there is a significant role for PI3K pathway survival-related genes in patients with GBM, and putative prognostic markers associated with glioma tumorigenesis were identified. The detailed study of these candidate genes and the molecular pathways regulating PI3K activation reveal that they are promising targets for the clinical management of patients with glioma.
authors.affiliation: Genetics Department, Virgen de la Salud Hospital, Toledo, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Ruano
authors.forename: Manuela
authors.initials: M
authors.lastname: Mollejo
authors.forename: Francisca I
authors.initials: FI
authors.lastname: Camacho
authors.forename: Angel
authors.initials: A
authors.lastname: Rodríguez de Lope
authors.forename: Concepción
authors.initials: C
authors.lastname: Fiaño
authors.forename: Teresa
authors.initials: T
authors.lastname: Ribalta
authors.forename: Pedro
authors.initials: P
authors.lastname: Martínez
authors.forename: Jose-Luis
authors.initials: JL
authors.lastname: Hernández-Moneo
authors.forename: Bárbara
authors.initials: B
authors.lastname: Meléndez
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002470:Cell Survival; D005260:Female; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism; D005910:Glioma / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt