title: Fluorescence in situ hybridization analysis and immunophenotyping of c-Kit/PDGFRA and Bcl-2 expression in gastrointestinal stromal tumors.
abstract: OBJECTIVE
  To investigate c-Kit/PDGFRA genomic alterations, KIT-PDGFRA coexpression in gastrointestinal stromal tumors (GISTs) and the role of Bcl-2.
  
  
  METHODS
  We analyzed 70 primary tumors, 6 recurrences, 4 metastases and 1 recurrence plus metastasis, all molecularly characterized. Alterations in gene copy number were detected by fluorescence in situ hybridization (FISH) and expression of KIT, PDGFRA and Bcl-2 by immunohistochemistry.
  
  
  RESULTS
  c-Kit/PDGFRA gene alterations affected 38% of all cases and 39% of primary tumors, with major changes accounting for 15% in both all the cases and primary tumors. Cytoplasmic KIT/PDGFRA coexpression was present in 96.5% of the c-Kit-mutated cases, 100% of the wt c-Kit/PDGFRA cases and 66.6% of the PDGFRA-mutated cases. Bcl-2 immunoreactivity was present in 70% of cases, with expression levels of +++ in 29%, ++ in 38% and + in 33%.
  
  
  CONCLUSIONS
  FISH confirmed cytogenetic alterations in about 40% of primary GISTs at the onset. The high rate of c-Kit/PDGFRA coexpression suggests that both receptors are involved in oncogenicity and may affect imatinib efficacy. The assumption that Bcl-2 expression is supported by the KIT pathway and that its imatinib-mediated down-regulation contributes to autophagic cell death, although attractive, needs to be further confirmed.
authors: Unit of Experimental Molecular Pathology, Department of Pathology, Fondazione Istituto di Ricerca e di Cura a Carattere Scientifico (IRCCS), Istituto Nazionale dei Tumori, Milan, Italy.
authors: Marta
authors: M
authors: Orsenigo
authors: Silvia
authors: S
authors: Brich
authors: Carla
authors: C
authors: Riva
authors: Elena
authors: E
authors: Conca
authors: Rossella
authors: R
authors: Bertulli
authors: Palma
authors: P
authors: Dileo
authors: Alessandro
authors: A
authors: Gronchi
authors: Paolo G
authors: PG
authors: Casali
authors: Marco A
authors: MA
authors: Pierotti
authors: Elena
authors: E
authors: Tamborini
authors: Silvana
authors: S
authors: Pilotti
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D001706:Biopsy; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha