title: Chromosome copy number changes carry prognostic information independent of KIT/PDGFRA point mutations in gastrointestinal stromal tumors.
abstract: BACKGROUND
  Oncogenic point mutations in KIT or PDGFRA are recognized as the primary events responsible for the pathogenesis of most gastrointestinal stromal tumors (GIST), but additional genomic alterations are frequent and presumably required for tumor progression. The relative contribution of such alterations for the biology and clinical behavior of GIST, however, remains elusive.
  
  
  METHODS
  In the present study, somatic mutations in KIT and PDGFRA were evaluated by direct sequencing analysis in a consecutive series of 80 GIST patients. For a subset of 29 tumors, comparative genomic hybridization was additionally used to screen for chromosome copy number aberrations. Genotype and genomic findings were cross-tabulated and compared with available clinical and follow-up data.
  
  
  RESULTS
  We report an overall mutation frequency of 87.5%, with 76.25% of the tumors showing alterations in KIT and 11.25% in PDGFRA. Secondary KIT mutations were additionally found in two of four samples obtained after imatinib treatment. Chromosomal imbalances were detected in 25 out of 29 tumors (86%), namely losses at 14q (88% of abnormal cases), 22q (44%), 1p (44%), and 15q (36%), and gains at 1q (16%) and 12q (20%). In addition to clinico-pathological high-risk groups, patients with KIT mutations, genomic complexity, genomic gains and deletions at either 1p or 22q showed a significantly shorter disease-free survival. Furthermore, genomic complexity was the best predictor of disease progression in multivariate analysis.
  
  
  CONCLUSIONS
  In addition to KIT/PDGFRA mutational status, our findings indicate that secondary chromosomal changes contribute significantly to tumor development and progression of GIST and that genomic complexity carries independent prognostic value that complements clinico-pathological and genotype information.
authors.affiliation: Department of Genetics, Portuguese Oncology Institute - Porto, Rua Dr, António Bernardino Almeida, 4200-072 Porto, Portugal.
authors.forename: Mara
authors.initials: M
authors.lastname: Silva
authors.forename: Isabel
authors.initials: I
authors.lastname: Veiga
authors.forename: Franclim R
authors.initials: FR
authors.lastname: Ribeiro
authors.forename: Joana
authors.initials: J
authors.lastname: Vieira
authors.forename: Carla
authors.initials: C
authors.lastname: Pinto
authors.forename: Manuela
authors.initials: M
authors.lastname: Pinheiro
authors.forename: Bárbara
authors.initials: B
authors.lastname: Mesquita
authors.forename: Catarina
authors.initials: C
authors.lastname: Santos
authors.forename: Marta
authors.initials: M
authors.lastname: Soares
authors.forename: José
authors.initials: J
authors.lastname: Dinis
authors.forename: Lúcio
authors.initials: L
authors.lastname: Santos
authors.forename: Paula
authors.initials: P
authors.lastname: Lopes
authors.forename: Mariana
authors.initials: M
authors.lastname: Afonso
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopes
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
mesh_terms: D000328:Adult; D000368:Aged; D000782:Aneuploidy; D002877:Chromosomes, Human; D055028:Comparative Genomic Hybridization; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000175:diagnosis* / Q000473:pathology*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D057089:Pathology, Molecular / Q000379:methods*; D017354:Point Mutation; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha
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