title: Mitotic checkpoints and chromosome instability are strong predictors of clinical outcome in gastrointestinal stromal tumors.
abstract: OBJECTIVE
  The importance of KIT and PDGFRA mutations in the oncogenesis of gastrointestinal stromal tumors (GIST) is well established, but the genetic basis of GIST metastasis is poorly understood. We recently published a 67 gene expression prognostic signature related to genome complexity (CINSARC for Complexity INdex in SARComas) and asked whether it could predict outcome in GISTs.
  
  
  METHODS
  We carried out genome and expression profiling on 67 primary untreated GISTs.
  
  
  RESULTS
  We show and validate here that it can predict metastasis in a new data set of 67 primary untreated GISTs. The gene whose expression was most strongly associated with metastasis was AURKA, but the AURKA locus was not amplified. Instead, we identified deletion of the p16 (CDKN2A) and retinoblastoma (RB1) genes as likely causal events leading to increased AURKA and CINSARC gene expression, to chromosome rearrangement, and ultimately to metastasis. On the basis of these findings, we established a Genomic Index that integrates the number and type of DNA copy number alterations. This index is a strong prognostic factor in GISTs. We show that CINSARC class, AURKA expression, and Genomic Index all outperform the Armed Forces Institute of Pathology (AFIP) grading system in determining the prognosis of patients with GISTs. Interestingly, these signatures can identify poor prognosis patients in the group classified as intermediate-risk by the AFIP classification.
  
  
  CONCLUSIONS
  We propose that a high Genomic Index determined by comparative genomic hybridization from formalin-fixed, paraffin-embedded samples could be used to identify AFIP intermediate-risk patients who would benefit from imatinib therapy.
authors.affiliation: INSERM U916: Genetics and Biology of Sarcomas, Paris Cedex, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Lagarde
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Pérot
authors.forename: Audrey
authors.initials: A
authors.lastname: Kauffmann
authors.forename: Céline
authors.initials: C
authors.lastname: Brulard
authors.forename: Valérie
authors.initials: V
authors.lastname: Dapremont
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hostein
authors.forename: Agnès
authors.initials: A
authors.lastname: Neuville
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wozniak
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Alain
authors.initials: A
authors.lastname: Aurias
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Coindre
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.forename: Frédéric
authors.initials: F
authors.lastname: Chibon
mesh_terms: D043171:Chromosomal Instability / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics*; D008297:Male; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction