title: Tumor genotype is an independent prognostic factor in primary gastrointestinal stromal tumors of gastric origin: a european multicenter analysis based on ConticaGIST.
abstract: OBJECTIVE
  Although the mutational status in gastrointestinal stromal tumors (GIST) can predict the response to treatment with tyrosine kinase inhibitors, the role of tumor genotype as a prognostic factor remains controversial. The ConticaGIST study sought to determine the pathologic and molecular factors associated with disease-free survival (DFS) in patients with operable, imatinib-naive GIST.
  
  
  METHODS
  Clinicopathologic and molecular data from 1,056 patients with localized GIST who underwent surgery with curative intention (R0/R1) and were registered in the European ConticaGIST database were prospectively obtained and reviewed. Risk of tumor recurrence was stratified using the modified NIH criteria. The median follow-up was 52 months.
  
  
  RESULTS
  On testing for potential prognostic parameters, the following were associated with inferior DFS on multivariable Cox model analysis: primary nongastric site, size >10 cm, mitotic index >10 mitoses per 50 high power field, and the KIT exon 9 duplication [hazard ratio (HR), 1.47; 95% confidence interval (CI), 0.9-2.5; P = 0.037] and KIT exon 11 deletions involving codons 557 and/or 558 [KITdel-inc557/558; HR, 1.45; 95% CI, 1.0-2.2; P = 0.004]. Conversely, PDGFRA exon 18 mutations were indicators of better prognosis [HR, 0.23; 95% CI, 0.1-0.6; P = 0.002]. KITdel-inc557/558 were an adverse indicator only in GIST localized in the stomach (P < 0.001) but not in tumors with nongastric origin. In gastric GIST, all other mutations presented remarkably superior 5-year DFS.
  
  
  CONCLUSIONS
  In conclusion, tumor genotype is an independent molecular prognostic variable associated with gastric GIST and should be used for optimizing tailored adjuvant imatinib treatment.
authors.affiliation: Laboratory of Experimental Oncology and Department of General Medical Oncology, KU Leuven and University Hospitals in Leuven, Leuven, Belgium.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wozniak
authors.affiliation: Department of Soft Tissue/Bone Sarcoma and Melanoma, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Rutkowski
authors.affiliation: Laboratory of Experimental Oncology and Department of General Medical Oncology, KU Leuven and University Hospitals in Leuven, Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.affiliation: Department of Medical Oncology, Centre Léon Bérard, Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.affiliation: Department of Biopathology, Institut Bergonié; INSERMU916 and University Victor Segalen, Bordeaux, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hostein
authors.affiliation: Institute of Pathology, University Hospital Goettingen, Goettingen, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Schildhaus
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: Axel
authors.initials: A
authors.lastname: Le Cesne
authors.affiliation: Department of Soft Tissue/Bone Sarcoma and Melanoma, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Bylina
authors.affiliation: Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Limon
authors.affiliation: Department of Medical Oncology, Centre Léon Bérard, Lyon, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.affiliation: Department of Molecular and Translational Oncology, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Janusz A
authors.initials: JA
authors.lastname: Siedlecki
authors.affiliation: Gerhard Domagk Institute of Pathology, University Hospital Muenster, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Wardelmann
authors.affiliation: Department of Pathology, KU Leuven and University Hospitals in Leuven, Leuven, Belgium.
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.affiliation: Department of Biopathology, Institut Bergonié; INSERMU916 and University Victor Segalen, Bordeaux, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Coindre
authors.affiliation: Department of Human Genetics, KU Leuven and University Hospitals in Leuven, Leuven, Belgium. maria.debiec-rychter@med.kuleuven.be.
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
mesh_terms: D000328:Adult; D000368:Aged; D005060:Europe; D005091:Exons; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D012042:Registries; D047368:Tumor Burden
chemical_list: D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha