title: Molecular characterization of an Italian series of sporadic GISTs.
abstract: OBJECTIVE
  Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract. Most (80 %) contain activating mutations in the KIT receptor tyrosine kinase, roughly 10 % in platelet-derived growth factor receptor-alpha (PDGFRA). In a small subset, BRAF mutations are an alternative molecular pathway. GISTs respond well to imatinib, but low response is seen in patients with wild-type KIT or PDGFRA. Resistance has also been reported as a result of mutations in downstream effectors such as BRAF.
  
  
  METHODS
  We provide here a molecular characterization of a series of primary GISTs from Italian patients. Of 121 GIST cases diagnosed between 2000 and 2012, 83 were evaluated by PCR amplification and direct sequencing for mutations in KIT exons 8, 9, 11, 13, and 17, PDGFRA exons 12, 14, and 18, and BRAF exon 15. Eighty-one GISTs also underwent K-RAS testing.
  
  
  RESULTS
  Sixty-four GISTs were positive: 55 had mutations in KIT and 9 in PDGFRA; 16 patients were mutation negative. Three samples came from NF1 patients and were KIT- and PDGFRA negative. Overall, we identified six novel mutations in KIT (p.K550_M552delinsL, p.Q556_W557delinsG p.Q556_G575del, p.W557_V559delinsQ p.P573_R588dup, p.G592_K593dup) and one novel mutation in PDGFRA (p.D842_N848delinsVDV), thus contributing to widening the spectrum of known mutations in GIST tumors and confirming the most frequently altered regions underlying GIST development.
  
  
  CONCLUSIONS
  Among the 64 KIT- and PDGFRA-positive sporadic patients in our series, no BRAF or KRAS mutations were identified, suggesting that co-occurrence of these mutations is likely to be rare in the northwestern Italian population and not a frequent cause of primary resistance to imatinib in KIT-positive GIST patients.
authors.affiliation: Department of Internal Medicine, University of Genova, Viale Benedetto XV, 6, Genoa, Italy, origone@unige.it.
authors.forename: P
authors.initials: P
authors.lastname: Origone
authors.forename: S
authors.initials: S
authors.lastname: Gargiulo
authors.forename: L
authors.initials: L
authors.lastname: Mastracci
authors.forename: A
authors.initials: A
authors.lastname: Ballestrero
authors.forename: L
authors.initials: L
authors.lastname: Battistuzzi
authors.forename: C
authors.initials: C
authors.lastname: Casella
authors.forename: D
authors.initials: D
authors.lastname: Comandini
authors.forename: R
authors.initials: R
authors.lastname: Cusano
authors.forename: A P
authors.initials: AP
authors.lastname: Dei Tos
authors.forename: R
authors.initials: R
authors.lastname: Fiocca
authors.forename: A
authors.initials: A
authors.lastname: Garuti
authors.forename: P
authors.initials: P
authors.lastname: Ghiorzo
authors.forename: C
authors.initials: C
authors.lastname: Martinuzzi
authors.forename: L
authors.initials: L
authors.lastname: Toffolatti
authors.forename: G
authors.initials: G
authors.lastname: Bianchi Scarrà
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010879:Piperazines / Q000627:therapeutic use; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011743:Pyrimidines / Q000627:therapeutic use; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D012189:Retrospective Studies; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins