title: KIT and platelet-derived growth factor receptor alpha tyrosine kinase gene mutations and KIT amplifications in human solid tumors.
abstract: OBJECTIVE
  Mutated KIT and platelet-derived growth factor receptor alpha (PDGFRalpha) tyrosine kinases are the principal targets for imatinib mesylate in the treatment of gastrointestinal stromal tumors (GISTs). The frequency of activating KIT and PDGFRA gene mutations in most other histologic types of human cancer is not known.
  
  
  METHODS
  KIT exons 9, 11, 13, and 17 and PDGFRA exons 11 and 17 of 334 human cancers were screened for mutations using sensitive denaturing high-performance liquid chromatography (DHPLC). In addition, all KIT exons from 9 to 21 of 115 tumors were screened. Thirty-two histologic tumor types were examined. Samples with abnormal findings in DHLPC were sequenced. Immunostaining for the KIT protein (CD117) was performed in 322 (96.4%) of the 334 cases.
  
  
  RESULTS
  Of the 3,039 exons screened, only 17 had mutation. All 17 cases with either mutated KIT (n = 15) or PDGFRA (n = 2) were histologically GIST tumors, whereas none of the other histologic types of cancer (n = 316) harbored KIT or PDGFRA mutation. KIT immunostaining was rarely positive except in GISTs (18 of 18), small-cell lung cancer (10 of 30; 33%), and testicular teratocarcinoma (four of 17; 24%). Wild-type KIT gene amplification or chromosome 4 aneuploidy was common (seven of 12) in non-GIST tumors with strong KIT protein expression when studied with fluorescence in situ hybridization.
  
  
  CONCLUSIONS
  Despite frequent KIT protein expression in some tumor types, KIT and PDGFRA gene mutations are uncommon in most human cancers. Cancer KIT expression is frequently associated with multiple copies of the wild-type KIT gene.
authors.affiliation: Department of Oncology, Helsinki University Central Hospital, Haartmaninkatu 4, PO Box 180, FIN-00029 Helsinki, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Sihto
authors.forename: Maarit
authors.initials: M
authors.lastname: Sarlomo-Rikala
authors.forename: Olli
authors.initials: O
authors.lastname: Tynninen
authors.forename: Minna
authors.initials: M
authors.lastname: Tanner
authors.forename: Leif C
authors.initials: LC
authors.lastname: Andersson
authors.forename: Kaarle
authors.initials: K
authors.lastname: Franssila
authors.forename: Nina N
authors.initials: NN
authors.lastname: Nupponen
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
mesh_terms: D000782:Aneuploidy; D018288:Carcinoma, Small Cell / Q000235:genetics; D002894:Chromosomes, Human, Pair 4; D005091:Exons; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009154:Mutation; D015513:Oncogene Proteins / Q000032:analysis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D018243:Teratocarcinoma / Q000235:genetics; D013736:Testicular Neoplasms / Q000235:genetics
chemical_list: D015513:Oncogene Proteins; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha