Originally published as JCO Early Release 10.1200/JCO.2005.02.093 on November 15 2004

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KIT and Platelet-Derived Growth Factor Receptor Alpha Tyrosine Kinase Gene Mutations and KIT Amplifications in Human Solid Tumors

From the Departments of Oncology and Pathology, Helsinki University Central Hospital, Helsinki; and Department of Oncology, Tampere University Hospital, Tampere, Finland

Address reprint requests to Heikki Joensuu, MD, Department of Oncology, Helsinki University Central Hospital, Haartmaninkatu 4, PO Box 180, FIN-00029 Helsinki, Finland; e-mail: heikki.joensuu{at}hus.fi

PURPOSE: Mutated KIT and platelet-derived growth factor receptor alpha (PDGFR) 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.

MATERIALS AND 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.

CONCLUSION: 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.

Supported by grants from the Cancer Society of Finland, Foundation for the Finnish Cancer Institute, Helsinki University Research Grants, and the Sigrid Juselius Foundation.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

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