title: Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis.
abstract: Gastrointestinal stromal tumors (GISTs) are often associated with activating KIT mutations, affecting regulatory domains of the KIT tyrosine kinase. Sporadic mastocytosis in adults is usually also caused by KIT mutations that, however, activate KIT by affecting the intracellular enzymatic site of the molecule. Most GISTs respond to KIT inhibitors that bind to the enzymatic site; in most cases of mastocytosis, however, the modified enzymatic site is not affected by these drugs. We present a kindred with both familial GISTs and mastocytosis that express a novel germline KIT mutation in exon 8, resulting in deletion of codon 419 and affecting the extracellular domain of KIT. This mutation activates KIT, and the mutant KIT is inhibited by the tyrosine kinase inhibitor imatinib mesylate. Our studies identify a new regulatory region in the KIT molecule and strongly suggest that patients with extracellular KIT mutations respond to tyrosine kinase inhibitors.
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany. karin.hartmann@uni-koeln.de
authors.forename: Karin
authors.initials: K
authors.lastname: Hartmann
authors.forename: Eva
authors.initials: E
authors.lastname: Wardelmann
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Ma
authors.forename: Sabine
authors.initials: S
authors.lastname: Merkelbach-Bruse
authors.forename: Liane M
authors.initials: LM
authors.lastname: Preussner
authors.forename: Carla
authors.initials: C
authors.lastname: Woolery
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Baldus
authors.forename: Thomas
authors.initials: T
authors.lastname: Heinicke
authors.forename: Juergen
authors.initials: J
authors.lastname: Thiele
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
authors.forename: B Jack
authors.initials: BJ
authors.lastname: Longley
mesh_terms: D000328:Adult; D002648:Child; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000473:pathology; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008415:Mastocytosis / Q000235:genetics*; D008875:Middle Aged; D010375:Pedigree; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D019009:Proto-Oncogene Proteins c-kit