Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis.
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.
Hartmann
Karin
K
Department of Dermatology, University of Cologne, Cologne, Germany. karin.hartmann@uni-koeln.de
Wardelmann
Eva
E
Ma
Yongsheng
Y
Merkelbach-Bruse
Sabine
S
Preussner
Liane M
LM
Woolery
Carla
C
Baldus
Stephan E
SE
Heinicke
Thomas
T
Thiele
Juergen
J
Buettner
Reinhard
R
Longley
B Jack
BJ
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
D019009:Proto-Oncogene Proteins c-kit