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(American Journal of Pathology. 2000;157:1581-1585.)
© 2000 American Society for Investigative Pathology

Regular Articles

Germline-Activating Mutation in the Kinase Domain of KIT Gene in Familial Gastrointestinal Stromal Tumors

Koji Isozaki^*, Benoit Terris, Jacques Belghiti, Serge Schiffmann^*, Seiichi Hirota^§ and Jean-Marie Vanderwinden^*

From the Laboratoire de Neurophysiologie,^*
Faculté de Médecine, Université Libre de Bruxelles, Brussels, Belgium; the Service d’Anatomie Pathologique
and the Service de Chirurgie Digestive,
Hôpital Beaujon, Clichy, France; and the Department of Pathology,^§
Osaka University Graduate School of Medicine, Osaka, Japan

The proto-oncogene KIT encodes the receptor tyrosine kinase KIT. Gain-of-function mutations in the juxtamembrane domain of KIT have been reported in human gastrointestinal stromal tumors. In a family with multiple gastrointestinal stromal tumors and diffuse hyperplasia of myenteric plexus layer, we have identified another mutation of KIT, a single base mutation, resulting in the substitution of Glu for Lys⁶⁴² in the kinase I domain, and studied its biological effect in a cellular system. The mouse homologue of the human KIT mutant was generated by site-directed mutagenesis and stably transfected into the interleukin-3-dependent Ba/F3 murine cell line. The oncogenic potential of the mutated KIT was assessed in vitro by a proliferation assay and in vivo by transplantation into nude mice. Transfected Ba/F3 cells grew autonomously in absence of growth factors and formed tumors in nude mice. Substitution of Glu for Lys⁶⁴² is an oncogenic mutation in the tyrosine kinase domain of KIT. As germline heterozygous mutation, it causes a diffuse hyperplasia of myenteric interstitial cells of Cajal during embryonic development and occurrence of multiple gastrointestinal stromal tumors at adulthood.

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