Mutations of c-kit JM domain are found in a minority of human gastrointestinal stromal tumors

The c-kit gene encodes a transmembrane receptor kinase (KIT) which is expre ssed in the majority of human gastrointestinal stromal tumors (GISTs), a su btype of gastrointestinal mesenchymal neoplasms. A previous study identifie d mutations in the juxtamembrane (JR I) domain of c-X-it in five of six GIS Ts (Science 279: 577, 1998), To better define the frequency and spectrum of c-kit gene mutations in mesenchymal neoplasms of the GI tract that had bee n characterized for KIT protein expression, we examined archived tissue sam ples for mutations in the JM domain by PCR amplification and DNA sequencing . c-kit JM domain mutations were found in nine of 56 mesenchymal tumors (46 GISTs, eight leiomyomas, two leiomyosarcomas) and occurred exclusively in GISTs (21%), Seven of the nine mutations consisted of intragenic deletions of one to 19 codons, There was one insertion mutation that added 12 codons and one missense mutation (Val560Asp), None of the mutations disrupted the downstream reading frame of the gene, The single missense mutation (Val560A sp) is very similar to the only other missense mutation reported in GISTs ( Val599Asp). Of the 46 GISTs, 43,were strongly positive for KIT protein expr ession and negative for diffuse expression of desmin, Neither KIT expressio n nor gene mutations,were found in gastrointestinal leiomyomas or leiomyosa rcomas. We conclude that mutation of the c-kit JM domain does not occur in gastrointestinal mesenchymal neoplasms,vith well developed-smooth muscle di fferentiation, and is restricted to GISTs, However, since these mutations a re only found in a minority of GISTs, further investigation into the mechan isms of c-kit gene activation in this group of neoplasms is warranted.