The proto-oncogene c-KIT encodes a growth factor receptor, KIT, with ligand-dependent tyrosine kinase activity that is expressed by several cell types including mast cells. c-KIT juxtamembrane coding region mutations causing constitutive activation of KIT are capable of transforming cell lines and have been identified in a human mast cell line and in situ in human gastrointestinal stromal tumors, but have not been demonstrated in situ in neoplastic mast cells from any species.
To better define the frequency and spectrum of c-kit gene mutations in mesenchymal neoplasms of the GI tract that had been characterized for KIT protein expression, we examined archived tissue samples 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%).
Co-expression of KIT or CD34, which is also expressed in GIST and ICCs, was demonstrated in 18 (100%) and 16 SMemb-positive tumors (89%), respectively.
C-kit gene mutations in GIST are not always related to a poor prognosis, but further comparative studies are necessary in Western and Japanese populations.
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 Lys(642) in the kinase I domain, and studied its biological effect in a cellular system.
Activating mutations in the tyrosine kinase or juxtamembrane domains of c-kit gene have been found in mastocytoma, seminoma, and gastrointestinal stromal tumors.
These results show that KIT-positive GISTs are more common than LMSs of the colon, and these tumor groups have clinicopathologic differences that warrant their separation.