Relation between gain-of-function mutation of c-kit gene and development of GIST

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The c-kit protooncogene encodes a receptor tyrosine kinase, KIT receptor and its ligand is stem cell factor, SCF. We found that the gain-of-function mutations at juxtamembrane domain of c-kit gene were frequently observed in gastrointestinal stromal tumors (GISTs). Since GISTs and interstitial cells of Cajal (ICCs) are double-positive for c-kit and CD34, GISTs were considered to originate from ICCs. We also found two families with multiple GISTs. The patients of both families had mutations of c-kit gene not only in tumor tissues but also in normal peripheral blood leukocytes or normal tissues. Therefore, the mutation was determined to be a germline one. The mutations found in the individual families were different each other, but both located in codons 550 to 560 where the mutations of c-kit gene were frequently observed in solitary GISTs. Diffuse hyperplasia of spindle-shaped cells was observed in the myenteric plexus layer of small intestine of the patients.GISTs are the most popular mesenchymal tumor in the gastrointestinal wall, but the differential diagnosis between malignant GISTs and benign GISTs is difficult by conventional histopathological methods. We examined whether the c-kit mutation makes an effect on prognosis of GIST patients. The patients with c-kit mutation showed poorer prognosis than those without c-kit mutation did.