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

c-kit原癌基因编码酪氨酸激酶受体，KIT受体及其配体是干细胞因子。我们发现在胃肠道间质瘤（gist）中经常观察到c-kit基因近膜结构域的功能获得性突变。由于gist和Cajal间质细胞（ICCs） c-kit和CD34双阳性，因此认为gist起源于ICCs。我们还发现了两个患有多发性胃肠道间质瘤的家庭。两家患者不仅在肿瘤组织中存在c-kit基因突变，而且在正常外周血白细胞或正常组织中也存在c-kit基因突变。因此，该突变被确定为种系突变。在单个家系中发现的突变各不相同，但都位于550 ~ 560密码子中，c-kit基因的突变在孤立gist中最常见。患者小肠肌丛层呈弥漫性梭形细胞增生。胃肠道间质瘤是最常见的胃肠道壁间质肿瘤，但常规的组织病理学方法难以鉴别其恶性和良性。我们研究了c-kit突变是否对GIST患者的预后有影响。c-kit突变患者的预后较无c-kit突变患者差。

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.