Role of the c-kit tyrosine kinase in the genesis of gastrointestinal stromal tumors.

胃肠道间质瘤（GIST）的病因和细胞来源尚不清楚，对5例GIST的c-KIT互补DNA进行测序发现，所有相应的突变型KIT蛋白在没有KIT配体的情况下都被组成性激活，稳定转染突变型c-myc互补DNA可诱导Ba/myc细胞恶性转化，由于Cajal间质细胞（interstitial cells of Cajal，ICCs）的发育依赖于SCF与KIT的相互作用，并且由于GIST和ICCs均表达KIT和CD 34，因此GIST可能起源于ICCs。其中多个家系成员患有多发性GIST及相关症状，多发性GIST家系成员均表现出相同的膜结构域的c-SNP突变，该家系的c-SNP突变不仅见于GIST，也见于白细胞，因此，家族性GIST似乎是一种癌症综合征。接下来，我们研究了c-GST突变的存在与GIST预后之间的关系。分析了124例GIST患者。大多数GIST（89%）表达c-GST突变。在124例GIST中，有71例突变阳性（+）GIST的肿瘤体积较大，侵犯癌旁组织的频率较高。突变（+）GIST细胞核分裂相增多，坏死和出血增多，突变（+）GIST细胞核分裂相增多，坏死和出血增多，突变（+）GIST细胞核分裂相增多，坏死和出血增多。GIST的复发率和死亡率均高于突变（-）GIST，c-GST突变是影响GIST患者总体和病因特异性生存率的独立预后因素。

The etiology and cellular origin of gastrointestinal stroma tumors (GISTs) are unknown.Sequencing of c-kil complementary DNA from five GISTs revealed mutations in the juxtamembrane domain.All corresponding mutant KIT proteins were constitutively activated without KIT ligand, the stem cell factor (SCF).Stable transfection of the mutant c-kil complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells.Because the development of the interstitial cells of Cajal (ICCs) is dependent on the SCF-KlT interaction and because both GISTs and ICCs express KIT and CD 34, GISTs may originate from the ICCs.We have found a family with multiple GISTs, of which many family members suffered from multiple GISTs and related symptoms.The family members with multiple GISTs showed the same c-kil mutation in the juxtamembrance domain.The c-kil mutation of this family was detected not only in GISTs but also in leukocytes, thus, familial GISTs appeared to be a cancer syndrome.Next we examined the correlation between the presence of c-kil mutation and the prognosis of GISTs.One hundred and twenty four patients with GIST were analyzed.Most GISTs (89%) express the c-kil protein, and missense mutations of exon 11 were found in 71 out of 124 GISTs.These 71 mutation-positive (+) GISTs were larger in size and invaded more frequently to adjacent tissues compared with the 53 mutation-negative (-) GISTs.Histologically, the mutation (+) GISTs showed higher mitotic figures and more necrosis and hemorrhage.The patients with mutation (+) GISTs showed more frequent recurrences and higher mortality than those with mutation (-) GISTs.The c-kil mutation was an independent prognostic factor for overall and cause-specific survival of the patients with GISTs.