Hirota Seiichi, Isozaki Koji
Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan.
Pathol Int. 2006 Jan;56(1):1-9. doi: 10.1111/j.1440-1827.2006.01924.x.
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the gastrointestinal tract. It was found that most GIST expressed KIT, a receptor tyrosine kinase encoded by protooncogene c-kit. In normal gastrointestinal wall, KIT is expressed by interstitial cells of Cajal (ICC), which are a pacemaker for autonomous gastrointestinal movement. Because both GIST and ICC are double-positive for KIT and CD34, and because familial and multiple GIST appear to develop from diffuse hyperplasia of ICC, GIST are considered to originate from ICC or their precursor cells. It was also found that approximately 90% of the sporadic GIST have somatic gain-of-function mutations of the c-kit gene, and that the patients with familial and multiple GIST have germline gain-of-function mutations of the c-kit gene. These facts strongly suggest that the c-kit gene mutations are a cause of GIST. Approximately half of the sporadic GIST without c-kit gene mutations were demonstrated to have gain-of-function mutations in platelet-derived growth factor receptor-alpha (PDGFRA) gene that encodes another receptor tyrosine kinase. Because KIT is immunohistochemically negative in a minority of GIST, especially in PDGFRA gene mutation-harboring GIST, mutational analyses of c-kit and PDGFRA genes may be required to diagnose such GIST definitely. Imatinib mesylate was developed as a selective tyrosine kinase inhibitor. It inhibits constitutive activation of mutated KIT and PDGFRA, and is now being used for KIT-positive metastatic or unresectable GIST as a molecular target drug. Confirmation of KIT expression by immunohistochemistry is necessary for application of the drug. The effect of imatinib mesylate is different in various types of c-kit and PDGFRA gene mutations, and the secondary resistance against imatinib mesylate is often acquired by the second mutation of the identical genes. Mutational analyses of c-kit and PDGFRA genes are also significant for prediction of effectiveness of drugs including newly developed agents.
胃肠道间质瘤（GIST）是胃肠道最常见的间叶组织肿瘤。研究发现，大多数GIST表达KIT，它是原癌基因c-kit编码的一种受体酪氨酸激酶。在正常胃肠道壁中，KIT由 Cajal间质细胞（ICC）表达，ICC是胃肠道自主运动的起搏细胞。由于GIST和ICC均为KIT和CD34双阳性，且家族性和多发性GIST似乎由ICC弥漫性增生发展而来，因此GIST被认为起源于ICC或其前体细胞。还发现，约90%的散发性GIST存在c-kit基因的体细胞功能获得性突变，而家族性和多发性GIST患者存在c-kit基因的种系功能获得性突变。这些事实有力地表明，c-kit基因突变是GIST的病因。约一半无c-kit基因突变的散发性GIST被证实存在血小板衍生生长因子受体α（PDGFRA）基因的功能获得性突变，该基因编码另一种受体酪氨酸激酶。由于少数GIST，尤其是携带PDGFRA基因突变的GIST，KIT免疫组化呈阴性，因此可能需要对c-kit和PDGFRA基因进行突变分析以明确诊断此类GIST。甲磺酸伊马替尼是作为一种选择性酪氨酸激酶抑制剂开发的。它抑制突变型KIT和PDGFRA的组成性激活，目前作为分子靶向药物用于KIT阳性的转移性或不可切除的GIST。应用该药物需要通过免疫组化确认KIT表达。甲磺酸伊马替尼在不同类型的c-kit和PDGFRA基因突变中的效果不同，对甲磺酸伊马替尼的继发性耐药通常由相同基因的第二次突变获得。c-kit和PDGFRA基因的突变分析对于预测包括新开发药物在内的药物疗效也具有重要意义。
