c-kit gene mutation is common and widely distributed in intracranial germinomas

目的：随着积极的多模式治疗的出现，颅内生殖细胞肿瘤（igct）得到了良好的控制；然而，10%的生殖细胞瘤和许多非生殖细胞瘤亚型仍然难以治疗。本研究的目的是研究酪氨酸激酶受体KIT在igct中的表达和遗传改变，其中甲磺酸伊马替尼分子靶向治疗已经开始或计划用于几种肿瘤。方法：连续26例igct患者，包括13例生殖细胞瘤、5例混合生殖细胞瘤、4例未成熟畸胎瘤、2例卵黄囊瘤和绒毛膜癌。在石蜡切片上进行KIT和CD34的免疫组化，并在PCR-SSCP预筛选或未预筛选的情况下，在2、8-11、13和17外显子进行c-kit突变分析。在igct和其他脑肿瘤的组织学亚型中，KIT在生殖细胞瘤（germinoma）、生殖细胞瘤（germinomas）和mgct （mgct）的细胞膜上表达较多（100%），在ITs的分化上皮细胞和平滑肌细胞的细胞质上表达较多（80%）。相比之下，CD34的膜性表达在mgct（60%）、ITs（100%）和绒毛膜癌（50%）的肿瘤细胞和非包膜瘤成分的软骨细胞中检测到，但在生殖细胞瘤细胞中未检测到。在3个生殖细胞瘤中共检测到5个c-kit错义突变（23%），它们分布在外显子2、11、13和17。在单个肿瘤中首次检测到E73K、T96M（均为外显子2）和A636V（外显子13）三个突变。c-kit突变与患者预后无相关性。结论：KIT免疫组化有助于对生殖细胞瘤的正确诊断。考虑到本研究采用的是低灵敏度方法，推测c-kit突变在生殖细胞瘤中的真实频率更高，分布范围更广。本研究有望有助于澄清生殖细胞瘤的发病机制和甲磺酸伊马替尼的未来临床应用。少

OBJECT : With the advent of aggressive multimodality therapy, intracranial germ cell tumors (IGCTs) are becoming favorably controlled ; however, 10% of the germinomas and many of the nongerminomatous subtypes remain refractory to therapy. The goal of this study was to investigate the expression and genetic alteration of the tyrosine kinase receptor, KIT, in IGCTs for which molecular targeting therapy with imatinib mesylate has been commenced or planned in several kinds of neoplasms. METHODS : Twenty-six consecutive IGCTs, including thirteen germinomas, five mixed germ cell tumors (MGCTs), four immature teratomas (ITs) and two each of yolk sac tumors (YSTs) and choriocarcinomas, were examined. Immunohistochemistry for KIT and CD34 was performed on paraffin sections and c-kit mutation analysis was accomplished in exons 2, 8-11, 13 and 17 with or without prescreening by PCR-SSCP. Among the histologic subtypes of IGCTs and other brain tumors, KIT was strongly expressed at the cell membrane … More of germinoma cells, germinomas (100%) and MGCTs (80%), and in the cytoplasm of differentiated epithelial and smooth muscle cells of ITs. In contrast, the membranous expression of CD34 was detected in the tumor cells and the chondrocytes of the nongerminomatous component of MGCTs (60%), ITs (100%) and choriocarcinoma (50%), but not in germinoma cells. A total of five missense mutations of c-kit were detected in three germinomas (23%) and they were distributed in exons 2, 11, 13 and 17. Three mutations, E73K, T96M (both exon 2) and A636V (exon 13), were detected for the first time in a single tumor. The c-kit mutations were not correlated with patient's prognosis. CONCLUSIONS : KIT immunohistochemistry is useful for the correct diagnosis of germinoma. Considering that low sensitivity methods were employed here, the real frequency and distribution of the c-kit mutation in germinomas are speculated to be higher and broader, respectively. This study is expected to contribute to the clarification of the pathogenesis of germinoma and the future clinical use of imatinib mesylate. Less