| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Research Abstract |
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
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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
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