Chilton-Macneill Susan, Ho Michael, Hawkins Cynthia, Gassas Adam, Zielenska Maria, Baruchel Sylvain
Department of Pediatric Laboratory Medicine, Hospital for Sick Children, 555 University Avenue, M5G 1X8, Toronto, ON, Canada.
Pediatr Dev Pathol. 2004 Sep-Oct;7(5):493-8. doi: 10.1007/s10024-004-1116-7. Epub 2004 Jul 30.
The proto-oncogene c-kit is a receptor tyrosine kinase recognized to initiate essential signal transduction pathways that transmit biological signals for cellular proliferation, differentiation, and metastasis. Aberrant expression or mutation of c-kit has been shown to be involved in the pathogenesis of many cancers. Studies using imatinib mesylate (STI 571, Gleevec, Novartis, East Hannover, NJ, USA), an inhibitor of the tyrosine kinases brc-abl, c-kit, and PDGFR, have shown significant response in patients with chronic myelogenous leukemia and gastrointestinal stromal tumor. With the aim of identifying additional groups of tumors that may use the stem cell factor/c-kit pathway and, secondarily, may be responsive to imatinib mesylate treatment, we looked at the expression of c-kit in medulloblastoma. Medulloblastoma, a highly invasive primitive neuroectodermal tumor of the cerebellum, is the most common, malignant central nervous system tumor of childhood. Histologic features of medulloblastoma have failed to provide an accurate prediction of the clinical-biological behavior of these tumors. Characterizing the genetic events that play a role in the biology of these tumors may allow for molecular sub-typing and could lead to the development of novel therapeutic strategies. This study evaluated c-kit expression and mutational status in 10 medulloblastoma tumor samples. All 10 medulloblastoma tumors expressed c-kit by reverse transcriptase-polymerase chain reaction and 9 by immunohistochemical analysis. All tumor samples were screened for mutations in exons 9, 11, and 13 of the c-kit gene by direct sequencing. No sequence abnormalities were detected in these exons. These experiments lead us to the conclusion that c-kit activation in medulloblastoma is independent of mutation.
原癌基因c-kit是一种受体酪氨酸激酶，已知其可启动重要的信号转导通路，该通路能传递细胞增殖、分化和转移的生物学信号。c-kit的异常表达或突变已被证明与多种癌症的发病机制有关。使用甲磺酸伊马替尼（STI 571、格列卫，诺华公司，美国新泽西州东哈嫩）进行的研究表明，该酪氨酸激酶抑制剂对bcr-abl、c-kit和PDGFR具有显著疗效，对慢性粒细胞白血病和胃肠道间质瘤患者有明显反应。为了确定可能利用干细胞因子/c-kit通路且可能对甲磺酸伊马替尼治疗有反应的其他肿瘤群体，我们研究了髓母细胞瘤中c-kit的表达。髓母细胞瘤是小脑的一种高度侵袭性的原始神经外胚层肿瘤，是儿童最常见的恶性中枢神经系统肿瘤。髓母细胞瘤的组织学特征未能准确预测这些肿瘤的临床生物学行为。确定在这些肿瘤生物学中起作用的遗传事件可能有助于分子亚型分类，并可能导致新治疗策略的开发。本研究评估了10个髓母细胞瘤肿瘤样本中c-kit的表达和突变状态。通过逆转录聚合酶链反应，所有10个髓母细胞瘤肿瘤均表达c-kit，免疫组织化学分析显示9个表达。通过直接测序对所有肿瘤样本进行c-kit基因外显子9、11和13的突变筛查。在这些外显子中未检测到序列异常。这些实验使我们得出结论，髓母细胞瘤中c-kit的激活与突变无关。
