Lau N, Feldkamp M M, Roncari L, Loehr A H, Shannon P, Gutmann D H, Guha A
Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
J Neuropathol Exp Neurol. 2000 Sep;59(9):759-67. doi: 10.1093/jnen/59.9.759.
Neurofibromatosis 1 (NF1) is a common autosomal dominant cancer predisposition syndrome, in which 15% to 20% of affected individuals develop astrocytomas. Neurofibromin, the protein product of the NF1 gene, functions as a tumor suppressor, largely by inhibiting Ras activity. While loss of neurofibromin has been implicated in the molecular pathogenesis of other NF1-associated tumors, there is no formal evidence demonstrating loss of neurofibromin function in NF1-associated astrocytomas. In this report, we describe an NF1 patient from whom both astrocytoma tumor tissue as well as corresponding non-neoplastic white matter were available for analysis. Loss of neurofibromin expression was observed in the tumor and was associated with elevated levels of Ras-GTP. However, elevated Ras-GTP levels were not the result of oncogenic Ras mutations, altered p120-GAP function, growth factor receptor activation, or abnormal p53, Rb, or p16 expression. Furthermore, increased Raf-MAPK and PI3-K/Akt activity was detected in the NF1 astrocytoma compared with the corresponding normal white matter. These results support a role for neurofibromin as the critical GAP in the molecular pathogenesis of NF1 astrocytomas.
神经纤维瘤病1型（NF1）是一种常见的常染色体显性遗传性癌症易感综合征，其中15%至20%的患者会发生星形细胞瘤。神经纤维瘤蛋白是NF1基因的蛋白质产物，主要通过抑制Ras活性发挥肿瘤抑制作用。虽然神经纤维瘤蛋白的缺失与其他NF1相关肿瘤的分子发病机制有关，但尚无正式证据表明其在NF1相关星形细胞瘤中功能缺失。在本报告中，我们描述了一名NF1患者，其星形细胞瘤肿瘤组织以及相应的非肿瘤性白质均可用于分析。在肿瘤中观察到神经纤维瘤蛋白表达缺失，且与Ras-GTP水平升高相关。然而，Ras-GTP水平升高并非致癌性Ras突变、p120-GAP功能改变、生长因子受体激活或p53、Rb或p16表达异常所致。此外，与相应的正常白质相比，在NF1星形细胞瘤中检测到Raf-MAPK和PI3-K/Akt活性增加。这些结果支持神经纤维瘤蛋白在NF1星形细胞瘤分子发病机制中作为关键GAP的作用。
