Loss of neurofibromin is associated with activation of Ras/MAPK and PI3-K/Akt signaling in a neurofibromatosis 1 astrocytoma

Neurofibromatosis 1 (NF1) is a common autosomal dominant cancer predisposit ion syndrome, in which 15% to 20% of affected individuals develop astrocyto mas. Neurofibromin, the protein product of the NF1 gene, functions as a tum or suppressor. largely by inhibiting Ras activity. While loss of neurofibro min has been implicated in the molecular pathogenesis of other NF1-associat ed 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 n on-neoplastic white matter were available for analysis. Loss of neurofibrom in expression was observed in the tumor and was associated with elevated le vels of Ras-GTP. However, elevated Ras-GTP levels were nor the result of on cogenic Ras mutations, altered p120-GAP function, growth factor receptor ac tivation, or abnormal p53, Rb, or p16 expression. Furthermore, increased Ra f-MAPK and PI3-K/Akt activity was detected in the NF1 astrocytoma compared with the corresponding normal white matter. These results support a role fo r neurofibromin as the critical GAP in the molecular pathogenesis of NF1 as trocytomas.