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 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.
Lau
N
N
Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
Feldkamp
M M
MM
Roncari
L
L
Loehr
A H
AH
Shannon
P
P
Gutmann
D H
DH
Guha
A
A
D000328:Adult; D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D006801:Humans; D019656:Loss of Heterozygosity; D008279:Magnetic Resonance Imaging; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics*; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025542:Neurofibromin 1; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D020703:ras GTPase-Activating Proteins / Q000378:metabolism
D020928:Mitogen-Activated Protein Kinases; D009419:Nerve Tissue Proteins; D025542:Neurofibromin 1; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020703:ras GTPase-Activating Proteins; C494918:AKT1 protein, human