RAS pathway activation and an oncogenic RAS mutation in sporadic pilocytic astrocytoma

Pilocytic astrocytoma (PA) is the second most common brain tumor found in children, but compared to fibrillary astrocytoma, comparatively less is known about the molecular events associated with its formation and progression. Some insights have derived from the observation that one-third of these tumors arise in children with the neurofibromatosis 1 (NF1) inherited tumor predisposition syndrome, implicating the NF1 gene in the molecular pathogenesis of PA.¹ The NF1 gene encodes a protein (neurofibromin) that functions as a RAS inhibitor, such that NF1 inactivation in tumors results in high levels of activated RAS and increased cell growth. However, sporadic PAs lack NF1 gene mutations and do not demonstrate loss of neurofibromin expression.²

In patients with myeloid leukemia,^3,4 tumor cells exhibit NF1 inactivation, mutational RAS activation, or mutational activation of a positive RAS regulator (PTPN11), all of which result in high levels of RAS activity (figure, A). In this report, we demonstrate RAS pathway hyperactivation in sporadic PA, and in a subsequent analysis for potential RAS and PTPN11 mutational activation in the absence of NF1 loss, we identify an oncogenic RAS mutation in one sporadic PA.