Detection of a KRAS Mutation in a Pilocytic Astrocytoma

Pilocytic astrocytoma (PA) are the most common brain tumors of childhood. Apart from Neurofibromatosis type I (NF1) which is well known to be associated with PA, knowledge of the molecular etiology of PA is very limited. Patients with a mutation in the NF1 gene have a dysfunction of neurofibromin. Neurofibromin normally leads to a down-regulation of the Ras pathway due to a GAP domain (GTPase-activating protein-related domain). In patients with NF1 an increased activity of Ras can be measured. Further genetic diseases such as Noonan syndrome, LEOPARD syndrome, Cardio-Facio-Cutaneous syndrome, and Costello syndrome also go along with an activation of the ras pathway. Somatic mutations in the genes responsible for these syndromes (PTPN11, KRAS, BRAF, HRAS) are involved in the formation of malignoma.

Based on these observations we analyzed 25 PA for somatic mutations in the Ras pathway. Therefore we amplified the genomic DNA and screened for mutations in PTPN11, KRAS, HRAS, and NRAS by DHPLC (denaturing high performance liquid chromatography). Positive screening results were further investigated by DNA sequencing. In one of our DNA probes we detected the activating G12A mutation in the KRAS gene. The G12A mutation is regularly detected in colorectal carcinoma. Thus we provide the first evidence of a KRAS mutation in PA.

Our results underline the assumption that somatic mutations in different components of the Ras pathway predispose to the formation of PA. We plan to investigate further genes of the Ras pathway as well as a greater number of PAs.