Brain tumors are the most common solid tumors of childhood, and pilocytic astrocytomas (PA) are the most common central nervous system tumor in 5 to 19 year olds. Little is known about the genetic alterations underlying their development. Here, we describe a tandem duplication of f2 Mb at 7q34 occurring in 66% of PAs. This rearrangement, which was not observed in a series of 244 higher-grade astrocytomas, results in an in-frame fusion gene incorporating the kinase domain of the BRAF oncogene. We further show that the resulting fusion protein has constitutive BRAF kinase activity and is able to transform NIH3T3 cells. This is the first report of BRAF activation through rearrangement as a frequent feature in a sporadic tumor. The frequency and specificity of this change underline its potential both as a therapeutic target and as a diagnostic tool. [Cancer Res 2008;68(21):8673-7]

We screened exon 4 of the gene isocitrate dehydrogenase 1 (NADP+), soluble (IDH1) for mutations in 596 primary intracranial tumors of all major types. Codon 132 mutation was seen in 54% of astrocytomas and 65% of oligodendroglial tumors but in only 6% of glioblastomas (3% of primary and 50% of secondary glioblastomas). There were no mutations in any other type of tumor studied. While mutations in the tumor protein p53 gene (TP53) and total 1p/19q deletions were mutually exclusive, IDH1 mutations were strongly correlated with these genetic abnormalities. All four types of mutant IDH1 proteins showed decreased enzymatic activity. The data indicate that IDH1 mutation combined with either TP53 mutation or total 1p/19q loss is a frequent and early change in the majority of oligodendroglial tumors, diffuse astrocytomas, anaplastic astrocytomas, and secondary glioblastomas but not in primary glioblastomas.