Malignant
astrocytomas are a deadly solid
tumor in children. Limited understanding of their underlying genetic basis has contributed to modest progress in developing more effective
therapies. In an effort to identify such alterations, we performed a genome-wide search for
DNA copy number aberrations (CNA) in a panel of 33
tumors encompassing grade 1 through grade 4
tumors. Genomic amplifications of 10-fold or greater were restricted to grade 3 and 4
astrocytomas and included the MDM4 (1q32), PDGFRA (4q12), MET (7q21), CMYC (8q24), PVT1 (8q24), WNT5B (12p13), and IGF1R (15q26) genes. Homozygous deletions of CDKN2A (9p21), PTEN (10q26), and TP53 (17p3.1) were evident among grade 2 to 4
tumors. BRAF gene rearrangements that were indicated in three
tumors prompted the discovery of KIAA1549-BRAF fusion transcripts expressed in 10 of 10 grade 1
astrocytomas and in none of the grade 2 to 4
tumors. In contrast, an oncogenic missense BRAF mutation (BRAF(V600E)) was detected in 7 of 31 grade 2 to 4
tumors but in none of the grade 1
tumors. BRAF(V600E) mutation seems to define a subset of malignant
astrocytomas in children, in which there is frequent concomitant homozygous deletion of CDKN2A (five of seven cases). Taken together, these findings highlight BRAF as a frequent mutation target in pediatric
astrocytomas, with distinct types of BRAF alteration occurring in grade 1 versus grade 2 to 4
tumors.