Objective: Independent studies have previously demonstrated that both the HIPK2 and BRAF genes are amplified and rearranged, respectively, in pilocytic astrocytomas (PAs). The purpose of this study was to further investigate the frequency of BRAF and HIPK2 alterations in PAs, the concordance of these events, and their relationship to clinical phenotype.
Methods: We performed extensive characterization by array-based copy number assessment (aCGH), HIPK2 copy number analysis, and BRAF rearrangement and mutation analysis in a set of 79 PAs, including 9 tumors from patients with neurofibromatosis type 1 (NF1).
Results: We identified 1 of 3 previously identified BRAF rearrangements in 42/70 sporadic PAs. An additional 2 tumors with no rearrangement also exhibited BRAF mutation, including a novel 3-base insertion. As predicted from the genomic organization at this locus, 22/36 tumors with BRAF rearrangement also exhibited corresponding HIPK2 amplification. However, 14/36 tumors with BRAF rearrangement had no detectable HIPK2 gene amplification and 6/20 tumors demonstrated HIPK2 amplification without apparent BRAF rearrangement or mutation. Only 12/70 PAs lacked detectable BRAF or HIPK2 alterations. Importantly, none of the 9 PA tumors from NF1 patients exhibited BRAF rearrangement or mutation.
Conclusions: BRAF rearrangement represents the most common genetic alteration in sporadic, but not neurofibromatosis type 1-associated, pilocytic astrocytomas (PAs). These findings implicate BRAF in the pathogenesis of these common low-grade astrocytomas in children, and suggest that PAs arise either from NF1 inactivation or BRAF gain of function.