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Comparative Study
. 2009 Nov 10;73(19):1526-31.
doi: 10.1212/WNL.0b013e3181c0664a. Epub 2009 Sep 30.

Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma

J Yu  1 , H Deshmukh, R J Gutmann, R J Emnett, F J Rodriguez, M A Watson, R Nagarajan, D H Gutmann
Affiliations
Comparative Study

Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma

J Yu et al. Neurology. .

Abstract

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.

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Figures

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Figure 1 Comparison of quantitative array comparative genomic hybridization (aCGH) analysis and HIPK2 amplification/BRAF rearrangement status in 20 sporadic pilocytic astrocytoma tumors The area intervening between the reported BRAF and KIAA1549 rearranged loci is shown. Gray bars indicate regions of HIPK2 and BRAF genes. Vertical lines demonstrate the extent of amplification in each tumor sample as determined by aCGH. Above, the BRAF fusion type and HIPK2 amplification status is noted. *Samples with no detectable molecular alteration at either gene locus.
None
Figure 2 Sequencing of BRAF in pilocytic astrocytomas (PA) (A) Coverage plot showing extent of double stranded sequence coverage of BRAF exons in 33 PA samples. (B) Three-nucleotide insertion detected in BRAF at amino acid residue 599. Sequence traces from forward and reverse strand are shown, along with resulting sequence and predicted reading frame.
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