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From the Departments of Pathology (J.Y., H.D., M.A.W., R.N.) and Neurology (R.J.G., R.J.E., D.H.G.), Washington University School of Medicine, St. Louis, MO; and Department of Laboratory Medicine and Pathology (F.J.R.), Mayo Clinic Foundation, Rochester, MN.
Address correspondence and reprint requests to Dr. David H. Gutmann, Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, Saint Louis, MO 63110 gutmannd{at}neuro.wustl.edu
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.
Abbreviations: aCGH = array comparative genomic hybridization; GBM = glioblastoma multiforme; NF1 = neurofibromatosis type 1; PA = pilocytic astrocytoma.
Supplemental data at www.neurology.org
e-Pub ahead of print on September 30, 2009, at www.neurology.org.
Supported by funding from the Brain Tumor Society to D.H.G. The Alvin J. Siteman Cancer Center at the Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, MO, provided the Tissue Procurement Core, Multiplexed Gene Analysis Core, and Bioinformatics Core, which provided support for the microarray and mutation profiling analyses. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant (P30 CA91842).
Disclosure: Author disclosures are provided at the end of the article.
Received March 31, 2009. Accepted in final form July 17, 2009.
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Neurology 2009 73: 1522-1523.
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  S. L. Pomeroy Pathologic intracellular signaling in childhood pilocytic astrocytomas Neurology, November 10, 2009; 73(19): 1522 - 1523. [Full Text] [PDF]
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