Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas

• Published in: The Journal of pathology Vol. 218; no. 2; pp. 172 - 181
• Main Authors: Forshew, Tim, Tatevossian, Ruth G, Lawson, Andrew RJ, Ma, Jing, Neale, Geoff, Ogunkolade, Babatunji W, Jones, Tania A, Aarum, Johan, Dalton, James, Bailey, Simon, Chaplin, Tracy, Carter, Rowena L, Gajjar, Amar, Broniscer, Alberto, Young, Bryan D, Ellison, David W, Sheer, Denise
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-06-2009; Wiley
• Subjects: Adolescent; Adult; Astrocytoma; Astrocytoma - enzymology; Astrocytoma - genetics; Biological and medical sciences; BRAF; Brain Neoplasms - enzymology; Brain Neoplasms - genetics; Brain tumors; cerebellum; Child; Child, Preschool; copy number; DNA copy number; DNA Mutational Analysis; DNA, Complementary - analysis; Enzyme Activation; Extracellular signal-regulated kinase; Gene fusion; Glioma; GTPase-Activating Proteins - genetics; Humans; Infant; Investigative techniques, diagnostic techniques (general aspects); K-Ras protein; MAP kinase; MAP Kinase Signaling System - physiology; Medical sciences; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; Mutation; Neurology; Oncogene Proteins, Fusion - genetics; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Pediatrics; pilocytic; Polymerase chain reaction; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins c-raf - genetics; RAF1; Single-nucleotide polymorphism; Tumors; Tumors of the nervous system. Phacomatoses; Young Adult; Cerebellum; Extracellular signal-regulated protein kinase; Copy number; Central nervous system; Activation; Encephalon; BRAF Gene; gene fusion; Tumor; Genetics; Posterior fossa; Astrocytoma; Protooncogene; pilocytic; Nervous system diseases; Enzyme; Transferases; Mitogen-activated protein kinase; BRAF; Anatomic pathology; Glioma; DNA; C-Onc gene; DNA copy number; Central nervous system disease; RAF1
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2558

We report genetic aberrations that activate the ERK/MAP kinase pathway in 100% of posterior fossa pilocytic astrocytomas, with a high frequency of gene fusions between KIAA1549 and BRAF among these tumours. These fusions were identified from analysis of focal copy number gains at 7q34, detected using Affymetrix 250K and 6.0 SNP arrays. PCR and sequencing confirmed the presence of five KIAA1549–BRAF fusion variants, along with a single fusion between SRGAP3 and RAF1. The resulting fusion genes lack the auto‐inhibitory domains of BRAF and RAF1, which are replaced in‐frame by the beginning of KIAA1549 and SRGAP3, respectively, conferring constitutive kinase activity. An activating mutation of KRAS was identified in the single pilocytic astrocytoma without a BRAF or RAF1 fusion. Further fusions and activating mutations in BRAF were identified in 28% of grade II astrocytomas, highlighting the importance of the ERK/MAP kinase pathway in the development of paediatric low‐grade gliomas. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.