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Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas
Author(s) -
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
Publication year - 2009
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2558
Subject(s) - mapk/erk pathway , pilocytic astrocytoma , kras , fusion gene , cancer research , astrocytoma , biology , gene , kinase , medicine , mutation , genetics , glioma
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.