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

@article{citeulike:5414086, abstract = {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 {\copyright} 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley \& Sons, Ltd.}, address = {Neuroscience Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Institute of Cell and Molecular Science, Turner Street, London E1 2AD, UK; Cancer Research UK London Research Institute, London WC2A 3PX, UK; Hartwell Center for Bioinformatics and Biotechnology, St Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Pathology, St Jude Children's Research Hospital, Memphis, TN 38105, USA; Sir James Spence Institute of Child Health, Royal Victoria Infirmary, Newcastle upon Tyne, UK; Cancer Genomics Unit, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA}, author = {Forshew, Tim and Tatevossian, Ruth G. and Lawson, Andrew R. J. and Ma, Jing and Neale, Geoff and Ogunkolade, Babatunji W. and Jones, Tania A. and Aarum, Johan and Dalton, James and Bailey, Simon and Chaplin, Tracy and Carter, Rowena L. and Gajjar, Amar and Broniscer, Alberto and Young, Bryan D. and Ellison, David W. and Sheer, Denise}, citeulike-article-id = {5414086}, citeulike-linkout-0 = {http://dx.doi.org/10.1002/path.2558}, citeulike-linkout-1 = {http://www3.interscience.wiley.com/cgi-bin/abstract/122268352/ABSTRACT}, doi = {10.1002/path.2558}, issn = {1096-9896}, journal = {The Journal of Pathology}, keywords = {astrocytoom, braf, erk, neuropathologie, pilocytair\_astrocytoom}, number = {2}, pages = {172--181}, posted-at = {2009-08-11 07:20:40}, priority = {2}, title = {Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas}, url = {http://dx.doi.org/10.1002/path.2558}, volume = {218}, year = {2009} }

TY - JOUR ID - citeulike:5414086 L3 - citeulike-article-id:5414086 N2 - 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. IS - 2 JF - The Journal of Pathology SN - 1096-9896 AD - Neuroscience Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Institute of Cell and Molecular Science, Turner Street, London E1 2AD, UK; Cancer Research UK London Research Institute, London WC2A 3PX, UK; Hartwell Center for Bioinformatics and Biotechnology, St Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Pathology, St Jude Children's Research Hospital, Memphis, TN 38105, USA; Sir James Spence Institute of Child Health, Royal Victoria Infirmary, Newcastle upon Tyne, UK; Cancer Genomics Unit, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA EP - 181 TI - Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas VL - 218 SP - 172 KW - astrocytoom KW - braf KW - erk KW - neuropathologie KW - pilocytair_astrocytoom AU - Forshew, Tim AU - Tatevossian, Ruth AU - Lawson, Andrew AU - Ma, Jing AU - Neale, Geoff AU - Ogunkolade, Babatunji AU - Jones, Tania AU - Aarum, Johan AU - Dalton, James AU - Bailey, Simon AU - Chaplin, Tracy AU - Carter, Rowena AU - Gajjar, Amar AU - Broniscer, Alberto AU - Young, Bryan AU - Ellison, David AU - Sheer, Denise PY - 2009/// UR - http://dx.doi.org/10.1002/path.2558 ER -