Hotspot Mutations in H3F3A and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma

Dominik Sturm, Hendrik Witt, Volker Hovestadt, Dong Anh Khuong-Quang, David T.W. Jones, Carolin Konermann, Elke Pfaff, Martje Tönjes, Martin Sill, Sebastian Bender, Marcel Kool, Marc Zapatka, Natalia Becker, Manuela Zucknick, Thomas Hielscher, Xiao Yang Liu, Adam M. Fontebasso, Marina Ryzhova, Steffen Albrecht, Karine JacobMarietta Wolter, Martin Ebinger, Martin U. Schuhmann, Timothy van Meter, Michael C. Frühwald, Holger Hauch, Arnulf Pekrun, Bernhard Radlwimmer, Tim Niehues, Gregor Von Komorowski, Matthias Dürken, Andreas E. Kulozik, Jenny Madden, Andrew Donson, Nicholas K. Foreman, Rachid Drissi, Maryam Fouladi, Wolfram Scheurlen, Andreas von Deimling, Camelia Monoranu, Wolfgang Roggendorf, Christel Herold-Mende, Andreas Unterberg, Christof M. Kramm, Jörg Felsberg, Christian Hartmann, Benedikt Wiestler, Wolfgang Wick, Till Milde, Olaf Witt, Anders M. Lindroth, Jeremy Schwartzentruber, Damien Faury, Adam Fleming, Magdalena Zakrzewska, Pawel P. Liberski, Krzysztof Zakrzewski, Peter Hauser, Miklos Garami, Almos Klekner, Laszlo Bognar, Sorana Morrissy, Florence Cavalli, Michael D. Taylor, Peter van Sluis, Jan Koster, Rogier Versteeg, Richard Volckmann, Tom Mikkelsen, Kenneth Aldape, Guido Reifenberger, V. Peter Collins, Jacek Majewski, Andrey Korshunov, Peter Lichter, Christoph Plass, Nada Jabado, Stefan M. Pfister

Research output: Contribution to journalArticle

930 Citations (Scopus)

Abstract

Glioblastoma (GBM) is a brain tumor that carries a dismal prognosis and displays considerable heterogeneity. We have recently identified recurrent H3F3A mutations affecting two critical amino acids (K27 and G34) of histone H3.3 in one-third of pediatric GBM. Here, we show that each H3F3A mutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern, and that they are mutually exclusive with IDH1 mutations, which characterize a third mutation-defined subgroup. Three further epigenetic subgroups were enriched for hallmark genetic events of adult GBM and/or established transcriptomic signatures. We also demonstrate that the two H3F3A mutations give rise to GBMs in separate anatomic compartments, with differential regulation of transcription factors OLIG1, OLIG2, and FOXG1, possibly reflecting different cellular origins.

Original languageEnglish
Pages (from-to)425-437
Number of pages13
JournalCancer Cell
Volume22
Issue number4
DOIs
Publication statusPublished - Oct 16 2012

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Sturm, D., Witt, H., Hovestadt, V., Khuong-Quang, D. A., Jones, D. T. W., Konermann, C., Pfaff, E., Tönjes, M., Sill, M., Bender, S., Kool, M., Zapatka, M., Becker, N., Zucknick, M., Hielscher, T., Liu, X. Y., Fontebasso, A. M., Ryzhova, M., Albrecht, S., ... Pfister, S. M. (2012). Hotspot Mutations in H3F3A and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma. Cancer Cell, 22(4), 425-437. https://doi.org/10.1016/j.ccr.2012.08.024