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 Jacob; Marietta 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

doi:10.1016/j.ccr.2012.08.024

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

Pathology

Research output: Contribution to journal › Article › peer-review

1398 Scopus citations

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 language	English (US)
Pages (from-to)	425-437
Number of pages	13
Journal	Cancer cell
Volume	22
Issue number	4
DOIs	https://doi.org/10.1016/j.ccr.2012.08.024
State	Published - 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

Sturm, D, Witt, H, Hovestadt, V, Khuong-Quang, DA, Jones, DTW, Konermann, C, Pfaff, E, Tönjes, M, Sill, M, Bender, S, Kool, M, Zapatka, M, Becker, N, Zucknick, M, Hielscher, T, Liu, XY, Fontebasso, AM, Ryzhova, M, Albrecht, S, Jacob, K, Wolter, M, Ebinger, M, Schuhmann, MU, van Meter, T, Frühwald, MC, Hauch, H, Pekrun, A, Radlwimmer, B, Niehues, T, Von Komorowski, G, Dürken, M, Kulozik, AE, Madden, J, Donson, A, Foreman, NK, Drissi, R, Fouladi, M, Scheurlen, W, von Deimling, A, Monoranu, C, Roggendorf, W, Herold-Mende, C, Unterberg, A, Kramm, CM, Felsberg, J, Hartmann, C, Wiestler, B, Wick, W, Milde, T, Witt, O, Lindroth, AM, Schwartzentruber, J, Faury, D, Fleming, A, Zakrzewska, M, Liberski, PP, Zakrzewski, K, Hauser, P, Garami, M, Klekner, A, Bognar, L, Morrissy, S, Cavalli, F, Taylor, MD, van Sluis, P, Koster, J, Versteeg, R, Volckmann, R, Mikkelsen, T, Aldape, K, Reifenberger, G, Collins, VP, Majewski, J, Korshunov, A, Lichter, P, Plass, C, Jabado, N & Pfister, SM 2012, 'Hotspot Mutations in H3F3A and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma', Cancer cell, vol. 22, no. 4, pp. 425-437. https://doi.org/10.1016/j.ccr.2012.08.024

@article{044818da2bd94378a1a59d9eac8409b1,

title = "Hotspot Mutations in H3F3A and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma",

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.",

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

note = "Funding Information: We thank Andrea Wittmann and Laura Sieber from the Division of Pediatric Neurooncology at the DKFZ for excellent technical support and Matthias Schick and Roger Fischer from the DKFZ Genomics and Proteomics Core Facility for performing the microarray analyses to a very high standard. We also acknowledge the outstanding technical assistance of Hannelore Schraut (University of W{\"u}rzburg) and Leonore Senf (N{\"u}rnberg Children{\textquoteright}s Hospital). The project was supported by grants from the German Cancer Aid (109252 and 108456); the BMBF (to A.K., B.R., O.W., P.L., S.M.P., G.R., and J.F.; ICGC PedBrain, NGFN Plus #01GS0883); Koningin Wilhelmina Fonds (UvA-2010-4713) and KIKA (to M.K.); the Cole Foundation; the Canadian Institute of Health Research; the Institute of Cancer Research, G{\'e}nome Canada and G{\'e}nome Quebec (to N.J.); and the Alfred-M{\"u}ller Award for Neuro-Oncology to S.M.P. ",

year = "2012",

month = oct,

day = "16",

doi = "10.1016/j.ccr.2012.08.024",

language = "English (US)",

volume = "22",

pages = "425--437",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "4",

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TY - JOUR

T1 - Hotspot Mutations in H3F3A and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma

AU - Sturm, Dominik

AU - Witt, Hendrik

AU - Hovestadt, Volker

AU - Khuong-Quang, Dong Anh

AU - Jones, David T.W.

AU - Konermann, Carolin

AU - Pfaff, Elke

AU - Tönjes, Martje

AU - Sill, Martin

AU - Bender, Sebastian

AU - Kool, Marcel

AU - Zapatka, Marc

AU - Becker, Natalia

AU - Zucknick, Manuela

AU - Hielscher, Thomas

AU - Liu, Xiao Yang

AU - Fontebasso, Adam M.

AU - Ryzhova, Marina

AU - Albrecht, Steffen

AU - Jacob, Karine

AU - Wolter, Marietta

AU - Ebinger, Martin

AU - Schuhmann, Martin U.

AU - van Meter, Timothy

AU - Frühwald, Michael C.

AU - Hauch, Holger

AU - Pekrun, Arnulf

AU - Radlwimmer, Bernhard

AU - Niehues, Tim

AU - Von Komorowski, Gregor

AU - Dürken, Matthias

AU - Kulozik, Andreas E.

AU - Madden, Jenny

AU - Donson, Andrew

AU - Foreman, Nicholas K.

AU - Drissi, Rachid

AU - Fouladi, Maryam

AU - Scheurlen, Wolfram

AU - von Deimling, Andreas

AU - Monoranu, Camelia

AU - Roggendorf, Wolfgang

AU - Herold-Mende, Christel

AU - Unterberg, Andreas

AU - Kramm, Christof M.

AU - Felsberg, Jörg

AU - Hartmann, Christian

AU - Wiestler, Benedikt

AU - Wick, Wolfgang

AU - Milde, Till

AU - Witt, Olaf

AU - Lindroth, Anders M.

AU - Schwartzentruber, Jeremy

AU - Faury, Damien

AU - Fleming, Adam

AU - Zakrzewska, Magdalena

AU - Liberski, Pawel P.

AU - Zakrzewski, Krzysztof

AU - Hauser, Peter

AU - Garami, Miklos

AU - Klekner, Almos

AU - Bognar, Laszlo

AU - Morrissy, Sorana

AU - Cavalli, Florence

AU - Taylor, Michael D.

AU - van Sluis, Peter

AU - Koster, Jan

AU - Versteeg, Rogier

AU - Volckmann, Richard

AU - Mikkelsen, Tom

AU - Aldape, Kenneth

AU - Reifenberger, Guido

AU - Collins, V. Peter

AU - Majewski, Jacek

AU - Korshunov, Andrey

AU - Lichter, Peter

AU - Plass, Christoph

AU - Jabado, Nada

AU - Pfister, Stefan M.

N1 - Funding Information: We thank Andrea Wittmann and Laura Sieber from the Division of Pediatric Neurooncology at the DKFZ for excellent technical support and Matthias Schick and Roger Fischer from the DKFZ Genomics and Proteomics Core Facility for performing the microarray analyses to a very high standard. We also acknowledge the outstanding technical assistance of Hannelore Schraut (University of Würzburg) and Leonore Senf (Nürnberg Children’s Hospital). The project was supported by grants from the German Cancer Aid (109252 and 108456); the BMBF (to A.K., B.R., O.W., P.L., S.M.P., G.R., and J.F.; ICGC PedBrain, NGFN Plus #01GS0883); Koningin Wilhelmina Fonds (UvA-2010-4713) and KIKA (to M.K.); the Cole Foundation; the Canadian Institute of Health Research; the Institute of Cancer Research, Génome Canada and Génome Quebec (to N.J.); and the Alfred-Müller Award for Neuro-Oncology to S.M.P.

PY - 2012/10/16

Y1 - 2012/10/16

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=84867606428&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2012.08.024

DO - 10.1016/j.ccr.2012.08.024

M3 - Article

C2 - 23079654

AN - SCOPUS:84867606428

SN - 1535-6108

VL - 22

SP - 425

EP - 437

JO - Cancer cell

JF - Cancer cell

IS - 4

ER -

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

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