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

被引：1425

作者：

Sturm, Dominik ^{[2
]}

Witt, Hendrik ^{[2
,7
]}

Hovestadt, Volker ^{[3
]}

Dong-Anh Khuong-Quang ^{[11
,12
]}

Jones, David T. W. ^{[2
]}

Konermann, Carolin ^{[1
]}

Pfaff, Elke ^{[2
]}

Toenjes, Marge ^{[3
]}

Sill, Martin ^{[4
]}

Bender, Sebastian ^{[2
]}

Kool, Marcel ^{[2
]}

Zapatka, Marc ^{[3
]}

Becker, Natalia ^{[4
]}

Zucknick, Manuela ^{[4
]}

Hielscher, Thomas ^{[4
]}

Liu, Xiao-Yang ^{[11
,12
]}

Fontebasso, Adam M. ^{[13
]}

Ryzhova, Marina ^{[14
]}

Albrecht, Steffen ^{[15
]}

Jacob, Karine ^{[11
,12
]}

Wolter, Marietta ^{[16
]}

Ebinger, Martin ^{[17
]}

Schuhmann, Martin U. ^{[18
]}

van Meter, Timothy ^{[19
]}

Fruehwald, Michael C. ^{[20
]}

Hauch, Holger ^{[21
]}

Pekrun, Arnulf ^{[22
]}

Radlwimmer, Bernhard ^{[3
]}

Niehues, Tim ^{[23
]}

von Komorowski, Gregor ^{[24
]}

Duerken, Matthias ^{[24
]}

Kulozik, Andreas E. ^{[7
]}

Madden, Jenny ^{[25
]}

Donson, Andrew ^{[25
]}

Foreman, Nicholas K. ^{[25
]}

Drissi, Rachid ^{[26
]}

Fouladi, Maryam ^{[26
]}

Scheurlen, Wolfram ^{[27
]}

von Deimling, Andreas ^{[5
,9
]}

Monoranu, Camelia ^{[28
]}

Roggendorf, Wolfgang ^{[28
]}

Herold-Mende, Christel ^{[8
]}

Unterberg, Andreas ^{[8
]}

Kramm, Christof M. ^{[29
]}

Felsberg, Joerg ^{[16
]}

Hartmann, Christian ^{[30
]}

Wiestler, Benedikt ^{[10
]}

Wick, Wolfgang ^{[10
]}

Milde, Till ^{[6
,7
]}

Witt, Olaf ^{[6
,7
]}

机构：

[1] German Canc Res Ctr DKFZ Heidelberg, Div Epigenet & Canc Risk Factors, D-69120 Heidelberg, Germany

[2] German Canc Res Ctr DKFZ Heidelberg, Div Pediat Neurooncol, D-69120 Heidelberg, Germany

[3] German Canc Res Ctr DKFZ Heidelberg, Div Mol Genet, D-69120 Heidelberg, Germany

[4] German Canc Res Ctr DKFZ Heidelberg, Div Biostat, D-69120 Heidelberg, Germany

[5] German Canc Res Ctr DKFZ Heidelberg, Clin Cooperat Unit Neuropathol, D-69120 Heidelberg, Germany

[6] German Canc Res Ctr DKFZ Heidelberg, Clin Cooperat Unit Pediat Oncol, D-69120 Heidelberg, Germany

[7] Heidelberg Univ Hosp, Dept Pediat Oncol Hematol & Immunol, D-69120 Heidelberg, Germany

[8] Heidelberg Univ Hosp, Dept Neurosurg, D-69120 Heidelberg, Germany

[9] Heidelberg Univ Hosp, Dept Neuropathol, D-69120 Heidelberg, Germany

[10] Heidelberg Univ Hosp, Dept Neurooncol, D-69120 Heidelberg, Germany

[11] McGill Univ, Ctr Hlth, Res Inst, Dept Pediat, Montreal, PQ H3Z 2Z3, Canada

[12] McGill Univ, Ctr Hlth, Res Inst, Dept Human Genet, Montreal, PQ H3Z 2Z3, Canada

[13] McGill Univ, Ctr Hlth, Res Inst, Div Expt Med,Montreal Childrens Hosp, Montreal, PQ H3Z 2Z3, Canada

[14] NN Burdenko Inst Neurosurg, Moscow 125047, Russia

[15] McGill Univ, Montreal Childrens Hosp, Dept Pathol, Hlth Ctr,Res Inst, Montreal, PQ H3H 1P3, Canada

[16] Univ Dusseldorf, Dept Neuropathol, D-40225 Dusseldorf, Germany

[17] Childrens Univ Hosp Tubingen, Dept Hematol & Oncol, D-72076 Tubingen, Germany

[18] Univ Hosp Tubingen, Dept Neurosurg, D-72076 Tubingen, Germany

[19] Virginia Commonwealth Univ, Richmond, VA 23298 USA

[20] Klinikum Augsburg, Pediat Hosp, D-86156 Augsburg, Germany

[21] Klinikum Heilbronn, Pediat Hosp, D-74078 Heilbronn, Germany

[22] Klinikum Bremen Mitte, Prof Hess Kinderklin, D-28177 Bremen, Germany

[23] Childrens Hosp, Helios Clin, D-47805 Krefeld, Germany

[24] Childrens Univ Hosp, D-68135 Mannheim, Germany

[25] Univ Colorado Denver, Dept Pediat, Aurora, CO 80045 USA

[26] Cincinnati Childrens Hosp, Med Ctr, Div Oncol, Cincinnati, OH 45229 USA

[27] Nurnberg Childrens Hosp, Cnopfsche Kinderklin, D-90419 Nurnberg, Germany

[28] Univ Wurzburg, Dept Neuropathol, Inst Pathol, D-97080 Wurzburg, Germany

[29] Univ Halle Wittenberg, Univ Childrens Hosp, D-06120 Halle, Germany

[30] Hannover Med Sch, Dept Neuropathol, Inst Pathol, D-30175 Hannover, Germany

[31] McGill Univ, Montreal, PQ H3A 1A4, Canada

[32] Genome Quebec Innovat Ctr, Montreal, PQ H3A 1A4, Canada

[33] Med Univ Lodz, Dept Mol Pathol & Neuropathol, PL-92216 Lodz, Poland

[34] Polish Mothers Mem Hosp Res Inst, Dept Neurosurg, PL-93338 Lodz, Poland

[35] Semmelweis Univ, Dept Paediat 2, H-1094 Budapest, Hungary

[36] Univ Debrecen, Med & Hlth Sci Ctr, Dept Neurosurg, H-4032 Debrecen, Hungary

[37] Univ Toronto, Hosp Sick Children, Program Dev & Stem Cell Biol, Div Neurosurg,Arthur & Sonia Labatt Brain Tumour, Toronto, ON M4N 1X8, Canada

[38] Univ Amsterdam, AMC, Dept Oncogenom, NL-1105 AZ Amsterdam, Netherlands

[39] Henry Ford Hosp, Dept Neurol, Detroit, MI 48202 USA

[40] Henry Ford Hosp, Dept Neurosurg, Detroit, MI 48202 USA

[41] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA

[42] Univ Cambridge, Dept Pathol, Div Mol Histopathol, Cambridge CB2 0QQ, England

来源：

CANCER CELL | 2012年 / 22卷 / 04期

关键词：

INTEGRATED GENOMIC ANALYSIS; COPY-NUMBER ABERRATIONS; DNA METHYLATION; ONCOMETABOLITE; 2-HYDROXYGLUTARATE; CLASS DISCOVERY; HISTONE H3.3; GLIOMA; CHROMATIN; GENES; EXPRESSION;

D O I：

10.1016/j.ccr.2012.08.024

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：425 / 437

页数：13

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