Advertisement

Journal of Neuro-Oncology

, Volume 141, Issue 1, pp 43–55 | Cite as

Functional relevance of genes predicted to be affected by epigenetic alterations in atypical teratoid/rhabdoid tumors

  • Isabel Tegeder
  • Katharina Thiel
  • Serap Erkek
  • Pascal D. Johann
  • Johannes Berlandi
  • Venu Thatikonda
  • Michael C. Frühwald
  • Marcel Kool
  • Astrid Jeibmann
  • Martin HasselblattEmail author
Laboratory Investigation

Abstract

Purpose

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly arising in infants. Mutations of SWI/SNF chromatin remodeling complex members SMARCB1/INI1 or (rarely) SMARCA4/Brg1 are the sole recurrent genetic lesions. Epigenetic studies revealed a large number of genes predicted to be affected by differential histone modifications in ATRT, but the role of these genes in the biology of ATRT remains uncertain. We therefore aimed at exploring the role of these genes in the detrimental effects of SMARCB1-deficiency.

Methods

The functional relevance of 1083 genes predicted to be affected by epigenetic alterations in ATRT was examined in vivo using a Drosophila melanogaster model of SMARCB1-deficiency. Human orthologues of genes whose knockdown modified the phenotype in the Gal4-UAS fly model were further examined in ATRT samples and SMARCB1-deficient rhabdoid tumor cells.

Results

Knockdown of Snr1, the fly orthologue of SMARCB1, resulted in a lethal phenotype and epigenetic alterations in the fly model. The lethal phenotype was shifted to later stages of development upon additional siRNA knockdown of 89 of 1083 genes screened in vivo. These included TGF-beta receptor signaling pathway related genes, e.g. CG10348, the fly orthologue of transcriptional regulator PRDM16. Subsequently, PRDM16 was found to be over-expressed in ATRT samples and knockdown of PRDM16 in SMARCB1-deficient rhabdoid tumor cells reduced proliferation.

Conclusions

These results suggest that a subset of genes affected by differential histone modification in ATRT is involved in the detrimental effects of SMARCB1-deficiency and also relevant in the biology of ATRT.

Keywords

Drosophila melanogaster Malignant rhabdoid tumor Histone modifications SMARCB1 TGFbeta signaling PRDM16 

Notes

Funding

This study was funded by the Interdisciplinary Centre for Clinical Research (IZKF), Medical Faculty of the University of Münster (Grant No. Ha3/019/15) and Deutsche Forschungsgemeinschaft (Grant No. HA3060/5-1). Infrastructural support was received from the Medical Faculty of the University Münster (Technology Platform “Drosophila”).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or vertebrates performed by any of the authors. Human tumor samples for immunohistochemistry had been obtained in the context of the European Rhabdoid Tumor Registry EU-RHAB. EU-RHAB has received ethical committee approval (Ethics committee of the University Hospital Münster, 2009-532-f-S) and all parents had given informed consent for scientific use of the archival samples.

Supplementary material

11060_2018_3018_MOESM1_ESM.xlsx (53 kb)
Supplementary material 1 (XLSX 52 KB)
11060_2018_3018_MOESM2_ESM.xlsx (25 kb)
Supplementary material 2 (XLSX 24 KB)
11060_2018_3018_MOESM3_ESM.pptx (275 kb)
Supplementary material 3 (XLSX 275 KB)

References

  1. 1.
    Frühwald MC, Biegel JA, Bourdeaut F, Roberts CW, Chi SN (2016) Atypical teratoid/rhabdoid tumors-current concepts, advances in biology, and potential future therapies. Neuro Oncol 18:764–778.  https://doi.org/10.1093/neuonc/nov264 CrossRefGoogle Scholar
  2. 2.
    Biegel JA, Zhou J-Y, Rorke LB, Stenstrom C, Wainwright LM, Fogelgren B (1999) Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res 59:74–79Google Scholar
  3. 3.
    Schneppenheim R, Frühwald MC, Gesk S, Hasselblatt M, Jeibmann A, Kordes U, Kreuz M, Leuschner I, Subero JIM, Obser T (2010) Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am J Human Genet 86:279–284CrossRefGoogle Scholar
  4. 4.
    Kieran MW, Roberts CW, Chi SN, Ligon KL, Rich BE, Macconaill LE, Garraway LA, Biegel JA (2012) Absence of oncogenic canonical pathway mutations in aggressive pediatric rhabdoid tumors. Pediatr Blood Cancer 59:1155–1157.  https://doi.org/10.1002/pbc.24315 CrossRefGoogle Scholar
  5. 5.
    Hasselblatt M, Isken S, Linge A, Eikmeier K, Jeibmann A, Oyen F, Nagel I, Richter J, Bartelheim K, Kordes U, Schneppenheim R, Frühwald M, Siebert R, Paulus W (2013) High-resolution genomic analysis suggests the absence of recurrent genomic alterations other than SMARCB1 aberrations in atypical teratoid/rhabdoid tumors. Genes Chromosomes Cancer 52:185–190.  https://doi.org/10.1002/gcc.22018 CrossRefGoogle Scholar
  6. 6.
    Johann PD, Erkek S, Zapatka M, Kerl K, Buchhalter I, Hovestadt V, Jones DTW, Sturm D, Hermann C, Segura Wang M, Korshunov A, Rhyzova M, Gröbner S, Brabetz S, Chavez L, Bens S, Gröschel S, Kratochwil F, Wittmann A, Sieber L, Geörg C, Wolf S, Beck K, Oyen F, Capper D, van Sluis P, Volckmann R, Koster J, Versteeg R, von Deimling A, Milde T, Witt O, Kulozik AE, Ebinger M, Shalaby T, Grotzer M, Sumerauer D, Zamecnik J, Mora J, Jabado N, Taylor MD, Huang A, Aronica E, Bertoni A, Radlwimmer B, Pietsch T, Schüller U, Schneppenheim R, Northcott PA, Korbel JO, Siebert R, Frühwald MC, Lichter P, Eils R, Gajjar A, Hasselblatt M, Pfister SM, Kool M (2016) Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell 29:379–393CrossRefGoogle Scholar
  7. 7.
    Torchia J, Golbourn B, Feng S, Ho KC, Sin-Chan P, Vasiljevic A, Norman JD, Guilhamon P, Garzia L, Agamez NR, Lu M, Chan TS, Picard D, de Antonellis P, Khuong-Quang DA, Planello AC, Zeller C, Barsyte-Lovejoy D, Lafay-Cousin L, Letourneau L, Bourgey M, Yu M, Gendoo DMA, Dzamba M, Barszczyk M, Medina T, Riemenschneider AN, Morrissy AS, Ra YS, Ramaswamy V, Remke M, Dunham CP, Yip S, Ng HK, Lu JQ, Mehta V, Albrecht S, Pimentel J, Chan JA, Somers GR, Faria CC, Roque L, Fouladi M, Hoffman LM, Moore AS, Wang Y, Choi SA, Hansford JR, Catchpoole D, Birks DK, Foreman NK, Strother D, Klekner A, Bognar L, Garami M, Hauser P, Hortobagyi T, Wilson B, Hukin J, Carret AS, Van Meter TE, Hwang EI, Gajjar A, Chiou SH, Nakamura H, Toledano H, Fried I, Fults D, Wataya T, Fryer C, Eisenstat DD, Scheinemann K, Fleming AJ, Johnston DL, Michaud J, Zelcer S, Hammond R, Afzal S, Ramsay DA, Sirachainan N, Hongeng S, Larbcharoensub N, Grundy RG, Lulla RR, Fangusaro JR, Druker H, Bartels U, Grant R, Malkin D, McGlade CJ, Nicolaides T, Tihan T, Phillips J, Majewski J, Montpetit A, Bourque G, Bader GD, Reddy AT, Gillespie GY, Warmuth-Metz M, Rutkowski S, Tabori U, Lupien M, Brudno M, Schuller U, Pietsch T, Judkins AR, Hawkins CE, Bouffet E, Kim SK, Dirks PB, Taylor MD, Erdreich-Epstein A, Arrowsmith CH, De Carvalho DD, Rutka JT, Jabado N, Huang A (2016) Integrated (epi)-genomic analyses identify subgroup-specific therapeutic targets in CNS rhabdoid tumors. Cancer Cell 30:891–908.  https://doi.org/10.1016/j.ccell.2016.11.003 CrossRefGoogle Scholar
  8. 8.
    Gonzalez C (2013) Drosophila melanogaster: a model and a tool to investigate malignancy and identify new therapeutics. Nat Rev Cancer 13:172–183.  https://doi.org/10.1038/nrc3461 CrossRefGoogle Scholar
  9. 9.
    Kvon EZ, Kazmar T, Stampfel G, Yáñez-Cuna JO, Pagani M, Schernhuber K, Dickson BJ, Stark A (2014) Genome-scale functional characterization of Drosophila developmental enhancers in vivo. Nature 512:91CrossRefGoogle Scholar
  10. 10.
    Jeibmann A, Eikmeier K, Linge A, Kool M, Koos B, Schulz J, Albrecht S, Bartelheim K, Frühwald MC, Pfister SM (2014) Identification of genes involved in the biology of atypical teratoid/rhabdoid tumours using Drosophila melanogaster. Nature Commun 5:4005CrossRefGoogle Scholar
  11. 11.
    Jeibmann A, Schulz J, Eikmeier K, Johann PD, Thiel K, Tegeder I, Ambree O, Fruhwald MC, Pfister SM, Kool M, Paulus W, Hasselblatt M (2017) SMAD dependent signaling plays a detrimental role in a fly model of SMARCB1-deficiency and the biology of atypical teratoid/rhabdoid tumors. J Neurooncol 131:477–484.  https://doi.org/10.1007/s11060-016-2326-3 CrossRefGoogle Scholar
  12. 12.
    Zerbino DR, Achuthan P, Akanni W, Amode MR, Barrell D, Bhai J, Billis K, Cummins C, Gall A, Girón CG, Gil L, Gordon L, Haggerty L, Haskell E, Hourlier T, Izuogu OG, Janacek SH, Juettemann T, To JK, Laird MR, Lavidas I, Liu Z, Loveland JE, Maurel T, McLaren W, Moore B, Mudge J, Murphy DN, Newman V, Nuhn M, Ogeh D, Ong CK, Parker A, Patricio M, Riat HS, Schuilenburg H, Sheppard D, Sparrow H, Taylor K, Thormann A, Vullo A, Walts B, Zadissa A, Frankish A, Hunt SE, Kostadima M, Langridge N, Martin FJ, Muffato M, Perry E, Ruffier M, Staines DM, Trevanion SJ, Aken BL, Cunningham F, Yates A, Flicek P (2018) Ensembl 2018. Nucleic Acids Res 46:D754–D761.  https://doi.org/10.1093/nar/gkx1098 CrossRefGoogle Scholar
  13. 13.
    Huang da W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4:44–57.  https://doi.org/10.1038/nprot.2008.211 CrossRefGoogle Scholar
  14. 14.
    Huang da W, Sherman BT, Lempicki RA (2009) Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 37:1–13.  https://doi.org/10.1093/nar/gkn923 CrossRefGoogle Scholar
  15. 15.
    Koos B, Paulsson J, Jarvius M, Sanchez BC, Wrede B, Mertsch S, Jeibmann A, Kruse A, Peters O, Wolff JE, Galla HJ, Soderberg O, Paulus W, Ostman A, Hasselblatt M (2009) Platelet-derived growth factor receptor expression and activation in choroid plexus tumors. Am J Pathol 175:1631–1637.  https://doi.org/10.2353/ajpath.2009.081022 CrossRefGoogle Scholar
  16. 16.
    Kool M, Koster J, Bunt J, Hasselt NE, Lakeman A, van Sluis P, Troost D, Meeteren NS, Caron HN, Cloos J, Mrsic A, Ylstra B, Grajkowska W, Hartmann W, Pietsch T, Ellison D, Clifford SC, Versteeg R (2008) Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS ONE 3:e3088.  https://doi.org/10.1371/journal.pone.0003088 CrossRefGoogle Scholar
  17. 17.
    Robinson G, Parker M, Kranenburg TA, Lu C, Chen X, Ding L, Phoenix TN, Hedlund E, Wei L, Zhu X, Chalhoub N, Baker SJ, Huether R, Kriwacki R, Curley N, Thiruvenkatam R, Wang J, Wu G, Rusch M, Hong X, Becksfort J, Gupta P, Ma J, Easton J, Vadodaria B, Onar-Thomas A, Lin T, Li S, Pounds S, Paugh S, Zhao D, Kawauchi D, Roussel MF, Finkelstein D, Ellison DW, Lau CC, Bouffet E, Hassall T, Gururangan S, Cohn R, Fulton RS, Fulton LL, Dooling DJ, Ochoa K, Gajjar A, Mardis ER, Wilson RK, Downing JR, Zhang J, Gilbertson RJ (2012) Novel mutations target distinct subgroups of medulloblastoma. Nature 488:43–48.  https://doi.org/10.1038/nature11213 CrossRefGoogle Scholar
  18. 18.
    Fattet S, Haberler C, Legoix P, Varlet P, Lellouch-Tubiana A, Lair S, Manie E, Raquin MA, Bours D, Carpentier S, Barillot E, Grill J, Doz F, Puget S, Janoueix-Lerosey I, Delattre O (2009) Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics. J Pathol 218:86–94.  https://doi.org/10.1002/path.2514 CrossRefGoogle Scholar
  19. 19.
    Roth RB, Hevezi P, Lee J, Willhite D, Lechner SM, Foster AC, Zlotnik A (2006) Gene expression analyses reveal molecular relationships among 20 regions of the human CNS. Neurogenetics 7:67–80.  https://doi.org/10.1007/s10048-006-0032-6 CrossRefGoogle Scholar
  20. 20.
    Birks DK, Donson AM, Patel PR, Dunham C, Muscat A, Algar EM, Ashley DM, Kleinschmidt-Demasters BK, Vibhakar R, Handler MH, Foreman NK (2011) High expression of BMP pathway genes distinguishes a subset of atypical teratoid/rhabdoid tumors associated with shorter survival. Neuro Oncol 13:1296–1307.  https://doi.org/10.1093/neuonc/nor140 CrossRefGoogle Scholar
  21. 21.
    Saeed AI, Sharov V, White J, Li J, Liang W, Bhagabati N, Braisted J, Klapa M, Currier T, Thiagarajan M, Sturn A, Snuffin M, Rezantsev A, Popov D, Ryltsov A, Kostukovich E, Borisovsky I, Liu Z, Vinsavich A, Trush V, Quackenbush J (2003) TM4: a free, open-source system for microarray data management and analysis. Biotechniques 34:374–378CrossRefGoogle Scholar
  22. 22.
    Tsikitis M, Zhang Z, Edelman W, Zagzag D, Kalpana GV (2005) Genetic ablation of Cyclin D1 abrogates genesis of rhabdoid tumors resulting from Ini1 loss. Proc Natl Acad Sci USA 102:12129–12134.  https://doi.org/10.1073/pnas.0505300102 CrossRefGoogle Scholar
  23. 23.
    Weingart MF, Roth JJ, Hutt-Cabezas M, Busse TM, Kaur H, Price A, Maynard R, Rubens J, Taylor I, Mao XG, Xu J, Kuwahara Y, Allen SJ, Erdreich-Epstein A, Weissman BE, Orr BA, Eberhart CG, Biegel JA, Raabe EH (2015) Disrupting LIN28 in atypical teratoid rhabdoid tumors reveals the importance of the mitogen activated protein kinase pathway as a therapeutic target. Oncotarget 6:3165–3177.  https://doi.org/10.18632/oncotarget.3078 CrossRefGoogle Scholar
  24. 24.
    Dempersmier J, Sambeat A, Gulyaeva O, Paul SM, Hudak CS, Raposo HF, Kwan HY, Kang C, Wong RH, Sul HS (2015) Cold-inducible Zfp516 activates UCP1 transcription to promote browning of white fat and development of brown fat. Mol Cell 57:235–246.  https://doi.org/10.1016/j.molcel.2014.12.005 CrossRefGoogle Scholar
  25. 25.
    Takahata M, Inoue Y, Tsuda H, Imoto I, Koinuma D, Hayashi M, Ichikura T, Yamori T, Nagasaki K, Yoshida M, Matsuoka M, Morishita K, Yuki K, Hanyu A, Miyazawa K, Inazawa J, Miyazono K, Imamura T (2009) SKI and MEL1 cooperate to inhibit transforming growth factor-beta signal in gastric cancer cells. J Biol Chem 284:3334–3344.  https://doi.org/10.1074/jbc.M808989200 CrossRefGoogle Scholar
  26. 26.
    Warner DR, Horn KH, Mudd L, Webb CL, Greene RM, Pisano MM (2007) PRDM16/MEL1: a novel Smad binding protein expressed in murine embryonic orofacial tissue. Biochim Biophys Acta (BBA) 1773:814–820CrossRefGoogle Scholar
  27. 27.
    Yoshida M, Nosaka K, Yasunaga J, Nishikata I, Morishita K, Matsuoka M (2004) Aberrant expression of the MEL1S gene identified in association with hypomethylation in adult T-cell leukemia cells. Blood 103:2753–2760.  https://doi.org/10.1182/blood-2003-07-2482 CrossRefGoogle Scholar
  28. 28.
    Fog CK, Galli GG, Lund AH (2012) PRDM proteins: important players in differentiation and disease. Bioessays 34:50–60CrossRefGoogle Scholar
  29. 29.
    Mzoughi S, Tan YX, Low D, Guccione E (2016) The role of PRDMs in cancer: one family, two sides. Curr Opin Genet Dev 36:83–91.  https://doi.org/10.1016/j.gde.2016.03.009 CrossRefGoogle Scholar
  30. 30.
    Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M, Tavernier G, Langin D, Spiegelman BM (2007) Transcriptional control of brown fat determination by PRDM16. Cell Metab 6:38–54.  https://doi.org/10.1016/j.cmet.2007.06.001 CrossRefGoogle Scholar
  31. 31.
    Mochizuki N, Shimizu S, Nagasawa T, Tanaka H, Taniwaki M, Yokota J, Morishita K (2000) A novel gene, MEL1, mapped to 1p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3)(p36;q21)-positive leukemia cells. Blood 96:3209–3214Google Scholar
  32. 32.
    Nishikata I, Sasaki H, Iga M, Tateno Y, Imayoshi S, Asou N, Nakamura T, Morishita K (2003) A novel EVI1 gene family, MEL1, lacking a PR domain (MEL1S) is expressed mainly in t(1;3)(p36;q21)-positive AML and blocks G-CSF-induced myeloid differentiation. Blood 102:3323–3332.  https://doi.org/10.1182/blood-2002-12-3944 CrossRefGoogle Scholar
  33. 33.
    Shing DC, Trubia M, Marchesi F, Radaelli E, Belloni E, Tapinassi C, Scanziani E, Mecucci C, Crescenzi B, Lahortiga I, Odero MD, Zardo G, Gruszka A, Minucci S, Di Fiore PP, Pelicci PG (2007) Overexpression of sPRDM16 coupled with loss of p53 induces myeloid leukemias in mice. J Clin Invest 117:3696–3707.  https://doi.org/10.1172/jci32390 Google Scholar
  34. 34.
    Behrends U, Schneider I, Rössler S, Frauenknecht H, Golbeck A, Lechner B, Eigenstetter G, Zobywalski C, Müller-Weihrich S, Graubner U (2003) Novel tumor antigens identified by autologous antibody screening of childhood medulloblastoma cDNA libraries. Int J Cancer 106:244–251CrossRefGoogle Scholar
  35. 35.
    Liao J, Jiang J, Jun H, Qiao X, Emont MP, Kim DI, Wu J (2018) HDAC3-selective inhibition activates brown and beige fat through PRDM16. Endocrinology 159:2520–2527.  https://doi.org/10.1210/en.2018-00257 CrossRefGoogle Scholar
  36. 36.
    Kerl K, Ries D, Unland R, Borchert C, Moreno N, Hasselblatt M, Jürgens H, Kool M, Görlich D, Eveslage M (2013) The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells. BMC cancer 13:286CrossRefGoogle Scholar
  37. 37.
    Schneppenheim R, Frühwald MC, Gesk S, Hasselblatt M, Jeibmann A, Kordes U, Kreuz M, Leuschner I, Martin Subero JI, Obser T, Oyen F, Vater I, Siebert R (2010) Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet 86:279–284.  https://doi.org/10.1016/j.ajhg.2010.01.013 CrossRefGoogle Scholar
  38. 38.
    Jackson EM, Sievert AJ, Gai X, Hakonarson H, Judkins AR, Tooke L, Perin JC, Xie H, Shaikh TH, Biegel JA (2009) Genomic analysis using high-density single nucleotide polymorphism-based oligonucleotide arrays and multiplex ligation-dependent probe amplification provides a comprehensive analysis of INI1/SMARCB1 in malignant rhabdoid tumors. Clin Cancer Res 15:1923–1930.  https://doi.org/10.1158/1078-0432.ccr-08-2091 CrossRefGoogle Scholar
  39. 39.
    Hasselblatt M, Nagel I, Oyen F, Bartelheim K, Russell RB, Schuller U, Junckerstorff R, Rosenblum M, Alassiri AH, Rossi S, Schmid I, Gottardo NG, Toledano H, Viscardi E, Balbin M, Witkowski L, Lu Q, Betts MJ, Foulkes WD, Siebert R, Frühwald MC, Schneppenheim R (2014) SMARCA4-mutated atypical teratoid/rhabdoid tumors are associated with inherited germline alterations and poor prognosis. Acta Neuropathol 128:453–456.  https://doi.org/10.1007/s00401-014-1323-x CrossRefGoogle Scholar
  40. 40.
    Bookhout C, Bouldin TW, Ellison DW (2018) Atypical teratoid/rhabdoid tumor with retained INI1 (SMARCB1) expression and loss of BRG1 (SMARCA4). Neuropathology 38:305–308.  https://doi.org/10.1111/neup.12452 CrossRefGoogle Scholar
  41. 41.
    Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, Becksfort J, Qu C, Ding L, Huether R, Parker M, Zhang J, Gajjar A, Dyer MA, Mullighan CG, Gilbertson RJ, Mardis ER, Wilson RK, Downing JR, Ellison DW, Zhang J, Baker SJ (2012) Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44:251–253.  https://doi.org/10.1038/ng.1102 CrossRefGoogle Scholar
  42. 42.
    Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, Sturm D, Fontebasso AM, Quang DA, Tonjes M, Hovestadt V, Albrecht S, Kool M, Nantel A, Konermann C, Lindroth A, Jager N, Rausch T, Ryzhova M, Korbel JO, Hielscher T, Hauser P, Garami M, Klekner A, Bognar L, Ebinger M, Schuhmann MU, Scheurlen W, Pekrun A, Fruhwald MC, Roggendorf W, Kramm C, Durken M, Atkinson J, Lepage P, Montpetit A, Zakrzewska M, Zakrzewski K, Liberski PP, Dong Z, Siegel P, Kulozik AE, Zapatka M, Guha A, Malkin D, Felsberg J, Reifenberger G, von Deimling A, Ichimura K, Collins VP, Witt H, Milde T, Witt O, Zhang C, Castelo-Branco P, Lichter P, Faury D, Tabori U, Plass C, Majewski J, Pfister SM, Jabado N (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226–231.  https://doi.org/10.1038/nature10833 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Isabel Tegeder
    • 1
  • Katharina Thiel
    • 1
  • Serap Erkek
    • 2
    • 3
  • Pascal D. Johann
    • 2
    • 3
    • 4
  • Johannes Berlandi
    • 1
  • Venu Thatikonda
    • 2
    • 3
  • Michael C. Frühwald
    • 5
  • Marcel Kool
    • 2
    • 3
  • Astrid Jeibmann
    • 1
  • Martin Hasselblatt
    • 1
    Email author
  1. 1.Institute of NeuropathologyUniversity Hospital MünsterMünsterGermany
  2. 2.Hopp-Children’s Cancer Center at the NCT HeidelbergHeidelbergGermany
  3. 3.Division of Pediatric NeurooncologyGerman Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK)HeidelbergGermany
  4. 4.Department of Pediatric Oncology and HematologyUniversity Hospital HeidelbergHeidelbergGermany
  5. 5.Children’s Hospital Augsburg, Swabian Children’s Cancer CenterAugsburgGermany

Personalised recommendations