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11.04.2017 | Original Paper

H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers

verfasst von: Andrey Korshunov, Daniel Schrimpf, Marina Ryzhova, Dominik Sturm, Lukas Chavez, Volker Hovestadt, Tanvi Sharma, Antje Habel, Anna Burford, Chris Jones, Olga Zheludkova, Ella Kumirova, Christof M. Kramm, Andrey Golanov, David Capper, Andreas von Deimling, Stefan M. Pfister, David T. W. Jones

Erschienen in: Acta Neuropathologica | Ausgabe 3/2017

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Abstract

Pediatric glioblastoma (pedGBM) is an extremely aggressive pediatric brain tumor, accounting for ~6% of all central nervous system neoplasms in children. Approximately half of pedGBM harbor recurrent somatic mutations in histone 3 variants or, infrequently, IDH1/2. The remaining subset of pedGBM is highly heterogeneous, and displays a variety of genomic and epigenetic features. In the current study, we aimed to further stratify an H3-/IDH-wild type (wt) pedGBM cohort assessed through genome-wide molecular profiling. As a result, we identified three molecular subtypes of these tumors, differing in their genomic and epigenetic signatures as well as in their clinical behavior. We designated these subtypes ‘pedGBM_MYCN’ (enriched for MYCN amplification), ‘pedGBM_RTK1’ (enriched for PDGFRA amplification) and ‘pedGBM_RTK2’ (enriched for EGFR amplification). These molecular subtypes were associated with significantly different outcomes, i.e. pedGBM_RTK2 tumors show a significantly longer survival time (median OS 44 months), pedGBM_MYCN display extremely poor outcomes (median OS 14 months), and pedGBM_RTK1 tumors harbor an intermediate prognosis. In addition, the various molecular subtypes of H3-/IDH-wt pedGBM were clearly distinguishable from their adult counterparts, underlining their biological distinctiveness. In conclusion, our study demonstrates significant molecular heterogeneity of H3-/IDH-wt pedGBM in terms of DNA methylation and cytogenetic alterations. The recognition of three molecular subtypes of H3-/IDH-wt pedGBM further revealed close correlations with biological parameters and clinical outcomes and may therefore, be predictive of response to standard treatment protocols, but could also be useful for stratification for novel, molecularly based therapies.

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Arrondeau J, Huillard O, Tlemsani C, Cessot A, Boudou-Rouquette P, Blanchet B, Thomas-Schoemann A, Vidal M, Tigaud JM, Durand JP et al (2015) Investigational therapies up to Phase II which target PDGF receptors: potential anti-cancer therapeutics. Expert Opin Investig Drugs 24:673–687. doi:10.1517/13543784.2015.1005736 CrossRefPubMed

Bady P, Sciuscio D, Diserens AC, Bloch J, van den Bent MJ, Marosi C, Dietrich PY, Weller M, Mariani L, Heppner FL et al (2012) MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status. Acta Neuropathol 124:547–560. doi:10.1007/s00401-012-1016-2 CrossRefPubMedPubMedCentral

Bender S, Gronych J, Warnatz HJ, Hutter B, Groebner S, Ryzhova M, Pfaff E, Hovestadt V, Weinberg F, Halbach S et al (2016) Recurrent MET fusion genes represent a drug target in pediatric glioblastoma. Nat Med 22:1314–1320. doi:10.1038/nm.4204 CrossRef

Buczkowicz P, Hoeman C, Rakopoulos P, Pajovic S, Letourneau L, Dzamba M, Morrison A, Lewis P, Bouffet E, Bartels U et al (2014) Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat Genet 46:451–456. doi:10.1038/ng.2936 CrossRefPubMedPubMedCentral

Castel D, Philippe C, Calmon R, Le Dret L, Truffaux N, Boddaert N, Pages M, Taylor KR, Saulnier P, Lacroix L et al (2015) Histone H3F3A and HIST1H3B K27 M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol 130:815–827. doi:10.1007/s00401-015-1478-0 CrossRefPubMedPubMedCentral

Cohen KJ, Pollack IF, Zhou T, Buxton A, Holmes EJ, Burger PC, Brat DJ, Rosenblum MK, Hamilton RL, Lavey RS et al (2011) Temozolomide in the treatment of high-grade gliomas in children: a report from the Children’s Oncology Group. Neuro Oncol 13:317–323. doi:10.1093/neuonc/noq191 CrossRefPubMedPubMedCentral

Duffner PK, Horowitz ME, Krischer JP, Burger PC, Cohen ME, Sanford RA, Friedman HS, Kun LE (1999) The treatment of malignant brain tumors in infants and very young children: an update of the Pediatric Oncology Group experience. Neuro Oncol 1:152–161PubMedPubMedCentral

Fontebasso AM, Papillon-Cavanagh S, Schwartzentruber J, Nikbakht H, Gerges N, Fiset PO, Bechet D, Faury D, De Jay N, Ramkissoon LA et al (2014) Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat Genet 46:462–466. doi:10.1038/ng.2950 CrossRefPubMedPubMedCentral

Hovestadt V, Remke M, Kool M, Pietsch T, Northcott PA, Fischer R, Cavalli FM, Ramaswamy V, Zapatka M, Reifenberger G et al (2013) Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathol 125:913–916. doi:10.1007/s00401-013-1126-5 CrossRefPubMedPubMedCentral

10.

Jones C, Baker SJ (2014) Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma. Nat Rev Cancer. doi:10.1038/nrc3811

11.

Jones C, Perryman L, Hargrave D (2012) Paediatric and adult malignant glioma: close relatives or distant cousins? Nat Rev Clin Oncol 9:400–413. doi:10.1038/nrclinonc.2012.87 CrossRefPubMed

12.

Khuong-Quang DA, Buczkowicz P, Rakopoulos P, Liu XY, Fontebasso AM, Bouffet E, Bartels U, Albrecht S, Schwartzentruber J, Letourneau L et al (2012) K27 M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol 124:439–447. doi:10.1007/s00401-012-0998-0 CrossRefPubMedPubMedCentral

13.

Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr, Friedman AH, Friedman H, Gallia GL, Giovanella BC et al (2013) TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci USA 110:6021–6026. doi:10.1073/pnas.1303607110 CrossRefPubMedPubMedCentral

14.

Koelsche C, Sahm F, Capper D, Reuss D, Sturm D, Jones DT, Kool M, Northcott PA, Wiestler B, Bohmer K et al (2013) Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system. Acta Neuropathol 126:907–915. doi:10.1007/s00401-013-1195-5 CrossRefPubMed

15.

Korshunov A, Capper D, Reuss D, Schrimpf D, Ryzhova M, Hovestadt V, Sturm D, Meyer J, Jones C, Zheludkova O et al (2016) Histologically distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity. Acta Neuropathol 131:137–146. doi:10.1007/s00401-015-1493-1 CrossRefPubMed

16.

Korshunov A, Ryzhova M, Hovestadt V, Bender S, Sturm D, Capper D, Meyer J, Schrimpf D, Kool M, Northcott PA et al (2015) Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol 129:669–678. doi:10.1007/s00401-015-1405-4 CrossRefPubMed

17.

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Ellison DW, Figarella-Branger D, Perry A, Reifenberger G, Von Deimling A (2016) WHO classification of tumours of the central nervous system, revised, 4th edn. IARC, City

18.

Northcott PA, Pfister SM, Jones DT (2015) Next-generation (epi)genetic drivers of childhood brain tumours and the outlook for targeted therapies. Lancet Oncol 16:e293–e302. doi:10.1016/S1470-2045(14)71206-9 CrossRefPubMed

19.

Ostrom QT, de Blank PM, Kruchko C, Petersen CM, Liao P, Finlay JL, Stearns DS, Wolff JE, Wolinsky Y, Letterio JJ et al (2015) Alex’s Lemonade stand foundation infant and childhood primary brain and central nervous system tumors diagnosed in the United States in 2007–2011. Neuro Oncol 16(Suppl 10):x1–x36. doi:10.1093/neuonc/nou327 CrossRefPubMed

20.

Pajtler KW, Witt H, Sill M, Jones DT, Hovestadt V, Kratochwil F, Wani K, Tatevossian R, Punchihewa C, Johann P et al (2015) Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell 27:728–743. doi:10.1016/j.ccell.2015.04.002 CrossRefPubMedPubMedCentral

21.

Paugh BS, Qu C, Jones C, Liu Z, Adamowicz-Brice M, Zhang J, Bax DA, Coyle B, Barrow J, Hargrave D et al (2010) Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 28:3061–3068. doi:10.1200/JCO.2009.26.7252 CrossRefPubMedPubMedCentral

22.

Phillips JJ, Aranda D, Ellison DW, Judkins AR, Croul SE, Brat DJ, Ligon KL, Horbinski C, Venneti S, Zadeh G et al (2013) PDGFRA amplification is common in pediatric and adult high-grade astrocytomas and identifies a poor prognostic group in IDH1 mutant glioblastoma. Brain Pathol 23:565–573. doi:10.1111/bpa.12043 CrossRefPubMedPubMedCentral

23.

Puget S, Philippe C, Bax DA, Job B, Varlet P, Junier MP, Andreiuolo F, Carvalho D, Reis R, Guerrini-Rousseau L et al (2012) Mesenchymal transition and PDGFRA amplification/mutation are key distinct oncogenic events in pediatric diffuse intrinsic pontine gliomas. PLoS One 7:e30313. doi:10.1371/journal.pone.0030313 CrossRefPubMedPubMedCentral

24.

Puissant A, Frumm SM, Alexe G, Bassil CF, Qi J, Chanthery YH, Nekritz EA, Zeid R, Gustafson WC, Greninger P et al (2013) Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov 3:308–323. doi:10.1158/2159-8290.CD-12-0418 CrossRefPubMedPubMedCentral

25.

Reuss DE, Sahm F, Schrimpf D, Wiestler B, Capper D, Koelsche C, Schweizer L, Korshunov A, Jones DT, Hovestadt V et al (2015) ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an “integrated” diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma. Acta Neuropathol 129:133–146. doi:10.1007/s00401-014-1370-3 CrossRefPubMed

26.

Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, Sturm D, Fontebasso AM, Quang DA, Tonjes M et al (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226–231. doi:10.1038/nature10833 CrossRefPubMed

27.

Sturm D, Bender S, Jones DT, Lichter P, Grill J, Becher O, Hawkins C, Majewski J, Jones C, Costello JF et al (2014) Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nat Rev Cancer 14:92–107. doi:10.1038/nrc3655 CrossRefPubMedPubMedCentral

28.

Sturm D, Orr BA, Toprak UH, Hovestadt V, Jones DT, Capper D, Sill M, Buchhalter I, Northcott PA, Leis I et al (2016) New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 164:1060–1072. doi:10.1016/j.cell.2016.01.015 CrossRefPubMedPubMedCentral

29.

Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DT, Konermann C, Pfaff E, Tonjes M, Sill M, Bender S et al (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22:425–437. doi:10.1016/j.ccr.2012.08.024 CrossRefPubMed

30.

Taylor KR, Mackay A, Truffaux N, Butterfield YS, Morozova O, Philippe C, Castel D, Grasso CS, Vinci M, Carvalho D et al (2014) Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat Genet 46:457–461. doi:10.1038/ng.2925 CrossRefPubMedPubMedCentral

31.

van der Maarten L, Hinton G (2008) Visualizing high-dimensional data using t-SNE. J Mach Learn Res 9:2579–2605

32.

Worst BC, van Tilburg CM, Balasubramanian GP, Fiesel P, Witt R, Freitag A, Boudalil M, Previti C, Wolf S, Schmidt S et al (2016) Next-generation personalised medicine for high-risk paediatric cancer patients—the INFORM pilot study. Eur J Cancer 65:91–101. doi:10.1016/j.ejca.2016.06.009 CrossRefPubMed

33.

Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, Becksfort J, Qu C, Ding L, Huether R, Parker M et al (2012) Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44:251–253. doi:10.1038/ng.1102 CrossRefPubMedPubMedCentral

34.

Wu G, Diaz AK, Paugh BS, Rankin SL, Ju B, Li Y, Zhu X, Qu C, Chen X, Zhang J et al (2014) The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46:444–450. doi:10.1038/ng.2938 CrossRefPubMedPubMedCentral

Titel: H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers
verfasst von: Andrey Korshunov
Daniel Schrimpf
Marina Ryzhova
Dominik Sturm
Lukas Chavez
Volker Hovestadt
Tanvi Sharma
Antje Habel
Anna Burford
Chris Jones
Olga Zheludkova
Ella Kumirova
Christof M. Kramm
Andrey Golanov
David Capper
Andreas von Deimling
Stefan M. Pfister
David T. W. Jones
Publikationsdatum: 11.04.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: Acta Neuropathologica / Ausgabe 3/2017
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-017-1710-1

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H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers

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