Download PDF
Semin Neurol 2018; 38(01): 121-130
DOI: 10.1055/s-0038-1635106
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Gliomas in Children

Mariella G. Filbin
1   Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Cancer Center, Boston, Massachusetts
2   Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts
3   The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
,
Dominik Sturm
4   Hopp-Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany
5   Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
6   Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
16 March 2018 (online)

    Permissions and Reprints

Abstract

Gliomas are the most common primary central nervous system (CNS) neoplasms in children and adolescents and are thought to arise from their glial progenitors or stem cells. Although the exact cells of origin for most pediatric gliomas remain to be identified, our current understanding is that specific cell populations during CNS development are susceptible to particular oncogenic events during certain time windows and thus give rise to pediatric gliomas with distinct histological, molecular, and clinical features. These may be roughly segregated into low-grade gliomas (WHO grades I or II; including most mixed glial–neuronal tumors) and high-grade gliomas (WHO grades III or IV) according to their clinical course when untreated, even though this is not yet entirely clear for some of the recently emerging groups. The genetic and epigenetic characterization of pediatric gliomas across ages and histologies has facilitated the delineation of biologically relevant subgroups and have revealed potentially targetable alterations in some of them. This review outlines diagnostic features and molecular alterations in pediatric low- and high-grade gliomas and how the latter might be exploited with future targeted therapeutic strategies.

Keywords

CNS - brain tumor - pediatric glioma - astrocytoma - genetics - epigenetics - targeted therapy
 

  • References

  • 1 Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO Classification of Tumours of the Central Nervous System. Revised. 4th ed. Geneva, Switzerland: WHO Press; 2016
    Google Scholar
  • 2 Listernick R, Charrow J, Gutmann DH. Intracranial gliomas in neurofibromatosis type 1. Am J Med Genet 1999; 89 (01) 38-44
    CrossrefPubMedGoogle Scholar
  • 3 Northrup H, Krueger DA. ; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013; 49 (04) 243-254
    CrossrefPubMedGoogle Scholar
  • 4 Jones DT, Hutter B, Jäger N. , et al; International Cancer Genome Consortium PedBrain Tumor Project. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet 2013; 45 (08) 927-932
    CrossrefPubMedGoogle Scholar
  • 5 Zhang J, Wu G, Miller CP. , et al; St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 2013; 45 (06) 602-612
    CrossrefPubMedGoogle Scholar
  • 6 Jones DT, Kocialkowski S, Liu L. , et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 2008; 68 (21) 8673-8677
    CrossrefPubMedGoogle Scholar
  • 7 Schindler G, Capper D, Meyer J. , et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011; 121 (03) 397-405
    CrossrefPubMedGoogle Scholar
  • 8 Dougherty MJ, Santi M, Brose MS. , et al. Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro Oncol 2010; 12 (07) 621-630
    CrossrefPubMedGoogle Scholar
  • 9 Qaddoumi I, Orisme W, Wen J. , et al. Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol 2016; 131 (06) 833-845
    CrossrefPubMedGoogle Scholar
  • 10 Tatevossian RG, Tang B, Dalton J. , et al. MYB upregulation and genetic aberrations in a subset of pediatric low-grade gliomas. Acta Neuropathol 2010; 120 (06) 731-743
    CrossrefPubMedGoogle Scholar
  • 11 Ramkissoon LA, Horowitz PM, Craig JM. , et al. Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. Proc Natl Acad Sci U S A 2013; 110 (20) 8188-8193
    CrossrefPubMedGoogle Scholar
  • 12 Bandopadhayay P, Ramkissoon LA, Jain P. , et al. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet 2016; 48 (03) 273-282
    CrossrefPubMedGoogle Scholar
  • 13 Bergthold G, Bandopadhayay P, Bi WL. , et al. Pediatric low-grade gliomas: how modern biology reshapes the clinical field. Biochim Biophys Acta 2014; 1845 (02) 294-307
    PubMedGoogle Scholar
  • 14 Bandopadhayay P, Bergthold G, London WB. , et al. Long-term outcome of 4,040 children diagnosed with pediatric low-grade gliomas: an analysis of the Surveillance Epidemiology and End Results (SEER) database. Pediatr Blood Cancer 2014; 61 (07) 1173-1179
    CrossrefPubMedGoogle Scholar
  • 15 Grill J, Couanet D, Cappelli C. , et al. Radiation-induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol 1999; 45 (03) 393-396
    CrossrefPubMedGoogle Scholar
  • 16 Williams NL, Rotondo RL, Bradley JA. , et al. Late effects after radiotherapy for childhood low-grade glioma. Am J Clin Oncol 2016 (e-pub ahead of print)
    PubMedGoogle Scholar
  • 17 Dirks PB, Jay V, Becker LE. , et al. Development of anaplastic changes in low-grade astrocytomas of childhood. Neurosurgery 1994; 34 (01) 68-78
    PubMedGoogle Scholar
  • 18 Sharif S, Ferner R, Birch JM. , et al. Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy. J Clin Oncol 2006; 24 (16) 2570-2575
    CrossrefPubMedGoogle Scholar
  • 19 Gnekow AK, Falkenstein F, von Hornstein S. , et al. Long-term follow-up of the multicenter, multidisciplinary treatment study HIT-LGG-1996 for low-grade glioma in children and adolescents of the German Speaking Society of Pediatric Oncology and Hematology. Neuro Oncol 2012; 14 (10) 1265-1284
    CrossrefPubMedGoogle Scholar
  • 20 Ater JL, Xia C, Mazewski CM. , et al. Nonrandomized comparison of neurofibromatosis type 1 and non-neurofibromatosis type 1 children who received carboplatin and vincristine for progressive low-grade glioma: a report from the Children's Oncology Group. Cancer 2016; 122 (12) 1928-1936
    CrossrefPubMedGoogle Scholar
  • 21 Lassaletta A, Scheinemann K, Zelcer SM. , et al. Phase II weekly vinblastine for chemotherapy-naïve children with progressive low-grade glioma: a Canadian Pediatric Brain Tumor Consortium Study. J Clin Oncol 2016; 34 (29) 3537-3543
    CrossrefPubMedGoogle Scholar
  • 22 Packer RJ, Pfister S, Bouffet E. , et al. Pediatric low-grade gliomas: implications of the biologic era. Neuro Oncol 2017; 19 (06) 750-761
    PubMedGoogle Scholar
  • 23 Franz DN, Agricola K, Mays M. , et al. Everolimus for subependymal giant cell astrocytoma: 5-year final analysis. Ann Neurol 2015; 78 (06) 929-938
    CrossrefPubMedGoogle Scholar
  • 24 Krueger DA, Care MM, Holland K. , et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010; 363 (19) 1801-1811
    CrossrefPubMedGoogle Scholar
  • 25 Kieran MW, Yao X, Macy M. , et al. Final results of a prospective multi-institutional phase II study of everolimus (RAD001), an mTor inhibitor, in pediatric patients with recurrent or progressive low-grade glioma. A POETIC consortium trial. Neuro Oncol 2014; 16 (Suppl. 03) iii27
    PubMedGoogle Scholar
  • 26 Kieran MW, Bouffet E, Tabori U. , et al. The first study of dabrafenib in pediatric patients with BRAF V600–mutant relapsed or refractory low-grade gliomas. Ann Oncol 2016; 27 (06) 19
    PubMedGoogle Scholar
  • 27 Karajannis MA, Legault G, Fisher MJ. , et al. Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. Neuro Oncol 2014; 16 (10) 1408-1416
    CrossrefPubMedGoogle Scholar
  • 28 Sun Y, Alberta JA, Pilarz C. , et al. A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas. Neuro Oncol 2017; 19 (06) 774-785
    PubMedGoogle Scholar
  • 29 Banerjee A, Jakacki RI, Onar-Thomas A. , et al. A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study. Neuro Oncol 2017; 19 (08) 1135-1144
    CrossrefPubMedGoogle Scholar
  • 30 Dombi E, Baldwin A, Marcus LJ. , et al. Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N Engl J Med 2016; 375 (26) 2550-2560
    CrossrefPubMedGoogle Scholar
  • 31 Johansson G, Andersson U, Melin B. Recent developments in brain tumor predisposing syndromes. Acta Oncol 2016; 55 (04) 401-411
    CrossrefPubMedGoogle Scholar
  • 32 Buczkowicz P, Bartels U, Bouffet E, Becher O, Hawkins C. Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications. Acta Neuropathol 2014; 128 (04) 573-581
    CrossrefPubMedGoogle Scholar
  • 33 Huang TY, Piunti A, Lulla RR. , et al. Detection of histone H3 mutations in cerebrospinal fluid-derived tumor DNA from children with diffuse midline glioma. Acta Neuropathol Commun 2017; 5 (01) 28
    CrossrefPubMedGoogle Scholar
  • 34 Broniscer A, Chamdine O, Hwang S. , et al. Gliomatosis cerebri in children shares molecular characteristics with other pediatric gliomas. Acta Neuropathol 2016; 131 (02) 299-307
    CrossrefPubMedGoogle Scholar
  • 35 Schwartzentruber J, Korshunov A, Liu XY. , et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 2012; 482 (7384): 226-231
    CrossrefPubMedGoogle Scholar
  • 36 Wu G, Broniscer A, McEachron TA. , et al; St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 2012; 44 (03) 251-253
    CrossrefPubMedGoogle Scholar
  • 37 Sturm D, Orr BA, Toprak UH. , et al. New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 2016; 164 (05) 1060-1072
    CrossrefPubMedGoogle Scholar
  • 38 Sturm D, Witt H, Hovestadt V. , et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 2012; 22 (04) 425-437
    CrossrefPubMedGoogle Scholar
  • 39 Castel D, Philippe C, Calmon R. , et al. Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol 2015; 130 (06) 815-827
    CrossrefPubMedGoogle Scholar
  • 40 Lewis PW, Müller MM, Koletsky MS. , et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 2013; 340 (6134): 857-861
    CrossrefPubMedGoogle Scholar
  • 41 Wu G, Diaz AK, Paugh BS. , et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 2014; 46 (05) 444-450
    CrossrefPubMedGoogle Scholar
  • 42 Fontebasso AM, Papillon-Cavanagh S, Schwartzentruber J. , et al. Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat Genet 2014; 46 (05) 462-466
    CrossrefPubMedGoogle Scholar
  • 43 Buczkowicz P, Hoeman C, Rakopoulos P. , et al. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat Genet 2014; 46 (05) 451-456
    CrossrefPubMedGoogle Scholar
  • 44 Taylor KR, Mackay A, Truffaux N. , et al. Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat Genet 2014; 46 (05) 457-461
    CrossrefPubMedGoogle Scholar
  • 45 Korshunov A, Schrimpf D, Ryzhova M. , et al. H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers. Acta Neuropathol 2017; 134 (03) 507-516
    CrossrefPubMedGoogle Scholar
  • 46 Jones C, Baker SJ. Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma. Nat Rev Cancer 2014; 14(10)
    PubMedGoogle Scholar
  • 47 Jones C, Karajannis MA, Jones DTW. , et al. Pediatric high-grade glioma: biologically and clinically in need of new thinking. Neuro Oncol 2017; 19 (02) 153-161
    PubMedGoogle Scholar
  • 48 Cohen KJ, Pollack IF, Zhou T. , et al. Temozolomide in the treatment of high-grade gliomas in children: a report from the Children's Oncology Group. Neuro Oncol 2011; 13 (03) 317-323
    CrossrefPubMedGoogle Scholar
  • 49 Jenkin RD, Boesel C, Ertel I. , et al. Brain-stem tumors in childhood: a prospective randomized trial of irradiation with and without adjuvant CCNU, VCR, and prednisone. A report of the Childrens Cancer Study Group. J Neurosurg 1987; 66 (02) 227-233
    CrossrefPubMedGoogle Scholar
  • 50 Macy ME, Kieran MW, Chi SN. , et al. A pediatric trial of radiation/cetuximab followed by irinotecan/cetuximab in newly diagnosed diffuse pontine gliomas and high-grade astrocytomas: a Pediatric Oncology Experimental Therapeutics Investigators' Consortium study. Pediatr Blood Cancer 2017;64(11)
    PubMedGoogle Scholar
  • 51 Bailey S, Howman A, Wheatley K. , et al. Diffuse intrinsic pontine glioma treated with prolonged temozolomide and radiotherapy--results of a United Kingdom phase II trial (CNS 2007 04). Eur J Cancer 2013; 49 (18) 3856-3862
    CrossrefPubMedGoogle Scholar
  • 52 Hummel TR, Salloum R, Drissi R. , et al. A pilot study of bevacizumab-based therapy in patients with newly diagnosed high-grade gliomas and diffuse intrinsic pontine gliomas. J Neurooncol 2016; 127 (01) 53-61
    CrossrefPubMedGoogle Scholar
  • 53 Mandell LR, Kadota R, Freeman C. , et al. There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a Pediatric Oncology Group phase III trial comparing conventional vs. hyperfractionated radiotherapy. Int J Radiat Oncol Biol Phys 1999; 43 (05) 959-964
    CrossrefPubMedGoogle Scholar
  • 54 Packer RJ, Boyett JM, Zimmerman RA. , et al. Outcome of children with brain stem gliomas after treatment with 7800 cGy of hyperfractionated radiotherapy. A Childrens Cancer Group Phase I/II Trial. Cancer 1994; 74 (06) 1827-1834
    CrossrefPubMedGoogle Scholar
  • 55 Janssens GO, Gandola L, Bolle S. , et al. Survival benefit for patients with diffuse intrinsic pontine glioma (DIPG) undergoing re-irradiation at first progression: a matched-cohort analysis on behalf of the SIOP-E-HGG/DIPG working group. Eur J Cancer 2017; 73: 38-47
    CrossrefPubMedGoogle Scholar
  • 56 Morales La Madrid A, Santa-María V, Cruz Martinez O. , et al. Second re-irradiation for DIPG progression, re-considering “old strategies” with new approaches. Childs Nerv Syst 2017; 33 (05) 849-852
    CrossrefPubMedGoogle Scholar
  • 57 Korshunov A, Ryzhova M, Hovestadt V. , et al. Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol 2015; 129 (05) 669-678
    CrossrefPubMedGoogle Scholar
  • 58 Finlay JL, Boyett JM, Yates AJ. , et al; Childrens Cancer Group. Randomized phase III trial in childhood high-grade astrocytoma comparing vincristine, lomustine, and prednisone with the eight-drugs-in-1-day regimen. J Clin Oncol 1995; 13 (01) 112-123
    CrossrefPubMedGoogle Scholar
  • 59 Sposto R, Ertel IJ, Jenkin RD. , et al. The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: results of a randomized trial. A report from the Childrens Cancer Study Group. J Neurooncol 1989; 7 (02) 165-177
    CrossrefPubMedGoogle Scholar
  • 60 Pollack IF, Boyett JM, Yates AJ. , et al; Children's Cancer Group. The influence of central review on outcome associations in childhood malignant gliomas: results from the CCG-945 experience. Neuro Oncol 2003; 5 (03) 197-207
    CrossrefPubMedGoogle Scholar
  • 61 Jakacki RI, Cohen KJ, Buxton A. , et al. Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: a report of the Children's Oncology Group ACNS0423 study. Neuro Oncol 2016; 18 (10) 1442-1450
    CrossrefPubMedGoogle Scholar
  • 62 Ramkissoon SH, Bandopadhayay P, Hwang J. , et al. Clinical targeted exome-based sequencing in combination with genome-wide copy number profiling: precision medicine analysis of 203 pediatric brain tumors. Neuro Oncol 2017; 19 (07) 986-996
    PubMedGoogle Scholar
  • 63 Worst BC, van Tilburg CM, Balasubramanian GP. , et al. Next-generation personalised medicine for high-risk paediatric cancer patients - the INFORM pilot study. Eur J Cancer 2016; 65: 91-101
    CrossrefPubMedGoogle Scholar
  • 64 Mistry M, Zhukova N, Merico D. , et al. BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. J Clin Oncol 2015; 33 (09) 1015-1022
    CrossrefPubMedGoogle Scholar
  • 65 Paugh BS, Zhu X, Qu C. , et al. Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas. Cancer Res 2013; 73 (20) 6219-6229
    CrossrefPubMedGoogle Scholar
  • 66 Koschmann C, Zamler D, MacKay A. , et al. Characterizing and targeting PDGFRA alterations in pediatric high-grade glioma. Oncotarget 2016; 7 (40) 65696-65706
    CrossrefPubMedGoogle Scholar
  • 67 Hoffman LM, DeWire M, Ryall S. , et al. Spatial genomic heterogeneity in diffuse intrinsic pontine and midline high-grade glioma: implications for diagnostic biopsy and targeted therapeutics. Acta Neuropathol Commun 2016; 4: 1
    CrossrefPubMedGoogle Scholar
  • 68 Qaddoumi I, Kocak M, Pai Panandiker AS. , et al. Phase II trial of erlotinib during and after radiotherapy in children with newly diagnosed high-grade gliomas. Front Oncol 2014; 4: 67
    PubMedGoogle Scholar
  • 69 Sturm D, Bender S, Jones DT. , et al. Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nat Rev Cancer 2014; 14 (02) 92-107
    CrossrefPubMedGoogle Scholar
  • 70 Filbin MG, Suvà ML. Gliomas genomics and epigenomics: arriving at the start and knowing it for the first time. Annu Rev Pathol 2016; 11: 497-521
    CrossrefPubMedGoogle Scholar
  • 71 Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell 2012; 150 (01) 12-27
    CrossrefPubMedGoogle Scholar
  • 72 Saygin C, Carraway HE. Emerging therapies for acute myeloid leukemia. J Hematol Oncol 2017; 10 (01) 93
    CrossrefPubMedGoogle Scholar
  • 73 Grasso CS, Tang Y, Truffaux N. , et al. Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat Med 2015; 21 (06) 555-559
    CrossrefPubMedGoogle Scholar
  • 74 Singleton WG, Collins AM, Bienemann AS. , et al. Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model. Int J Nanomedicine 2017; 12: 1385-1399
    CrossrefPubMedGoogle Scholar
  • 75 Zhou Z, Singh R, Souweidane MM. Convection-enhanced delivery for diffuse intrinsic pontine glioma treatment. Curr Neuropharmacol 2017; 15 (01) 116-128
    PubMedGoogle Scholar
  • 76 Hummel TR, Wagner L, Ahern C. , et al. A pediatric phase 1 trial of vorinostat and temozolomide in relapsed or refractory primary brain or spinal cord tumors: a Children's Oncology Group phase 1 consortium study. Pediatr Blood Cancer 2013; 60 (09) 1452-1457
    CrossrefPubMedGoogle Scholar
  • 77 Hashizume R, Andor N, Ihara Y. , et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat Med 2014; 20 (12) 1394-1396
    CrossrefPubMedGoogle Scholar
  • 78 Mohammad F, Weissmann S, Leblanc B. , et al. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. Nat Med 2017; 23 (04) 483-492
    CrossrefPubMedGoogle Scholar
  • 79 Piunti A, Hashizume R, Morgan MA. , et al. Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas. Nat Med 2017; 23 (04) 493-500
    CrossrefPubMedGoogle Scholar