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NeuroMolecular Medicine

, Volume 19, Issue 2–3, pp 256–270 | Cite as

Molecular Basis of Pediatric Brain Tumors

  • Alexia Klonou
  • Christina Piperi
  • Antonios N. Gargalionis
  • Athanasios G. Papavassiliou
Review Paper

Abstract

Brain tumors emerge as the second commonest type of pediatric solid tumors following hematologic malignancies. Genomic profiling of low- and high-grade gliomas, ependymomas and medulloblastomas has revealed chromosomal abnormalities and specific gene mutations which have been associated with aberrant activation of crucial signal transduction pathways, including mitogen-activated protein kinase, mammalian target of rapamycin and retinoblastoma tumor suppressor signaling. Furthermore, pediatric high-grade gliomas are associated with chromatin remodeling defects and somatic histone gene mutations that affect prognosis. This review provides an update of the molecular and genetic alterations that characterize pediatric brain tumors, and discusses novel therapeutic approaches targeting these abnormalities.

Keywords

Pediatric gliomas Mutations MAPK mTOR RB 

Notes

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Antonelli, M., Badiali, M., Moi, L., Buttarelli, F., Baldi, C., Massimino, M., et al. (2015). KIAA1549: BRAF fusion gene in pediatric brain tumors of various histogenesis. Pediatric Blood and Cancer, 62(4), 724–727.PubMedCrossRefGoogle Scholar
  2. Bandopadhayay, P., Bergthold, G., Nguyen, B., Schubert, S., Gholamin, S., Tang, Y., et al. (2014). BET bromodomain inhibition of MYC-amplified medulloblastoma. Clinical Cancer Research, 20(4), 912–925.PubMedCrossRefGoogle Scholar
  3. Bautista, F., Paci, A., Minard-Colin, V., Dufour, C., Grill, J., Lacroix, L., et al. (2014). Vemurafenib in pediatric patients with BRAFV600E mutated high-grade gliomas. Pediatric Blood and Cancer, 61(6), 1101–1103.PubMedCrossRefGoogle Scholar
  4. Bax, D. A., Mackay, A., Little, S. E., Carvalho, D., Viana-Pereira, M., Tamber, N., et al. (2010). A distinct spectrum of copy number aberrations in pediatric high-grade gliomas. Clinical Cancer Research, 16(13), 3368–3377.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Becher, O. J., & Wechsler-Reya, R. J. (2014). Cancer. For pediatric glioma, leave no histone unturned. Science, 346(6216), 1458–1459.PubMedCrossRefGoogle Scholar
  6. Becker, A., Scapulatempo-Neto, C., Carloni, A., Paulino, A., Sheren, J., Aisner, D., et al. (2015). KIAA1549: BRAF gene fusion and FGFR1 hotspot mutations are prognostic factors in pilocytic astrocytomas. Journal of Neuropathology and Experimental Neurology, 74(7), 743–754.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Bergthold, G., Bandopadhayay, P., Bi, W. L., Ramkissoon, L., Stiles, C., Segal, R. A., et al. (2014). Pediatric low-grade gliomas: How modern biology reshapes the clinical field. Biochimica et Biophysica Acta, 1845(2), 294–307.PubMedPubMedCentralGoogle Scholar
  8. Bergthold, G., Bandopadhayay, P., Hoshida, Y., Ramkissoon, S., Ramkissoon, L., Rich, B., et al. (2015). Expression profiles of 151 pediatric low-grade gliomas reveal molecular differences associated with location and histological subtype. Neuro Oncology, 17(11), 1486–1496.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Bjerke, L., Mackay, A., Nandhabalan, M., Burford, A., Jury, A., Popov, S., et al. (2013). Histone H3.3. mutations drive pediatric glioblastoma through upregulation of MYCN. Cancer Discovery, 3(5), 512–519.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Buccoliero, A. M., Castiglione, F., Degl’Innocenti, D. R., Gheri, C. F., Genitori, L., & Taddei, G. L. (2012). IDH1 mutation in pediatric gliomas: Has it a diagnostic and prognostic value? Fetal and Pediatric Pathology, 31(5), 278–282.PubMedCrossRefGoogle Scholar
  11. Buczkowicz, P., Hoeman, C., Rakopoulos, P., Pajovic, S., Letourneau, L., Dzamba, M., et al. (2014). Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nature Genetics, 46(5), 451–456.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Cin, H., Meyer, C., Herr, R., Janzarik, W. G., Lambert, S., Jones, D. T., et al. (2011). Oncogenic FAM131B–BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma. Acta Neuropathologica, 121(6), 763–774.PubMedCrossRefGoogle Scholar
  13. Costa, R. M., Federov, N. B., Kogan, J. H., Murphy, G. G., Stern, J., Ohno, M., et al. (2002). Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature, 415(6871), 526–530.PubMedCrossRefGoogle Scholar
  14. Cruzeiro, G. A., Dos Reis, M. B., Silveira, V. S., Lira, R. C., Carlotti, C. G., Neder, L. et al. (2017). HIF1A is overexpressed in medulloblastoma and its inhibition reduces proliferation and increases EPAS1 and ATG16L1 methylation. Current Cancer Drug Targets. doi: 10.2174/1568009617666170315162525.PubMedGoogle Scholar
  15. Dasgupta, T., & Haas-Kogan, D. A. (2013). The combination of novel targeted molecular agents and radiation in the treatment of pediatric gliomas. Frontiers in Oncology, 3. Article 110.Google Scholar
  16. Downing, J. R., Wilson, R. K., Zhang, J., Mardis, E. R., Pui, C. H., Ding, L., et al. (2012). The pediatric cancer genome project. Nature Genetics, 44(6), 619–622.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Dubuc, A. M., Remke, M., Korshunov, A., Northcott, P. A., Zhan, S. H., Mendez-Lago, M., et al. (2013). Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma. Acta Neuropathologica, 125(3), 373–384.PubMedCrossRefGoogle Scholar
  18. Fattet, S., Haberler, C., Legoix, P., Varlet, P., Lellouch-Tubiana, A., Lair, S., et al. (2009). Beta-catenin status in paediatric medulloblastomas: Correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics. The Journal of Pathology, 218(1), 86–94.PubMedCrossRefGoogle Scholar
  19. Fontebasso, A. M., Gayden, T., Nikbakht, H., Neirinck, M., Papillon-Cavanagh, S., Majewski, J., et al. (2014a). Epigenetic dysregulation: A novel pathway of oncogenesis in pediatric brain tumors. Acta Neuropathologica, 128(5), 615–627.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Fontebasso, A. M., Liu, X. Y., Sturm, D., & Jabado, N. (2013). Chromatin remodeling defects in pediatric and young adult glioblastoma: A tale of a variant histone 3 tail. Brain Pathology, 23(2), 210–216.PubMedCrossRefGoogle Scholar
  21. Fontebasso, A. M., Papillon-Cavanagh, S., Schwartzentruber, J., Nikbakht, H., Gerges, N., Fiset, P. O., et al. (2014b). Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nature Genetics, 46(5), 462–466.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Forshew, T., Tatevossian, R. G., Lawson, A. R., Ma, J., Neale, G., Ogunkolade, B. W., et al. (2009). Activation of the ERK/MAPK pathway: A signature genetic defect in posterior fossa pilocytic astrocytomas. The Journal of Pathology, 218(2), 172–181.PubMedCrossRefGoogle Scholar
  23. Gajjar, A., Bowers, D. C., Karajannis, M. A., Leary, S., Witt, H., & Gottardo, N. G. (2015). Pediatric brain tumors: Innovative genomic information is transforming the diagnostic and clinical landscape. Journal of Clinical Oncology, 33(27), 2986–2998.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Gajjar, A., Pfister, S. M., Taylor, M. D., & Gilbertson, R. J. (2014). Molecular insights into pediatric brain tumors have the potential to transform therapy. Clinical Cancer Research, 20(22), 5630–5640.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Garcia, I., Crowther, A. J., Gama, V., Miller, C. R., Deshmukh, M., & Gershon, T. R. (2013). Bax deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation. Oncogene, 32(18), 2304–2314. doi: 10.1038/onc.2012.248.PubMedCrossRefGoogle Scholar
  26. Garcia, M. A., Solomon, D. A., & Haas-Kogan, D. A. (2016). Exploiting molecular biology for diagnosis and targeted management of pediatric low-grade gliomas. Future Oncology, 12(12), 1493–1506. doi: 10.2217/fon-2016-0039.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Gerges, N., Fontebasso, A. M., Albrecht, S., Faury, D., & Jabado, N. (2013). Pediatric high-grade astrocytomas: A distinct neuro-oncological paradigm. Genome Medicine, 5(7), 66.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Gielen, G. H., Gessi, M., Hammes, J., Kramm, C. M., Waha, A., & Pietsch, T. (2013). H3F3A K27M mutation in pediatric CNS tumors: A marker for diffuse high-grade astrocytomas. American Journal of Clinical Pathology, 139(3), 345–349.PubMedCrossRefGoogle Scholar
  29. Gilheeney, S. W., & Kieran, M. W. (2012). Differences in molecular genetics between pediatric and adult malignant astrocytomas: Age matters. Future Oncology, 8(5), 549–558.PubMedCrossRefGoogle Scholar
  30. Glod, J., Rahme, G., Kaur, H., Raabe, E. H., Hwang, E., & Israel, M. (2016). Pediatric brain tumors: Current knowledge and therapeutic opportunities. Journal of Pediatric Hematology/Oncology, 38(4), 249–260.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Goldberg, A. D., Banaszynski, L. A., et al. (2010). Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell, 140(5), 678–691.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Hargrave, D. (2009). Paediatric high and low grade glioma: The impact of tumour biology on current and future therapy. British Journal of Neurosurgery, 23(4), 351–363.PubMedCrossRefGoogle Scholar
  33. Hassan, B., Akcakanat, A., Holder, A. M., & Meric-Bernstam, F. (2013). Targeting the PI3-kinase/Akt/mTOR signaling pathway. Surgical Oncology Clinics of North America, 22(4), 641–664.PubMedCrossRefGoogle Scholar
  34. Heaphy, C. M., de Wilde, R. F., Jiao, Y., Klein, A. P., Edil, B. H., Shi, C., et al. (2011). Altered telomeres in tumors with ATRX and DAXX mutations. Science, 333(6041), 425.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Hemmati, H. D., Nakano, I., Lazareff, J. A., Masterman-Smith, M., Geschwind, D. H., Bronner-Fraser, M., et al. (2003). Cancerous stem cells can arise from pediatric brain tumors. Proceedings of the National Academy of Sciences USA, 100(25), 15178–15183.CrossRefGoogle Scholar
  36. Hernaiz Driever, P., von Hornstein, S., Pietsch, T., Kortmann, R., Warmuth-Metz, M., Emser, A., et al. (2010). Natural history and management of low-grade glioma in NF-1 children. Journal of Neuro-Oncology, 100(2), 199–207.PubMedCrossRefGoogle Scholar
  37. Hervey-Jumper, S. L., Garton, H. J., Lau, D., Altshuler, D., Quint, D. J., Robertson, P. L., et al. (2014). Differences in vascular endothelial growth factor receptor expression and correlation with the degree of enhancement in medulloblastoma. Journal of Neurosurgery: Pediatrics, 14(2), 121–128.PubMedGoogle Scholar
  38. Ho, C., Mobley, B., Gordish-Dressman, H., VandenBussche, C., Mason, G., Bornhorst, M., et al. (2015). A clinicopathologic study of diencephalic pediatric low-grade gliomas with BRAF V600 mutation. Acta Neuropathologica, 130(4), 575–585.PubMedCrossRefGoogle Scholar
  39. Hovestadt, V., Jones, D. T., Picelli, S., Wang, W., Kool, M., Northcott, P. A., et al. (2014). Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature, 510(7506), 537–541.PubMedCrossRefGoogle Scholar
  40. Huillard, E., Hashizume, R., Phillips, J. J., Griveau, A., Ihrie, R. A., Aoki, Y., et al. (2012). Cooperative interactions of BRAFV600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy. Proceedings of the National Academy of Sciences USA, 109(22), 8710–8715.CrossRefGoogle Scholar
  41. Huse, J. T., & Rosenblum, M. K. (2015). The emerging molecular foundations of pediatric brain tumors. Journal of Child Neurology, 30(13), 1838–1850.PubMedCrossRefGoogle Scholar
  42. Jacob, K., Albrecht, S., Sollier, C., Faury, D., Sader, E., Montpetit, A., et al. (2009). Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. British Journal of Cancer, 101(4), 722–733.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Jacob, K., Quang-Khuong, D. A., Jones, D. T., Witt, H., Lambert, S., Albrecht, S., et al. (2011). Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. Clinical Cancer Research, 17(14), 4650–4660.PubMedCrossRefGoogle Scholar
  44. Jones, C., Perryman, L., & Hargrave, D. (2012a). Paediatric and adult malignant glioma: Close relatives or distant cousins? Nature Reviews Clinical Oncology, 9(7), 400–413.PubMedCrossRefGoogle Scholar
  45. Jones, D. T., Gronych, J., Lichter, P., Witt, O., & Pfister, S. M. (2012b). MAPK pathway activation in pilocytic astrocytoma. Cellular and Molecular Life Sciences, 69(11), 1799–1811.PubMedCrossRefGoogle Scholar
  46. Jones, D. T., Hutter, B., Jager, N., Korshunov, A., Kool, M., Warnatz, H. J., et al. (2013). Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nature Genetics, 45(8), 927–932.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Jones, D. T., Ichimura, K., Liu, L., Pearson, D. M., Plant, K., & Collins, V. P. (2006). Genomic analysis of pilocytic astrocytomas at 0.97 Mb resolution shows an increasing tendency toward chromosomal copy number change with age. Journal of Neuropathology and Experimental Neurology, 65(11), 1049–1058.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Jones, D. T., Jager, N., Kool, M., Zichner, T., Hutter, B., Sultan, M., et al. (2012c). Dissecting the genomic complexity underlying medulloblastoma. Nature, 488(7409), 100–105.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Jones, D. T., Kocialkowski, S., Liu, L., Pearson, D. M., Backlund, L. M., Ichimura, K., et al. (2008). Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Research, 68(21), 8673–8677.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Jones, D. T., Kocialkowski, S., Liu, L., Pearson, D. M., Ichimura, K., & Collins, V. P. (2009). Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549: BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene, 28(20), 2119–2123.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Khuong-Quang, D. A., Buczkowicz, P., Rakopoulos, P., Liu, X. Y., Fontebasso, A. M., Bouffet, E., et al. (2012). K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathologica, 124(3), 439–447.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Kieran, M. W., Walker, D., Frappaz, D., & Prados, M. (2010). Brain tumors: From childhood through adolescence into adulthood. Journal of Clinical Oncology, 28(32), 4783–4789.PubMedCrossRefGoogle Scholar
  53. Kleiblova, P., Shaltiel, I. A., Benada, J., Ševčík, J., Pecháčková, S., Pohlreich, P., et al. (2013). Gain-of-function mutations of PPM1D/Wip1 impair the p53-dependent G1 checkpoint. Journal of Cell Biology, 201, 511–521.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Kleinschmidt-DeMasters, B. K., Aisner, D. L., Birks, D. K., & Foreman, N. K. (2013). Epithelioid GBMs show a high percentage of BRAF V600E mutation. The American Journal of Surgical Pathology, 37(5), 685–698.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Knobbe, C. B., Reifenberger, J., & Reifenberger, G. (2004). Mutation analysis of the Ras pathway genes NRAS, HRAS, KRAS and BRAF in glioblastomas. Acta Neuropathologica, 108(6), 467–470.PubMedCrossRefGoogle Scholar
  56. Krueger, D. A., Care, M. M., Agricola, K., Tudor, C., Mays, M., & Franz, D. N. (2013). Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology, 80(6), 574–580.PubMedPubMedCentralCrossRefGoogle Scholar
  57. Lassaletta, A., Zapotocky, M., Bouffet, E., Hawkins, C., & Tabori, U. (2016). An integrative molecular and genomic analysis of pediatric hemispheric low-grade gliomas: An update. Childs Nervous System, 32(10), 1789–1797.CrossRefGoogle Scholar
  58. Lawrence, M. S., Stojanov, P., Mermel, C. H., Robinson, J. T., Garraway, L. A., Golub, T. R., et al. (2014). Discovery and saturation analysis of cancer genes across 21 tumour types. Nature, 505(7484), 495–501.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Le, L. Q., & Parada, L. F. (2007). Tumor microenvironment and neurofibromatosis type I: Connecting the GAPs. Oncogene, 26(32), 4609–4616.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Lin, A., Rodriguez, F. J., Karajannis, M. A., Williams, S. C., Legault, G., Zagzag, D., et al. (2012). BRAF alterations in primary glial and glioneuronal neoplasms of the central nervous system with identification of 2 novel KIAA1549: BRAF fusion variants. Journal of Neuropathology and Experimental Neurology, 71(1), 66–72.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Liu, K., Pajtler, K., Worst, B., Pfister, S., & Wechsler-Reya, R. (2017). Molecular mechanisms and therapeutic targets in pediatric brain tumors. Science Signaling, 10(470), eaaf7593. doi: 10.1126/scisignal.aaf7593.CrossRefGoogle Scholar
  62. Liu, X. Y., Gerges, N., Korshunov, A., Sabha, N., Khuong-Quang, D. A., Fontebasso, A. M., et al. (2012). Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations. Acta Neuropathologica, 124(5), 615–625.PubMedCrossRefGoogle Scholar
  63. Louis, D. N., Ohgaki, H., Wiestler, O. D., Cavenee, W. K., Burger, P. C., Jouvet, A., et al. (2007). The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathologica, 114(2), 97–109.PubMedPubMedCentralCrossRefGoogle Scholar
  64. Louis, D. N., Perry, A., Reifenberger, G., von Deimling, A., Figarella-Branger, D., Cavenee, W. K., et al. (2016). The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathologica, 131(6), 803–820.PubMedCrossRefGoogle Scholar
  65. Lulla, R., Saratsis, A., & Hashizume, R. (2016). Mutations in chromatin machinery and pediatric high-grade glioma. Science Advances, 2(3), e1501354. doi: 10.1126/sciadv.1501354.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Mack, S. C., & Northcott, P. A. (2017). Genomic analysis of childhood brain tumors: Methods for genome-wide discovery and precision medicine become mainstream. Journal of Clinical Oncology, 35(21), 2346–2354.PubMedCrossRefGoogle Scholar
  67. Mack, S. C., Witt, H., Piro, R. M., Gu, L., Zuyderduyn, S., Stutz, A. M., et al. (2014). Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature, 506(7489), 445–450.PubMedPubMedCentralCrossRefGoogle Scholar
  68. McLendon, et al. (2008). Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature, 455(7216), 1061–1068.CrossRefGoogle Scholar
  69. Nicolaides, T. P., Li, H., Solomon, D. A., Hariono, S., Hashizume, R., Barkovich, K., et al. (2011). Targeted therapy for BRAFV600E malignant astrocytoma. Clinical Cancer Research, 17(24), 7595–7604.PubMedPubMedCentralCrossRefGoogle Scholar
  70. Northcott, P. A., Jones, D. T., Kool, M., Robinson, G. W., Gilbertson, R. J., Cho, Y. J., et al. (2012). Medulloblastomics: The end of the beginning. Nature Reviews Cancer, 12(12), 818–834.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Northcott, P. A., Lee, C., Zichner, T., Stutz, A. M., Erkek, S., Kawauchi, D., et al. (2014). Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature, 511(7510), 428–434.PubMedPubMedCentralCrossRefGoogle Scholar
  72. Northcott, P. A., Pfister, S. M., & Jones, D. T. (2015). Next-generation (epi)genetic drivers of childhood brain tumours and the outlook for targeted therapies. The Lancet Oncology, 16(6), e293–e302.PubMedCrossRefGoogle Scholar
  73. Park, S., Won, J., Kim, S., Lee, Y., Park, C., Kim, S., et al. (2017). Molecular testing of brain tumor. Journal of Pathology and Translational Medicine, 51(3), 205–223.PubMedPubMedCentralCrossRefGoogle Scholar
  74. Parsons, D. W., Jones, S., Zhang, X., Lin, J. C., Leary, R. J., Angenendt, P., et al. (2008). An integrated genomic analysis of human glioblastoma multiforme. Science, 321(5897), 1807–1812.PubMedPubMedCentralCrossRefGoogle Scholar
  75. Paugh, B. S., Broniscer, A., Qu, C., Miller, C. P., Zhang, J., Tatevossian, R. G., et al. (2011). Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. Journal of Clinical Oncology, 29(30), 3999–4006.PubMedPubMedCentralCrossRefGoogle Scholar
  76. Paugh, B. S., Qu, C., Jones, C., Liu, Z., Adamowicz-Brice, M., Zhang, J., et al. (2010). Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. Journal of Clinical Oncology, 28(18), 3061–3068.PubMedPubMedCentralCrossRefGoogle Scholar
  77. Paugh, B. S., Zhu, X., Qu, C., Endersby, R., Diaz, A. K., Zhang, J., et al. (2013). Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas. Cancer Research, 73(20), 6219–6229.PubMedPubMedCentralCrossRefGoogle Scholar
  78. Penman, C., Faulkner, C., Lowis, S., & Kurian, K. (2015). Current understanding of BRAF alterations in diagnosis, prognosis, and therapeutic targeting in pediatric low-grade gliomas. Frontiers in Oncology, eCollection 2015.Google Scholar
  79. Populo, H., Lopes, J. M., & Soares, P. (2012). The mTOR signalling pathway in human cancer. International Journal of Molecular Sciences, 13(2), 1886–1918.PubMedPubMedCentralCrossRefGoogle Scholar
  80. Puget, S., Philippe, C., Bax, D. A., Job, B., Varlet, P., Junier, M. P., et al. (2012). Mesenchymal transition and PDGFRA amplification/mutation are key distinct oncogenic events in pediatric diffuse intrinsic pontine gliomas. PLoS ONE, 7(2), e30313.PubMedPubMedCentralCrossRefGoogle Scholar
  81. Pugh, T. J., Weeraratne, S. D., Archer, T. C., Pomeranz Krummel, D. A., Auclair, D., Bochicchio, J., et al. (2012). Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature, 488(7409), 106–110.PubMedPubMedCentralCrossRefGoogle Scholar
  82. Qu, H. Q., Jacob, K., Fatet, S., Ge, B., Barnett, D., Delattre, O., et al. (2010). Genome-wide profiling using single-nucleotide polymorphism arrays identifies novel chromosomal imbalances in pediatric glioblastomas. Neuro Oncology, 12(2), 153–163.PubMedPubMedCentralCrossRefGoogle Scholar
  83. Raabe, E. H., Lim, K. S., Kim, J. M., Meeker, A., Mao, X. G., Nikkhah, G., et al. (2011). BRAF activation induces transformation and then senescence in human neural stem cells: A pilocytic astrocytoma model. Clinical Cancer Research, 17(11), 3590–3599.PubMedPubMedCentralCrossRefGoogle Scholar
  84. Ramkissoon, L. A., Horowitz, P. M., Craig, J. M., Ramkissoon, S. H., Rich, B. E., Schumacher, S. E., et al. (2013). Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. Proceedings of the National Academy of Sciences USA, 110(20), 8188–8193.CrossRefGoogle Scholar
  85. Rausch, T., Jones, D. T., Zapatka, M., Stütz, A. M., Zichner, T., Weischenfeldt, J., et al. (2012). Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell, 148(1–2), 59–71.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Reuss, D., & von Deimling, A. (2009). Hereditary tumor syndromes and gliomas. Recent Results in Cancer Research, 171, 83–102.PubMedCrossRefGoogle Scholar
  87. Robinson, G., Parker, M., Kranenburg, T. A., Lu, C., Chen, X., Ding, L., et al. (2012). Novel mutations target distinct subgroups of medulloblastoma. Nature, 488(7409), 43–48.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Rodriguez, E. F., Scheithauer, B. W., Giannini, C., Rynearson, A., Cen, L., Hoesley, B., et al. (2011). PI3K/AKT pathway alterations are associated with clinically aggressive and histologically anaplastic subsets of pilocytic astrocytoma. Acta Neuropathologica, 121(3), 407–420.PubMedCrossRefGoogle Scholar
  89. Rosner, M., Hanneder, M., Siegel, N., Valli, A., & Hengstschlager, M. (2008). The tuberous sclerosis gene products hamartin and tuberin are multifunctional proteins with a wide spectrum of interacting partners. Mutation Research, 658(3), 234–246.PubMedCrossRefGoogle Scholar
  90. Roujeau, T., Machado, G., Garnett, M. R., Miquel, C., Puget, S., Geoerger, B., et al. (2007). Stereotactic biopsy of diffuse pontine lesions in children. Journal of Neurosurgery, 107(1 Suppl), 1–4.PubMedGoogle Scholar
  91. Ryall, S., Krishnatry, R., Arnoldo, A., Buczkowicz, P., Mistry, M., Siddaway, R., et al. (2016). Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma. Acta Neuropathol Commun, 4(1), 93.PubMedPubMedCentralCrossRefGoogle Scholar
  92. Schiffman, J. D., Hodgson, J. G., VandenBerg, S. R., Flaherty, P., Polley, M. Y., Yu, M., et al. (2010). Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. Cancer Research, 70(2), 512–519.PubMedPubMedCentralCrossRefGoogle Scholar
  93. Schindler, G., Capper, D., Meyer, J., Janzarik, W., Omran, H., Herold-Mende, C., et al. (2011). 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 Neuropathologica, 121(3), 397–405.PubMedCrossRefGoogle Scholar
  94. Schneider, K., Zelley, K., Nichols, K. E., & Garber, J. (2013). Li-Fraumeni Syndrome. In R. A. Pagon, M. P. Adam, H. H. Ardinger, S. E. Wallace, A. Amemiya, L. J. H. Bean, et al. (Eds.), GeneReviews ® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2017.Google Scholar
  95. Schwartzentruber, J., Korshunov, A., Liu, X. Y., Jones, D. T., Pfaff, E., Jacob, K., et al. (2012). Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature, 482(7384), 226–231.PubMedCrossRefGoogle Scholar
  96. Segal, D., & Karajannis, M. A. (2016). Pediatric brain tumors: An update. Current Problems in Pediatric and Adolescent Health Care, 46(7), 242–250.PubMedCrossRefGoogle Scholar
  97. Shih, D. J., Northcott, P. A., Remke, M., et al. (2014). Cytogenetic prognostication within medulloblastoma subgroups. Journal of Clinical Oncology, 32(9), 886–896.PubMedPubMedCentralCrossRefGoogle Scholar
  98. Sie, M., den Dunnen, W. F., Hoving, E. W., & de Bont, E. S. (2014). Anti-angiogenic therapy in pediatric brain tumors: An effective strategy? Critical Reviews in Oncology Hematology, 89(3), 418–432.CrossRefGoogle Scholar
  99. Sobol-Milejska, G., Mizia-Malarz, A., Musiol, K., Chudek, J., Bożentowicz-Wikarek, M., Wos, H., et al. (2017). Serum levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in children with brain tumours. Advances in Clinical and Experimental Medicine. doi: 10.17219/acem/62320.PubMedGoogle Scholar
  100. Staedtke, V., A Dzaye, O. D., & Holdhoff, M. (2016). Actionable molecular biomarkers in primary brain tumors. Trends Cancer, 2(7), 338–349.PubMedCentralCrossRefGoogle Scholar
  101. Sturm, D., Witt, H., Hovestadt, V., Khuong-Quang, D. A., Jones, D. T., Konermann, C., et al. (2012). Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell, 22(4), 425–437.PubMedCrossRefGoogle Scholar
  102. Tang, Y., Gholamin, S., Schubert, S., Willardson, M. I., Lee, A., Bandopadhayay, P., et al. (2014). Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nature Medicine, 20(7), 732–740.PubMedPubMedCentralCrossRefGoogle Scholar
  103. Tatevossian, R. G., Tang, B., Dalton, J., Forshew, T., Lawson, A. R., Ma, J., et al. (2010). MYB upregulation and genetic aberrations in a subset of pediatric low-grade gliomas. Acta Neuropathologica, 120(6), 731–743.PubMedPubMedCentralCrossRefGoogle Scholar
  104. Taylor, K. R., Mackay, A., Truffaux, N., Butterfield, Y. S., Morozova, O., Philippe, C., et al. (2014). Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nature Genetics, 46(5), 457–461.PubMedPubMedCentralCrossRefGoogle Scholar
  105. van Slegtenhorst, M., de Hoogt, R., Hermans, C., Nellist, M., Janssen, B., Verhoef, S., et al. (1997). Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science, 277(5327), 805–808.PubMedCrossRefGoogle Scholar
  106. Venneti, S., Garimella, M. T., Sullivan, L. M., Martinez, D., Huse, J. T., Heguy, A., et al. (2013). Evaluation of histone 3 lysine 27 trimethylation (H3K27me3) and enhancer of Zest 2 (EZH2) in pediatric glial and glioneuronal tumors shows decreased H3K27me3 in H3F3A K27M mutant glioblastomas. Brain Pathology, 23(5), 558–564.PubMedCrossRefGoogle Scholar
  107. Venneti, S., Santi, M., Felicella, M. M., Yarilin, D., Phillips, J. J., Sullivan, L. M., et al. (2014). A sensitive and specific histopathologic prognostic marker for H3F3A K27M mutant pediatric glioblastomas. Acta Neuropathologica, 128(5), 743–753.PubMedPubMedCentralCrossRefGoogle Scholar
  108. Waldmann, T., & Schneider, R. (2013). Targeting histone modifications—Epigenetics in cancer. Current Opinion in Cell Biology, 25(2), 184–189.PubMedCrossRefGoogle Scholar
  109. Wells, E. M., & Packer, R. J. (2015). Pediatric brain tumors. Continuum (Minneap Minn), 21(2 Neuro-oncology), 373–396.Google Scholar
  110. Wu, G., Broniscer, A., McEachron, T. A., Lu, C., Paugh, B. S., Becksfort, J., et al. (2012). Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nature Genetics, 44(3), 251–253.PubMedPubMedCentralCrossRefGoogle Scholar
  111. Wu, G., Diaz, A. K., Paugh, B. S., Rankin, S. L., Ju, B., Li, Y., et al. (2014). The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nature Genetics, 46(5), 444–450.PubMedPubMedCentralCrossRefGoogle Scholar
  112. Yuen, B. T., & Knoepfler, P. S. (2013). Histone H3.3 mutations: A variant path to cancer. Cancer Cell, 24(5), 567–574.PubMedCrossRefGoogle Scholar
  113. Zhang, J., Wu, G., Miller, C. P., Tatevossian, R. G., Dalton, J. D., Tang, B., et al. (2013). Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nature Genetics, 45(6), 602–612.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Alexia Klonou
    • 1
  • Christina Piperi
    • 1
  • Antonios N. Gargalionis
    • 1
  • Athanasios G. Papavassiliou
    • 1
  1. 1.Department of Biological Chemistry, Medical SchoolNational and Kapodistrian University of AthensAthensGreece

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