Skip to main content
SpringerLink
Log in
Book cover

The Molecular Basis of Human Cancer pp 657–694Cite as

Molecular Biology of Human Brain Tumors

  • Chapter
  • First Online:

Abstract

The Central Brain Tumor Registry of the USA estimates the annual incidence of primary brain and central nervous system (CNS) tumors at 7.3/100,000 for malignant and 13.3/100,000 for nonmalignant tumors. A true comparison of incidence numbers across different time periods and countries is difficult given the inconsistency of data collection methods and the diversity in diagnostic criteria. Available diagnosis rates for malignant gliomas spanning the last three decades do not allow the determination of an increase or decline of age adapted incidence (Ohgaki and Kleihues, Acta Neuropathol 109:93–108, 2005; Ostrom et al., Neuro Oncol 16:896–913, 2014), despite remarkable changes of environment and lifestyle in industrial nations.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009 2011 (cited 2014 July); www.cbtrus.org.

  2. Ohgaki H, Kleihues P. Epidemiology and etiology of gliomas. Acta Neuropathol. 2005;109:93–108.

    Article  PubMed  Google Scholar 

  3. Ostrom QT, Bauchet L, Davis FG, et al. The epidemiology of glioma in adults: a “state of the science” review. Neuro Oncol. 2014;16:896–913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Malmer B, Iselius L, Holmberg E, et al. Genetic epidemiology of glioma. Br J Cancer. 2001;84:429–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Institute NC. Cancer Stat Rev 1975–2011. (July 2014). http://seer.cancer.gov.

  6. de Martel C, Ferlay J, Franceschi S, et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol. 2012;13:607–15.

    Article  PubMed  Google Scholar 

  7. Dziurzynski K, Chang SM, Heimberger AB, et al. Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol. 2012;14:246–55.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Soderberg-Naucler C, Rahbar A, Stragliotto G. Survival in patients with glioblastoma receiving valganciclovir. N Engl J Med. 2013;369:985–6.

    Article  PubMed  CAS  Google Scholar 

  9. Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Weller M, Stupp R, Hegi ME, et al. Personalized care in neuro-oncology coming of age: why we need MGMT and 1p/19q testing for malignant glioma patients in clinical practice. Neuro Oncol. 2012;14 Suppl 4:iv100–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Northcott PA, Korshunov A, Pfister SM, Taylor MD. The clinical implications of medulloblastoma subgroups. Nat Rev Neurol. 2012;8:340–51.

    Article  CAS  PubMed  Google Scholar 

  12. Dempfle A, Wudy SA, Saar K, et al. Evidence for involvement of the vitamin D receptor gene in idiopathic short stature via a genome-wide linkage study and subsequent association studies. Hum Mol Genet. 2006;15:2772–83.

    Article  CAS  PubMed  Google Scholar 

  13. Friedman JM. Epidemiology of neurofibromatosis type 1. Am J Med Genet. 1999;89:1–6.

    Article  CAS  PubMed  Google Scholar 

  14. National Institutes of Health Consensus Development Conference. Neurofibromatosis. Conference statement. Arch Neurol. 1988;45:575–8.

    Article  Google Scholar 

  15. DeBella K, Szudek J, Friedman JM. Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics. 2000;105:608–14.

    Article  CAS  PubMed  Google Scholar 

  16. Valero MC, Martin Y, Hernandez-Imaz E, et al. A highly sensitive genetic protocol to detect NF1 mutations. J Mol Diagn. 2011;13:113–22.

    Article  CAS  PubMed  Google Scholar 

  17. Listernick R, Ferner RE, Liu GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol. 2007;61:189–98.

    Article  CAS  PubMed  Google Scholar 

  18. Easton DF, Ponder MA, Huson SM, Ponder BA. An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am J Hum Genet. 1993;53:305–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Carey JC, Viskochil DH. Neurofibromatosis type 1: A model condition for the study of the molecular basis of variable expressivity in human disorders. Am J Med Genet. 1999;89:7–13.

    Article  CAS  PubMed  Google Scholar 

  20. Gutmann DH, Parada LF, Silva AJ, Ratner N. Neurofibromatosis type 1: modeling CNS dysfunction. J Neurosci. 2012;32:14087–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Marchuk DA, Saulino AM, Tavakkol R, et al. cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics. 1991;11:931–40.

    Article  CAS  PubMed  Google Scholar 

  22. Cawthon RM, O’Connell P, Buchberg AM, et al. Identification and characterization of transcripts from the neurofibromatosis 1 region: the sequence and genomic structure of EVI2 and mapping of other transcripts. Genomics. 1990;7:555–65.

    Article  CAS  PubMed  Google Scholar 

  23. Xu GF, O’Connell P, Viskochil D, et al. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell. 1990;62:599–608.

    Article  CAS  PubMed  Google Scholar 

  24. Abulencia A, Acosta D, Adelman J, et al. Measurement of the tt production cross section in pp collisions at square root of s = 1.96 TeV. Phys Rev Lett. 2006;97:082004.

    Article  CAS  PubMed  Google Scholar 

  25. Jett K, Friedman JM. Clinical and genetic aspects of neurofibromatosis 1. Genet Med. 2010;12:1–11.

    Article  PubMed  Google Scholar 

  26. Gutmann DH, Wood DL, Collins FS. Identification of the neurofibromatosis type 1 gene product. Proc Natl Acad Sci U S A. 1991;88:9658–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Xu GF, Lin B, Tanaka K, et al. The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell. 1990;63:835–41.

    Article  CAS  PubMed  Google Scholar 

  28. Dasgupta B, Gutmann DH. Neurofibromatosis 1: closing the GAP between mice and men. Curr Opin Genet Dev. 2003;13:20–7.

    Article  CAS  PubMed  Google Scholar 

  29. Dasgupta B, Gutmann DH. Neurofibromin regulates neural stem cell proliferation, survival, and astroglial differentiation in vitro and in vivo. J Neurosci. 2005;25:5584–94.

    Article  CAS  PubMed  Google Scholar 

  30. Kourea HP, Cordon-Cardo C, Dudas M, Leung D, Woodruff JM. Expression of p27(kip) and other cell cycle regulators in malignant peripheral nerve sheath tumors and neurofibromas: the emerging role of p27(kip) in malignant transformation of neurofibromas. Am J Pathol. 1999;155:1885–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Packer RJ, Gutmann DH, Rubenstein A, et al. Plexiform neurofibromas in NF1: toward biologic-based therapy. Neurology. 2002;58:1461–70.

    Article  CAS  PubMed  Google Scholar 

  32. Korf BR. Malignancy in neurofibromatosis type 1. Oncologist. 2000;5:477–85.

    Article  CAS  PubMed  Google Scholar 

  33. Evans DG, Baser ME, McGaughran J, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002;39:311–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Menon AG, Anderson KM, Riccardi VM, et al. Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis. Proc Natl Acad Sci U S A. 1990;87:5435–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cichowski K, Shih TS, Schmitt E, et al. Mouse models of tumor development in neurofibromatosis type 1. Science. 1999;286:2172–6.

    Article  CAS  PubMed  Google Scholar 

  36. Ward BA, Gutmann DH. Neurofibromatosis 1: from lab bench to clinic. Pediatr Neurol. 2005;32:221–8.

    Article  PubMed  Google Scholar 

  37. Gutmann, D.H. (2014) Eliminating barriers to personalized medicine: Learning from neurofibromatosis type 1. Neurology.

    Google Scholar 

  38. Gutmann DH, Blakeley JO, Korf BR, Packer RJ. Optimizing biologically targeted clinical trials for neurofibromatosis. Expert Opin Investig Drugs. 2013;22:443–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Study of RAD001 (everolimus) for children with NF1 and chemotherapy-refractory radiographic progressive low grade gliomas. 2014 (cited 2014 July); http://clinicaltrials.gov.

  40. Evans DG. Neurofibromatosis type 2 (NF2): a clinical and molecular review. Orphanet J Rare Dis. 2009;4:16.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Asthagiri AR, Parry DM, Butman JA, et al. Neurofibromatosis type 2. Lancet. 2009;373:1974–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Evans DG, Baser ME, O'Reilly B, et al. Management of the patient and family with neurofibromatosis 2: a consensus conference statement. Br J Neurosurg. 2005;19:5–12.

    Article  CAS  PubMed  Google Scholar 

  43. Rouleau GA, Wertelecki W, Haines JL, et al. Genetic linkage of bilateral acoustic neurofibromatosis to a DNA marker on chromosome 22. Nature. 1987;329:246–8.

    Article  CAS  PubMed  Google Scholar 

  44. Rouleau GA, Merel P, Lutchman M, et al. Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature. 1993;363:515–21.

    Article  CAS  PubMed  Google Scholar 

  45. Trofatter JA, MacCollin MM, Rutter JL, et al. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell. 1993;72:791–800.

    Article  CAS  PubMed  Google Scholar 

  46. Cooper J, Giancotti FG. Molecular insights into NF2/Merlin tumor suppressor function. FEBS Lett. 2014;588:2743–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lim SH, Ardern-Holmes S, McCowage G, de Souza P. Systemic therapy in neurofibromatosis type 2. Cancer Treat Rev. 2014;40:857–61.

    Article  CAS  PubMed  Google Scholar 

  48. McClatchey AI. Merlin and ERM proteins: unappreciated roles in cancer development? Nat Rev Cancer. 2003;3:877–83.

    Article  PubMed  CAS  Google Scholar 

  49. Ammoun S, Cunliffe CH, Allen JC, et al. ErbB/HER receptor activation and preclinical efficacy of lapatinib in vestibular schwannoma. Neuro Oncol. 2010;12:834–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. McClatchey AI, Saotome I, Ramesh V, Gusella JF, Jacks T. The Nf2 tumor suppressor gene product is essential for extraembryonic development immediately prior to gastrulation. Genes Dev. 1997;11:1253–65.

    Article  CAS  PubMed  Google Scholar 

  51. Giovannini M, Robanus-Maandag E, van der Valk M, et al. Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Genes Dev. 2000;14:1617–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Subbiah V, Slopis J, Hong DS, et al. Treatment of patients with advanced neurofibromatosis type 2 with novel molecularly targeted therapies: from bench to bedside. J Clin Oncol. 2012;30:e64–8.

    Article  CAS  PubMed  Google Scholar 

  53. Karajannis MA, Legault G, Hagiwara M, et al. Phase II trial of lapatinib in adult and pediatric patients with neurofibromatosis type 2 and progressive vestibular schwannomas. Neuro Oncol. 2012;14:1163–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hippel E. Ueber eine sehr seltene Erkrankung der Netzhaut. Albrecht von Graefes Archiv für Ophthalmologie. 1904;59:83–106.

    Article  Google Scholar 

  55. Lindau A. Zur Frage der Angiomatosis Rentinae und Ihrer Hirnkomplikationen. Acta Ophtalmologica. 1926;4:193–226.

    Article  Google Scholar 

  56. Robinson CM, Ohh M. The multifaceted von Hippel-Lindau tumour suppressor protein. FEBS Lett. 2014;588:2704–11.

    Article  CAS  PubMed  Google Scholar 

  57. Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993;260:1317–20.

    Article  CAS  PubMed  Google Scholar 

  58. Maddock IR, Moran A, Maher ER, et al. A genetic register for von Hippel-Lindau disease. J Med Genet. 1996;33:120–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Richards FM, Payne SJ, Zbar B, et al. Molecular analysis of de novo germ-line mutations in the von Hippel-Lindau disease gene. Hum Mol Genet. 1995;4:2139–43.

    Article  CAS  PubMed  Google Scholar 

  60. Catapano D, Muscarella LA, Guarnieri V, et al. Hemangioblastomas of central nervous system: molecular genetic analysis and clinical management. Neurosurgery. 2005;56:1215–21.

    Google Scholar 

  61. Wanebo JE, Lonser RR, Glenn GM, Oldfield EH. The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease. J Neurosurg. 2003;98:82–94.

    Article  PubMed  Google Scholar 

  62. Pause A, Lee S, Lonergan KM, Klausner RD. The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. Proc Natl Acad Sci U S A. 1998;95:993–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Koochekpour S, Jeffers M, Wang PH, et al. The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells. Mol Cell Biol. 1999;19:5902–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Peruzzi B, Athauda G, Bottaro DP. The von Hippel-Lindau tumor suppressor gene product represses oncogenic beta-catenin signaling in renal carcinoma cells. Proc Natl Acad Sci U S A. 2006;103:14531–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. An J, Liu H, Magyar CE, et al. Hyperactivated JNK is a therapeutic target in pVHL-deficient renal cell carcinoma. Cancer Res. 2013;73:1374–85.

    Article  CAS  PubMed  Google Scholar 

  66. Chen L, Han L, Zhang K, et al. VHL regulates the effects of miR-23b on glioma survival and invasion via suppression of HIF-1alpha/VEGF and beta-catenin/Tcf-4 signaling. Neuro Oncol. 2012;14:1026–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kwiatkowski DJ. Tuberous sclerosis: from tubers to mTOR. Ann Hum Genet. 2003;67:87–96.

    Article  CAS  PubMed  Google Scholar 

  68. Jozwiak S, Schwartz RA, Janniger CK, Bielicka-Cymerman J. Usefulness of diagnostic criteria of tuberous sclerosis complex in pediatric patients. J Child Neurol. 2000;15:652–9.

    Article  CAS  PubMed  Google Scholar 

  69. Goodman M, Lamm SH, Engel A, et al. Cortical tuber count: a biomarker indicating neurologic severity of tuberous sclerosis complex. J Child Neurol. 1997;12:85–90.

    Article  CAS  PubMed  Google Scholar 

  70. Short MP, Richardson EP, Haines JL, Kwiatkowski DJ. Clinical, neuropathological and genetic aspects of the tuberous sclerosis complex. Brain Pathol. 1995;5:173–9.

    Article  CAS  PubMed  Google Scholar 

  71. Weiner DM, Ewalt DH, Roach ES, Hensle TW. The tuberous sclerosis complex: a comprehensive review. J Am Coll Surg. 1998;187:548–61.

    Article  CAS  PubMed  Google Scholar 

  72. Sancak O, Nellist M, Goedbloed M, et al. Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype--phenotype correlations and comparison of diagnostic DNA techniques in Tuberous Sclerosis Complex. Eur J Hum Genet. 2005;13:731–41.

    Article  CAS  PubMed  Google Scholar 

  73. Jones AC, Shyamsundar MM, Thomas MW, et al. Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am J Hum Genet. 1999;64:1305–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Huang J, Dibble CC, Matsuzaki M, Manning BD. The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol. 2008;28:4104–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363:1801–11.

    Article  CAS  PubMed  Google Scholar 

  76. Krueger DA, Care MM, Agricola K, et al. Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology. 2013;80:574–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Evans DG, Farndon PA, Burnell LD, Gattamaneni HR, Birch JM. The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma. Br J Cancer. 1991;64:959–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Jones EA, Sajid MI, Shenton A, Evans DG. Basal cell carcinomas in gorlin syndrome: a review of 202 patients. J Skin Cancer. 2011;2011:217378.

    Article  PubMed  Google Scholar 

  79. Gorlin RJ. Nevoid basal cell carcinoma syndrome. Dermatol Clin. 1995;13:113–25.

    CAS  PubMed  Google Scholar 

  80. Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85:841–51.

    Article  CAS  PubMed  Google Scholar 

  81. Li FP, Fraumeni Jr JF. Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst. 1969;43:1365–73.

    CAS  PubMed  Google Scholar 

  82. Achatz MI, Olivier M, Le Calvez F, et al. The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. Cancer Lett. 2007;245:96–102.

    Article  CAS  PubMed  Google Scholar 

  83. Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germ-line mutations. J Clin Oncol. 2009;27:1250–6.

    Article  CAS  PubMed  Google Scholar 

  84. Bell DW, Varley JM, Szydlo TE, et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999;286:2528–31.

    Article  CAS  PubMed  Google Scholar 

  85. Watanabe T, Vital A, Nobusawa S, Kleihues P, Ohgaki H. Selective acquisition of IDH1 R132C mutations in astrocytomas associated with Li-Fraumeni syndrome. Acta Neuropathol. 2009;117:653–6.

    Article  CAS  PubMed  Google Scholar 

  86. Hamilton SR, Liu B, Parsons RE, et al. The molecular basis of Turcot’s syndrome. N Engl J Med. 1995;332:839–47.

    Article  CAS  PubMed  Google Scholar 

  87. Turcot J, Despres JP, St Pierre F. Malignant tumors of the central nervous system associated with familial polyposis of the colon: report of two cases. Dis Colon Rectum. 1959;2:465–8.

    Article  CAS  PubMed  Google Scholar 

  88. van Meir E, de Tribolet N. Microsatellite instability in human brain tumors. Neurosurgery. 1995;37:1231–2.

    Article  PubMed  Google Scholar 

  89. Hobert JA, Eng C. PTEN hamartoma tumor syndrome: an overview. Genet Med. 2009;11:687–94.

    Article  CAS  PubMed  Google Scholar 

  90. Lloyd 2nd KM, Dennis M. Cowden’s disease. A possible new symptom complex with multiple system involvement. Ann Intern Med. 1963;58:136–42.

    Article  PubMed  Google Scholar 

  91. Lhermitte D. Sur un ganglioneurome diffus du cortex du cervelet. Bull Assoc Fr Etud Cancer. 1920;9:99–107.

    Google Scholar 

  92. Padberg GW, Schot JD, Vielvoye GJ, Bots GT, de Beer FC. Lhermitte-Duclos disease and Cowden disease: a single phakomatosis. Ann Neurol. 1991;29:517–23.

    Article  CAS  PubMed  Google Scholar 

  93. Eng C. PTEN: one gene, many syndromes. Hum Mutat. 2003;22:183–98.

    Article  CAS  PubMed  Google Scholar 

  94. Myers MP, Pass I, Batty IH, et al. The lipid phosphatase activity of PTEN is critical for its tumor suppressor function. Proc Natl Acad Sci U S A. 1998;95:13513–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Orloff MS, Eng C. Genetic and phenotypic heterogeneity in the PTEN hamartoma tumour syndrome. Oncogene. 2008;27:5387–97.

    Article  CAS  PubMed  Google Scholar 

  96. Liaw D, Marsh DJ, Li J, et al. Germ-line mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997;16:64–7.

    Article  CAS  PubMed  Google Scholar 

  97. Marsh DJ, Coulon V, Lunetta KL, et al. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germ-line PTEN mutation. Hum Mol Genet. 1998;7:507–15.

    Article  CAS  PubMed  Google Scholar 

  98. Tan MH, Mester J, Peterson C, et al. A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. Am J Hum Genet. 2011;88:42–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Orloff MS, He X, Peterson C, et al. Germ-line PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes. Am J Hum Genet. 2013;92:76–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhou XP, Marsh DJ, Morrison CD, et al. Germ-line inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte-Duclos disease in adults. Am J Hum Genet. 2003;73:1191–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Abel TW, Baker SJ, Fraser MM, et al. Lhermitte-Duclos disease: a report of 31 cases with immunohistochemical analysis of the PTEN/AKT/mTOR pathway. J Neuropathol Exp Neurol. 2005;64:341–9.

    Article  PubMed  Google Scholar 

  102. Backman SA, Stambolic V, Suzuki A, et al. Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet. 2001;29:396–403.

    Article  CAS  PubMed  Google Scholar 

  103. Kwon CH, Zhu X, Zhang J, et al. Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease. Nat Genet. 2001;29:404–11.

    Article  CAS  PubMed  Google Scholar 

  104. Friedmann-Morvinski D, Bushong EA, Ke E, et al. Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science. 2012;338:1080–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Stiles CD, Rowitch DH. Glioma stem cells: a midterm exam. Neuron. 2008;58:832–46.

    Article  CAS  PubMed  Google Scholar 

  106. Capelle L, Fontaine D, Mandonnet E, et al. Spontaneous and therapeutic prognostic factors in adult hemispheric World Health Organization Grade II gliomas: a series of 1097 cases: clinical article. J Neurosurg. 2013;118:1157–68.

    Article  PubMed  Google Scholar 

  107. Sturm D, Bender S, Jones DT, et al. Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nat Rev Cancer. 2014;14:92–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ohgaki H, Dessen P, Jourde B, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res. 2004;64:6892–9.

    Article  CAS  PubMed  Google Scholar 

  109. Brennan CW, Verhaak RG, McKenna A, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155:462–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Hirose Y, Sasaki H, Miwa T, et al. Whole genome analysis from microdissected tissue revealed adult supratentorial grade II-III gliomas are divided into clinically relevant subgroups by genetic profile. Neurosurgery. 2011;69:376–90.

    Article  PubMed  Google Scholar 

  111. Hirose Y, Aldape K, Bollen A, et al. Chromosomal abnormalities subdivide ependymal tumors into clinically relevant groups. Am J Pathol. 2001;158:1137–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hirose Y, Sasaki H, Abe M, et al. Subgrouping of gliomas on the basis of genetic profiles. Brain Tumor Pathol. 2013;30:203–8.

    Article  CAS  PubMed  Google Scholar 

  113. Houillier C, Mokhtari K, Carpentier C, et al. Chromosome 9p and 10q losses predict unfavorable outcome in low-grade gliomas. Neuro Oncol. 2010;12:2–6.

    Article  CAS  PubMed  Google Scholar 

  114. Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res. 2013;19:764–72.

    Article  CAS  PubMed  Google Scholar 

  115. Sanborn JZ, Salama SR, Grifford M, et al. Double minute chromosomes in glioblastoma multiforme are revealed by precise reconstruction of oncogenic amplicons. Cancer Res. 2013;73:6036–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Reifenberger J, Reifenberger G, Liu L, et al. Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol. 1994;145:1175–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Bettegowda C, Agrawal N, Jiao Y, et al. Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science. 2011;333:1453–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Yip S, Butterfield YS, Morozova O, et al. Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers. J Pathol. 2012;226:7–16.

    Article  CAS  PubMed  Google Scholar 

  119. Ren X, Cui X, Lin S, et al. Co-deletion of chromosome 1p/19q and IDH1/2 mutation in glioma subsets of brain tumors in Chinese patients. PLoS One. 2012;7:e32764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Cairncross G, Wang M, Shaw E, et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013;31:337–43.

    Article  CAS  PubMed  Google Scholar 

  121. Iwadate Y, Matsutani T, Hasegawa Y, et al. Favorable long-term outcome of low-grade oligodendrogliomas irrespective of 1p/19q status when treated without radiotherapy. J Neurooncol. 2011;102:443–9.

    Article  PubMed  Google Scholar 

  122. van den Bent MJ, Brandes AA, Taphoorn MJ, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013;31:344–50.

    Article  PubMed  CAS  Google Scholar 

  123. Bourne TD, Schiff D. Update on molecular findings, management and outcome in low-grade gliomas. Nat Rev Neurol. 2010;6:695–701.

    Article  PubMed  Google Scholar 

  124. Dunn GP, Rinne ML, Wykosky J, et al. Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev. 2012;26:756–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Watanabe K, Tachibana O, Sata K, et al. Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol. 1996;6:217–23. discussion 223–214.

    Article  CAS  PubMed  Google Scholar 

  126. Ekstrand AJ, James CD, Cavenee WK, et al. Genes for epidermal growth factor receptor, transforming growth factor alpha, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res. 1991;51:2164–72.

    CAS  PubMed  Google Scholar 

  127. Hegi ME, Rajakannu P, Weller M. Epidermal growth factor receptor: a re-emerging target in glioblastoma. Curr Opin Neurol. 2012;25:774–9.

    Article  CAS  PubMed  Google Scholar 

  128. Contreras CM, Azamar-Arizmendi G, Saavedra M, Hernandez-Lozano M. A five-day gradual reduction regimen of chlormadinone reduces premenstrual anxiety and depression: a pilot study. Arch Med Res. 2006;37:907–13.

    Article  CAS  PubMed  Google Scholar 

  129. El Imam M, Omran M, Nugud F, et al. Obstructive uropathy in Sudanese patients. Saudi J Kidney Dis Transpl. 2006;17:415–9.

    PubMed  Google Scholar 

  130. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061–8.

    Article  CAS  Google Scholar 

  131. Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Balss J, Meyer J, Mueller W, et al. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 2008;116:597–602.

    Article  CAS  PubMed  Google Scholar 

  133. Nobusawa S, Watanabe T, Kleihues P, Ohgaki H. IDH1 mutations as molecular signature and predictive factor of secondary glioblastomas. Clin Cancer Res. 2009;15:6002–7.

    Article  CAS  PubMed  Google Scholar 

  134. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360:765–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Dubbink HJ, Taal W, van Marion R, et al. IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide. Neurology. 2009;73:1792–5.

    Article  CAS  PubMed  Google Scholar 

  136. Sanson M, Marie Y, Paris S, et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol. 2009;27:4150–4.

    Article  CAS  PubMed  Google Scholar 

  137. van den Bent MJ, Dubbink HJ, Marie Y, et al. IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Clin Cancer Res. 2010;16:1597–604.

    Article  PubMed  CAS  Google Scholar 

  138. Weller M, Felsberg J, Hartmann C, et al. Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J Clin Oncol. 2009;27:5743–50.

    Article  CAS  PubMed  Google Scholar 

  139. Wick W, Hartmann C, Engel C, et al. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009;27:5874–80.

    Article  CAS  PubMed  Google Scholar 

  140. Ichimura K, Pearson DM, Kocialkowski S, et al. IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro Oncol. 2009;11:341–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Watanabe T, Nobusawa S, Kleihues P, Ohgaki H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol. 2009;174:1149–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Kondo Y, Katsushima K, Ohka F, Natsume A, Shinjo K. Epigenetic dysregulation in glioma. Cancer Sci. 2014;105:363–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997–1003.

    Article  CAS  PubMed  Google Scholar 

  144. Wick W, Weller M, van den Bent M, et al. MGMT testing-the challenges for biomarker-based glioma treatment. Nat Rev Neurol. 2014;10:372–85.

    Article  CAS  PubMed  Google Scholar 

  145. Yan H, Bigner DD, Velculescu V, Parsons DW. Mutant metabolic enzymes are at the origin of gliomas. Cancer Res. 2009;69:9157–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Warburg O. On the origin of cancer cells. Science. 1956;123:309–14.

    Article  CAS  PubMed  Google Scholar 

  147. David CJ, Chen M, Assanah M, Canoll P, Manley JL. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature. 2010;463:364–8.

    Article  CAS  PubMed  Google Scholar 

  148. Wolf A, Agnihotri S, Micallef J, et al. Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J Exp Med. 2011;208:313–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Sanoudou D, Tingby O, Ferguson-Smith MA, Collins VP, Coleman N. Analysis of pilocytic astrocytoma by comparative genomic hybridization. Br J Cancer. 2000;82:1218–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Zattara-Cannoni H, Gambarelli D, Lena G, et al. Are juvenile pilocytic astrocytomas benign tumors? A cytogenetic study in 24 cases. Cancer Genet Cytogenet. 1998;104:157–60.

    Article  CAS  PubMed  Google Scholar 

  151. Bax DA, Mackay A, Little SE, et al. A distinct spectrum of copy number aberrations in pediatric high-grade gliomas. Clin Cancer Res. 2010;16:3368–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Paugh BS, Qu C, Jones C, et al. Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol. 2010;28:3061–8.

    Article  PubMed  PubMed Central  Google Scholar 

  153. Rickert CH, Strater R, Kaatsch P, et al. Pediatric high-grade astrocytomas show chromosomal imbalances distinct from adult cases. Am J Pathol. 2001;158:1525–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Sung T, Miller DC, Hayes RL, et al. Preferential inactivation of the p53 tumor suppressor pathway and lack of EGFR amplification distinguish de novo high grade pediatric astrocytomas from de novo adult astrocytomas. Brain Pathol. 2000;10:249–59.

    Article  CAS  PubMed  Google Scholar 

  155. Verhaak RG, Hoadley KA, Purdom E, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Bar EE, Lin A, Tihan T, Burger PC, Eberhart CG. Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol. 2008;67:878–87.

    Article  CAS  PubMed  Google Scholar 

  157. Jones DTW, Kocialkowski S, Liu L, et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008;68:8673–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Jones DTW, Kocialkowski S, Liu L, et al. Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene. 2009;28:2119–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Chen YH, Gutmann DH. The molecular and cell biology of pediatric low-grade gliomas. Oncogene. 2014;33:2019–26.

    Article  CAS  PubMed  Google Scholar 

  160. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.

    Article  CAS  PubMed  Google Scholar 

  161. Hudson TJ, Anderson W, Artez A, et al. International network of cancer genome projects. Nature. 2010;464:993–8.

    Article  CAS  PubMed  Google Scholar 

  162. Phillips HS, Kharbanda S, Chen R, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9:157–73.

    Article  CAS  PubMed  Google Scholar 

  163. Noushmehr H, Weisenberger DJ, Diefes K, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17:510–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. van den Bent MJ, Gravendeel LA, Gorlia T, et al. A hypermethylated phenotype is a better predictor of survival than MGMT methylation in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951. Clin Cancer Res. 2011;17:7148–55.

    Article  PubMed  Google Scholar 

  165. Wang J, Wechsler-Reya RJ. The role of stem cells and progenitors in the genesis of medulloblastoma. Exp Neurol. 2012;260:69–73.

    Article  PubMed  CAS  Google Scholar 

  166. Kool M, Korshunov A, Remke M, et al. Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol. 2012;123:473–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Bigner SH, Burger PC, Wong AJ, et al. Gene amplification in malignant human gliomas: clinical and histopathologic aspects. J Neuropathol Exp Neurol. 1988;47:191–205.

    Article  CAS  PubMed  Google Scholar 

  168. Northcott PA, Nakahara Y, Wu X, et al. Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nat Genet. 2009;41:465–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Giordana MT, Migheli A, Pavanelli E. Isochromosome 17q is a constant finding in medulloblastoma. An interphase cytogenetic study on tissue sections. Neuropathol Appl Neurobiol. 1998;24:233–8.

    Article  CAS  PubMed  Google Scholar 

  170. Pan E, Pellarin M, Holmes E, et al. Isochromosome 17q is a negative prognostic factor in poor-risk childhood medulloblastoma patients. Clin Cancer Res. 2005;11:4733–40.

    Article  CAS  PubMed  Google Scholar 

  171. McDonald JD, Daneshvar L, Willert JR, et al. Physical mapping of chromosome 17p13.3 in the region of a putative tumor suppressor gene important in medulloblastoma. Genomics. 1994;23:229–32.

    Article  CAS  PubMed  Google Scholar 

  172. Ferretti E, De Smaele E, Di Marcotullio L, Screpanti I, Gulino A. Hedgehog checkpoints in medulloblastoma: the chromosome 17p deletion paradigm. Trends Mol Med. 2005;11:537–45.

    Article  CAS  PubMed  Google Scholar 

  173. Shih DJ, Northcott PA, Remke M, et al. Cytogenetic prognostication within medulloblastoma subgroups. J Clin Oncol. 2014;32:886–96.

    Article  PubMed  PubMed Central  Google Scholar 

  174. Aldosari N, Wiltshire RN, Dutra A, et al. Comprehensive molecular cytogenetic investigation of chromosomal abnormalities in human medulloblastoma cell lines and xenograft. Neuro Oncol. 2002;4:75–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Eberhart CG, Kratz J, Wang Y, et al. Histopathological and molecular prognostic markers in medulloblastoma: c-myc, N-myc, TrkC, and anaplasia. J Neuropathol Exp Neurol. 2004;63:441–9.

    Article  CAS  PubMed  Google Scholar 

  176. Eberhart CG, Kratz JE, Schuster A, et al. Comparative genomic hybridization detects an increased number of chromosomal alterations in large cell/anaplastic medulloblastomas. Brain Pathol. 2002;12:36–44.

    Article  CAS  PubMed  Google Scholar 

  177. Gilbertson RJ, Clifford SC, MacMeekin W, et al. Expression of the ErbB-neuregulin signaling network during human cerebellar development: implications for the biology of medulloblastoma. Cancer Res. 1998;58:3932–41.

    CAS  PubMed  Google Scholar 

  178. Lee CJ, Chan WI, Scotting PJ. CIC, a gene involved in cerebellar development and ErbB signaling, is significantly expressed in medulloblastomas. J Neurooncol. 2005;73:101–8.

    Article  CAS  PubMed  Google Scholar 

  179. Gilbertson R, Hernan R, Pietsch T, et al. Novel ERBB4 juxtamembrane splice variants are frequently expressed in childhood medulloblastoma. Genes Chromosomes Cancer. 2001;31:288–94.

    Article  CAS  PubMed  Google Scholar 

  180. Gajjar A, Hernan R, Kocak M, et al. Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastoma. J Clin Oncol. 2004;22:984–93.

    Article  CAS  PubMed  Google Scholar 

  181. Erez A, Ilan T, Amariglio N, et al. GLI3 is not mutated commonly in sporadic medulloblastomas. Cancer. 2002;95:28–31.

    Article  CAS  PubMed  Google Scholar 

  182. Pietsch T, Koch A, Wiestler OD. Molecular genetic studies in medulloblastomas: evidence for tumor suppressor genes at the chromosomal regions 1q31-32 and 17p13. Klin Padiatr. 1997;209:150–5.

    Article  CAS  PubMed  Google Scholar 

  183. Reifenberger J, Wolter M, Weber RG, et al. Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 1998;58:1798–803.

    CAS  PubMed  Google Scholar 

  184. Taylor MD, Liu L, Raffel C, et al. Mutations in SUFU predispose to medulloblastoma. Nat Genet. 2002;31:306–10.

    Article  CAS  PubMed  Google Scholar 

  185. Dahmen RP, Koch A, Denkhaus D, et al. Deletions of AXIN1, a component of the WNT/wingless pathway, in sporadic medulloblastomas. Cancer Res. 2001;61:7039–43.

    CAS  PubMed  Google Scholar 

  186. Huang H, Mahler-Araujo BM, Sankila A, et al. APC mutations in sporadic medulloblastomas. Am J Pathol. 2000;156:433–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Kang DE, Soriano S, Xia X, et al. Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis. Cell. 2002;110:751–62.

    Article  CAS  PubMed  Google Scholar 

  188. Zurawel RH, Chiappa SA, Allen C, Raffel C. Sporadic medulloblastomas contain oncogenic beta-catenin mutations. Cancer Res. 1998;58:896–9.

    CAS  PubMed  Google Scholar 

  189. Zhukova N, Ramaswamy V, Remke M, et al. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J Clin Oncol. 2013;31:2927–35.

    Article  PubMed  PubMed Central  Google Scholar 

  190. Hovestadt V, Jones DT, Picelli S, et al. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature. 2014;510:537–41.

    Article  CAS  PubMed  Google Scholar 

  191. Remke M, Ramaswamy V, Taylor MD. Medulloblastoma molecular dissection: the way toward targeted therapy. Curr Opin Oncol. 2013;25:674–81.

    Article  CAS  PubMed  Google Scholar 

  192. Di C, Liao S, Adamson DC, et al. Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid. Cancer Res. 2005;65:919–24.

    CAS  PubMed  Google Scholar 

  193. Adamson DC, Shi Q, Wortham M, et al. OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas. Cancer Res. 2010;70:181–91.

    Article  CAS  PubMed  Google Scholar 

  194. Bunt J, Hasselt NA, Zwijnenburg DA, et al. OTX2 sustains a bivalent-like state of OTX2-bound promoters in medulloblastoma by maintaining their H3K27me3 levels. Acta Neuropathol. 2013;125:385–94.

    Article  CAS  PubMed  Google Scholar 

  195. Hovestadt V, Remke M, Kool M, et al. Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathol. 2013;125:913–6.

    Article  PubMed  PubMed Central  Google Scholar 

  196. Schwalbe EC, Williamson D, Lindsey JC, et al. DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies. Acta Neuropathol. 2013;125:359–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Taylor MD, Northcott PA, Korshunov A, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012;123:465–72.

    Article  CAS  PubMed  Google Scholar 

  198. Northcott PA, Korshunov A, Witt H, et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol. 2011;29:1408–14.

    Article  PubMed  Google Scholar 

  199. Northcott PA, Lee C, Zichner T, et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature. 2014;511:428–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Rudin CM, Hann CL, Laterra J, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med. 2009;361:1173–8.

    Article  CAS  PubMed  Google Scholar 

  201. Kieran MW. Targeted treatment for Sonic Hedgehog-dependent medulloblastoma. Neuro Oncol. 2014;16:1037–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Kleihues P, Louis DN, Scheithauer BW, et al. The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol. 2002;61:215–25.

    Article  PubMed  Google Scholar 

  203. Taylor MD, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell. 2005;8:323–35.

    Article  CAS  PubMed  Google Scholar 

  204. Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro Oncol. 2012;14 Suppl 5:v1–49.

    Article  PubMed  PubMed Central  Google Scholar 

  205. Ruda R, Gilbert M, Soffietti R. Ependymomas of the adult: molecular biology and treatment. Curr Opin Neurol. 2008;21:754–61.

    Article  PubMed  Google Scholar 

  206. Kilday JP, Rahman R, Dyer S, et al. Pediatric ependymoma: biological perspectives. Mol Cancer Res. 2009;7:765–86.

    Article  CAS  PubMed  Google Scholar 

  207. Johnson RA, Wright KD, Poppleton H, et al. Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature. 2010;466:632–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Mack SC, Taylor MD. The genetic and epigenetic basis of ependymoma. Childs Nerv Syst. 2009;25:1195–201.

    Article  PubMed  Google Scholar 

  209. Witt H, Mack SC, Ryzhova M, et al. Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell. 2011;20:143–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Huang B, Starostik P, Kuhl J, Tonn JC, Roggendorf W. Loss of heterozygosity on chromosome 22 in human ependymomas. Acta Neuropathol. 2002;103:415–20.

    Article  CAS  PubMed  Google Scholar 

  211. Plotkin SR, O'Donnell CC, Curry WT, et al. Spinal ependymomas in neurofibromatosis type 2: a retrospective analysis of 55 patients. J Neurosurg Spine. 2011;14:543–7.

    Article  PubMed  Google Scholar 

  212. Lamszus K, Lachenmayer L, Heinemann U, et al. Molecular genetic alterations on chromosomes 11 and 22 in ependymomas. Int J Cancer. 2001;91:803–8.

    Article  CAS  PubMed  Google Scholar 

  213. Suarez-Merino B, Hubank M, Revesz T, et al. Microarray analysis of pediatric ependymoma identifies a cluster of 112 candidate genes including four transcripts at 22q12.1-q13.3. Neuro Oncol. 2005;7:20–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Ward S, Harding B, Wilkins P, et al. Gain of 1q and loss of 22 are the most common changes detected by comparative genomic hybridisation in paediatric ependymoma. Genes Chromosomes Cancer. 2001;32:59–66.

    Article  CAS  PubMed  Google Scholar 

  215. Parker M, Mohankumar KM, Punchihewa C, et al. C11orf95-RELA fusions drive oncogenic NF-kappaB signalling in ependymoma. Nature. 2014;506:451–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Mendrzyk F, Korshunov A, Benner A, et al. Identification of gains on 1q and epidermal growth factor receptor overexpression as independent prognostic markers in intracranial ependymoma. Clin Cancer Res. 2006;12:2070–9.

    Article  CAS  PubMed  Google Scholar 

  217. Senetta R, Miracco C, Lanzafame S, et al. Epidermal growth factor receptor and caveolin-1 coexpression identifies adult supratentorial ependymomas with rapid unfavorable outcomes. Neuro Oncol. 2011;13:176–83.

    Article  CAS  PubMed  Google Scholar 

  218. Diedrich U, Soja S, Behnke J, Zoll B. Amplification of the c-erbB oncogene is associated with malignancy in primary tumours of neuroepithelial tissue. J Neurol. 1991;238:221–4.

    Article  CAS  PubMed  Google Scholar 

  219. Mack SC, Witt H, Piro RM, et al. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature. 2014;506:445–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Dirks PB, Hubbard SL, Murakami M, Rutka JT. Cyclin and cyclin-dependent kinase expression in human astrocytoma cell lines. J Neuropathol Exp Neurol. 1997;56:291–300.

    Article  CAS  PubMed  Google Scholar 

  221. Malumbres M, Barbacid M. To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer. 2001;1:222–31.

    Article  CAS  PubMed  Google Scholar 

  222. Ivanchuk SM, Rutka JT. The cell cycle: accelerators, brakes, and checkpoints. Neurosurgery. 2004;54:692–9.

    Article  PubMed  Google Scholar 

  223. Malumbres M. Physiological relevance of cell cycle kinases. Physiol Rev. 2011;91:973–1007.

    Article  CAS  PubMed  Google Scholar 

  224. Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Muller PA, Vousden KH. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell. 2014;25:304–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Zerdoumi Y, Aury-Landas J, Bonaiti-Pellie C, et al. Drastic effect of germ-line TP53 missense mutations in Li-Fraumeni patients. Hum Mutat. 2013;34:453–61.

    Article  CAS  PubMed  Google Scholar 

  227. Stewart CL, Soria AM, Hamel PA. Integration of the pRB and p53 cell cycle control pathways. J Neurooncol. 2001;51:183–204.

    Article  CAS  PubMed  Google Scholar 

  228. Malkin D. The role of p53 in human cancer. J Neurooncol. 2001;51:231–43.

    Article  CAS  PubMed  Google Scholar 

  229. Marine JC, Lozano G. Mdm2-mediated ubiquitylation: p53 and beyond. Cell Death Differ. 2010;17:93–102.

    Article  CAS  PubMed  Google Scholar 

  230. Shieh SY, Ikeda M, Taya Y, Prives C. DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell. 1997;91:325–34.

    Article  CAS  PubMed  Google Scholar 

  231. Siliciano JD, Canman CE, Taya Y, et al. DNA damage induces phosphorylation of the amino terminus of p53. Genes Dev. 1997;11:3471–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Kamijo T, Weber JD, Zambetti G, et al. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci U S A. 1998;95:8292–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Honda R, Yasuda H. Association of p19(ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J. 1999;18:22–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Pomerantz J, Schreiber-Agus N, Liegeois NJ, et al. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell. 1998;92:713–23.

    Article  CAS  PubMed  Google Scholar 

  235. Besson A, Yong VW. Mitogenic signaling and the relationship to cell cycle regulation in astrocytomas. J Neurooncol. 2001;51:245–64.

    Article  CAS  PubMed  Google Scholar 

  236. Nakamura M, Yonekawa Y, Kleihues P, Ohgaki H. Promoter hypermethylation of the RB1 gene in glioblastomas. Lab Invest. 2001;81:77–82.

    Article  CAS  PubMed  Google Scholar 

  237. Costello JF, Plass C, Arap W, et al. Cyclin-dependent kinase 6 (CDK6) amplification in human gliomas identified using two-dimensional separation of genomic DNA. Cancer Res. 1997;57:1250–4.

    CAS  PubMed  Google Scholar 

  238. Riemenschneider MJ, Buschges R, Wolter M, et al. Amplification and overexpression of the MDM4 (MDMX) gene from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM2 amplification. Cancer Res. 1999;59:6091–6.

    CAS  PubMed  Google Scholar 

  239. Ohgaki H, Kleihues P. Genetic alterations and signaling pathways in the evolution of gliomas. Cancer Sci. 2009;100:2235–41.

    Article  CAS  PubMed  Google Scholar 

  240. Holland EC, Hively WP, Gallo V, Varmus HE. Modeling mutations in the G1 arrest pathway in human gliomas: overexpression of CDK4 but not loss of INK4a-ARF induces hyperploidy in cultured mouse astrocytes. Genes Dev. 1998;12:3644–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Huang H, Colella S, Kurrer M, et al. Gene expression profiling of low-grade diffuse astrocytomas by cDNA arrays. Cancer Res. 2000;60:6868–74.

    CAS  PubMed  Google Scholar 

  242. Huszthy PC, Daphu I, Niclou SP, et al. In vivo models of primary brain tumors: pitfalls and perspectives. Neuro Oncol. 2012;14:979–93.

    Article  PubMed  PubMed Central  Google Scholar 

  243. Beier D, Hau P, Proescholdt M, et al. CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 2007;67:4010–5.

    Article  CAS  PubMed  Google Scholar 

  244. Burkhard C, Di Patre PL, Schuler D, et al. A population-based study of the incidence and survival rates in patients with pilocytic astrocytoma. J Neurosurg. 2003;98:1170–4.

    Article  PubMed  Google Scholar 

  245. Theeler BJ, Ellezam B, Sadighi ZS, et al. Adult pilocytic astrocytomas: clinical features and molecular analysis. Neuro Oncol. 2014;16:841–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Ogiwara H, Bowman RM, Tomita T. Long-term follow-up of pediatric benign cerebellar astrocytomas. Neurosurgery. 2012;70:40–7.

    Article  PubMed  Google Scholar 

  247. Jones DT, Ichimura K, Liu L, et al. Genomic analysis of pilocytic astrocytomas at 0.97 Mb resolution shows an increasing tendency toward chromosomal copy number change with age. J Neuropathol Exp Neurol. 2006;65:1049–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Jones DT, Gronych J, Lichter P, Witt O, Pfister SM. MAPK pathway activation in pilocytic astrocytoma. Cell Mol Life Sci. 2012;69:1799–811.

    Article  CAS  PubMed  Google Scholar 

  249. Jones DT, Hutter B, Jager N, et al. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet. 2013;45:927–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Pfister S, Janzarik WG, Remke M, et al. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest. 2008;118:1739–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Horbinski C, Nikiforova MN, Hagenkord JM, Hamilton RL, Pollack IF. Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Neuro Oncol. 2012;14:777–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Newton HB. Molecular neuro-oncology and the development of targeted therapeutic strategies for brain tumors. Part 3: brain tumor invasiveness. Expert Rev Anticancer Ther. 2004;4:803–21.

    Article  CAS  PubMed  Google Scholar 

  253. Cuddapah VA, Robel S, Watkins S, Sontheimer H. A neurocentric perspective on glioma invasion. Nat Rev Neurosci. 2014;15:455–65.

    Article  CAS  PubMed  Google Scholar 

  254. Raftopoulou M, Etienne-Manneville S, Self A, Nicholls S, Hall A. Regulation of cell migration by the C2 domain of the tumor suppressor PTEN. Science. 2004;303:1179–81.

    Article  CAS  PubMed  Google Scholar 

  255. Ridley AJ, Schwartz MA, Burridge K, et al. Cell migration: integrating signals from front to back. Science. 2003;302:1704–9.

    Article  CAS  PubMed  Google Scholar 

  256. Beadle C, Assanah MC, Monzo P, et al. The role of myosin II in glioma invasion of the brain. Mol Biol Cell. 2008;19:3357–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Terakawa Y, Agnihotri S, Golbourn B, et al. The role of drebrin in glioma migration and invasion. Exp Cell Res. 2013;319:517–28.

    Article  CAS  PubMed  Google Scholar 

  258. Abbadi S, Rodarte JJ, Abutaleb A, et al. Glucose-6-phosphatase is a key metabolic regulator of glioblastoma invasion. Mol Cancer Res. 2014;12:1547–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Watkins S, Sontheimer H. Hydrodynamic cellular volume changes enable glioma cell invasion. J Neurosci. 2011;31:17250–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Garzon-Muvdi T, Schiapparelli P, ap Rhys C, et al. Regulation of brain tumor dispersal by NKCC1 through a novel role in focal adhesion regulation. PLoS Biol. 2012;10:e1001320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Haas BR, Sontheimer H. Inhibition of the sodium-potassium-chloride cotransporter isoform-1 reduces glioma invasion. Cancer Res. 2010;70:5597–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Cuddapah VA, Sontheimer H. Molecular interaction and functional regulation of ClC-3 by Ca2+/calmodulin-dependent protein kinase II (CaMKII) in human malignant glioma. J Biol Chem. 2010;285:11188–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Preusser M, de Ribaupierre S, Wohrer A, et al. Current concepts and management of glioblastoma. Ann Neurol. 2011;70:9–21.

    Article  PubMed  Google Scholar 

  264. Giese A, Westphal M. Glioma invasion in the central nervous system. Neurosurgery. 1996;39:235–50.

    Article  CAS  PubMed  Google Scholar 

  265. Hsieh WT, Yeh WL, Cheng RY, et al. Exogenous endothelin-1 induces cell migration and matrix metalloproteinase expression in U251 human glioblastoma multiforme. J Neurooncol. 2014;118:257–69.

    Article  CAS  PubMed  Google Scholar 

  266. Lyons SA, Chung WJ, Weaver AK, Ogunrinu T, Sontheimer H. Autocrine glutamate signaling promotes glioma cell invasion. Cancer Res. 2007;67:9463–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Guha A, Mukherjee J. Advances in the biology of astrocytomas. Curr Opin Neurol. 2004;17:655–62.

    Article  PubMed  Google Scholar 

  268. Rao RD, James CD. Altered molecular pathways in gliomas: an overview of clinically relevant issues. Semin Oncol. 2004;31:595–604.

    Article  CAS  PubMed  Google Scholar 

  269. Sahai E, Marshall CJ. Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis. Nat Cell Biol. 2003;5:711–9.

    Article  CAS  PubMed  Google Scholar 

  270. Seol HJ, Chang JH, Yamamoto J, et al. Overexpression of CD99 Increases the Migration and Invasiveness of Human Malignant Glioma Cells. Genes Cancer. 2012;3:535–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Reymond N, Im JH, Garg R, et al. Cdc42 promotes transendothelial migration of cancer cells through beta1 integrin. J Cell Biol. 2012;199:653–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Ridley AJ, Hall A. Distinct patterns of actin organization regulated by the small GTP-binding proteins Rac and Rho. Cold Spring Harb Symp Quant Biol. 1992;57:661–71.

    Article  CAS  PubMed  Google Scholar 

  273. Nobes CD, Hall A. Rho GTPases control polarity, protrusion, and adhesion during cell movement. J Cell Biol. 1999;144:1235–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Bouzahzah B, Albanese C, Ahmed F, et al. Rho family GTPases regulate mammary epithelium cell growth and metastasis through distinguishable pathways. Mol Med. 2001;7:816–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  275. Senger DL, Tudan C, Guiot M-C, et al. Suppression of Rac activity induces apoptosis of human glioma cells but not normal human astrocytes. Cancer Res. 2002;62:2131–40.

    CAS  PubMed  Google Scholar 

  276. Salhia B, Rutten F, Nakada M, et al. Inhibition of Rho-kinase affects astrocytoma morphology, motility, and invasion through activation of Rac1. Cancer Res. 2005;65:8792–800.

    Article  CAS  PubMed  Google Scholar 

  277. Brem S. The role of vascular proliferation in the growth of brain tumors. Clin Neurosurg. 1976;23:440–53.

    CAS  PubMed  Google Scholar 

  278. Plate KH, Breier G, Risau W. Molecular mechanisms of developmental and tumor angiogenesis. Brain Pathol. 1994;4:207–18.

    Article  CAS  PubMed  Google Scholar 

  279. Plate KH, Breier G, Weich HA, Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 1992;359:845–8.

    Article  CAS  PubMed  Google Scholar 

  280. Jain RK, di Tomaso E, Duda DG, et al. Angiogenesis in brain tumours. Nat Rev Neurosci. 2007;8:610–22.

    Article  CAS  PubMed  Google Scholar 

  281. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011–27.

    Article  CAS  PubMed  Google Scholar 

  282. Yuan F, Chen Y, Dellian M, et al. Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc Natl Acad Sci U S A. 1996;93:14765–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. Benjamin LE, Keshet E. Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal. Proc Natl Acad Sci U S A. 1997;94:8761–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246:1306–9.

    Article  CAS  PubMed  Google Scholar 

  285. Harrigan MR. Angiogenic factors in the central nervous system. Neurosurgery. 2003;53:639–60.

    Article  PubMed  Google Scholar 

  286. Jansen M, de Witt Hamer PC, Witmer AN, Troost D, van Noorden CJF. Current perspectives on antiangiogenesis strategies in the treatment of malignant gliomas. Brain Res Brain Res Rev. 2004;45:143–63.

    Article  CAS  PubMed  Google Scholar 

  287. Kargiotis O, Rao JS, Kyritsis AP. Mechanisms of angiogenesis in gliomas. J Neurooncol. 2006;78:281–93.

    Article  CAS  PubMed  Google Scholar 

  288. Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci U S A. 1998;95:9349–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992;359:843–5.

    Article  CAS  PubMed  Google Scholar 

  290. Weindel K, Moringlane JR, Marme D, Weich HA. Detection and quantification of vascular endothelial growth factor/vascular permeability factor in brain tumor tissue and cyst fluid: the key to angiogenesis? Neurosurgery. 1994;35:439–48.

    Article  CAS  PubMed  Google Scholar 

  291. Plate KH, Breier G, Weich HA, Mennel HD, Risau W. Vascular endothelial growth factor and glioma angiogenesis: coordinate induction of VEGF receptors, distribution of VEGF protein and possible in vivo regulatory mechanisms. Int J Cancer. 1994;59:520–9.

    Article  CAS  PubMed  Google Scholar 

  292. Forsythe JA, Jiang BH, Iyer NV, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996;16:4604–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  293. Semenza GL. HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med. 2002;8:62–7.

    Article  Google Scholar 

  294. May D, Itin A, Gal O, et al. Ero1-L alpha plays a key role in a HIF-1-mediated pathway to improve disulfide bond formation and VEGF secretion under hypoxia: implication for cancer. Oncogene. 2005;24:1011–20.

    Article  CAS  PubMed  Google Scholar 

  295. Lobov IB, Brooks PC, Lang RA. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci U S A. 2002;99:11205–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  296. Koga K, Todaka T, Morioka M, et al. Expression of angiopoietin-2 in human glioma cells and its role for angiogenesis. Cancer Res. 2001;61:6248–54.

    CAS  PubMed  Google Scholar 

  297. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27:4733–40.

    Article  CAS  PubMed  Google Scholar 

  298. Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27:740–5.

    Article  CAS  PubMed  Google Scholar 

  299. Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370:709–22.

    Article  CAS  PubMed  Google Scholar 

  300. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370:699–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137:216–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  302. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284:770–6.

    Article  CAS  PubMed  Google Scholar 

  303. Lasky JL, Wu H. Notch signaling, brain development, and human disease. Pediatr Res. 2005;57:109.

    Article  Google Scholar 

  304. Samsioe A, Feinstein R, Saade G, et al. Intrauterine death, fetal malformation, and delayed pregnancy in Ljungan virus-infected mice. Birth Defects Res B Dev Reprod Toxicol. 2006;77:251–6.

    Article  CAS  PubMed  Google Scholar 

  305. Purow BW, Sundaresan TK, Burdick MJ, et al. Notch-1 regulates transcription of the epidermal growth factor receptor through p53. Carcinogenesis. 2008;29:918–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  306. Radtke F, Raj K. The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer. 2003;3:756–67.

    Article  CAS  PubMed  Google Scholar 

  307. Sjolund J, Manetopoulos C, Stockhausen M-T, Axelson H. The Notch pathway in cancer: differentiation gone awry. Eur J Cancer. 2005;41:2620–9.

    Article  PubMed  CAS  Google Scholar 

  308. Weng AP, Aster JC. Multiple niches for Notch in cancer: context is everything. Curr Opin Genet Dev. 2004;14:48–54.

    Article  CAS  PubMed  Google Scholar 

  309. Kageyama R, Ohtsuka T, Hatakeyama J, Ohsawa R. Roles of bHLH genes in neural stem cell differentiation. Exp Cell Res. 2005;306:343–8.

    Article  CAS  PubMed  Google Scholar 

  310. Hatakeyama J, Sakamoto S, Kageyama R. Hes1 and Hes5 regulate the development of the cranial and spinal nerve systems. Dev Neurosci. 2006;28:92–101.

    Article  CAS  PubMed  Google Scholar 

  311. Kanamori M, Kawaguchi T, Nigro JM, et al. Contribution of Notch signaling activation to human glioblastoma multiforme. J Neurosurg. 2007;106:417–27.

    Article  PubMed  Google Scholar 

  312. Purow BW, Haque RM, Noel MW, et al. Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res. 2005;65:2353–63.

    Article  CAS  PubMed  Google Scholar 

  313. Zhu TS, Costello MA, Talsma CE, et al. Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. Cancer Res. 2011;71:6061–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  314. Wang J, Wakeman TP, Lathia JD, et al. Notch promotes radioresistance of glioma stem cells. Stem Cells. 2010;28:17–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  315. Gilbert CA, Daou MC, Moser RP, Ross AH. Gamma-secretase inhibitors enhance temozolomide treatment of human gliomas by inhibiting neurosphere repopulation and xenograft recurrence. Cancer Res. 2010;70:6870–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  316. Saito N, Fu J, Zheng S, et al. A high Notch pathway activation predicts response to gamma secretase inhibitors in proneural subtype of glioma tumor-initiating cells. Stem Cells. 2014;32:301–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  317. Fan X, Mikolaenko I, Elhassan I, et al. Notch1 and notch2 have opposite effects on embryonal brain tumor growth. Cancer Res. 2004;64:7787–93.

    Article  CAS  PubMed  Google Scholar 

  318. Hallahan AR, Pritchard JI, Hansen S, et al. The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of Sonic Hedgehog-induced medulloblastomas. Cancer Res. 2004;64:7794–800.

    Article  CAS  PubMed  Google Scholar 

  319. Ingram WJ, McCue KI, Tran TH, Hallahan AR, Wainwright BJ. Sonic Hedgehog regulates Hes1 through a novel mechanism that is independent of canonical Notch pathway signalling. Oncogene. 2008;27:1489–500.

    Article  CAS  PubMed  Google Scholar 

  320. Fan X, Matsui W, Khaki L, et al. Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res. 2006;66:7445–52.

    Article  CAS  PubMed  Google Scholar 

  321. Wang Q, Li H, Liu N, et al. Correlative analyses of notch signaling with resveratrol-induced differentiation and apoptosis of human medulloblastoma cells. Neurosci Lett. 2008;438:168–73.

    Article  CAS  PubMed  Google Scholar 

  322. Hatton BA, Villavicencio EH, Pritchard J, et al. Notch signaling is not essential in Sonic Hedgehog-activated medulloblastoma. Oncogene. 2010;29:3865–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  323. Julian E, Dave RK, Robson JP, Hallahan AR, Wainwright BJ. Canonical Notch signaling is not required for the growth of Hedgehog pathway-induced medulloblastoma. Oncogene. 2010;29:3465–76.

    Article  CAS  PubMed  Google Scholar 

  324. Palm T, Figarella-Branger D, Chapon F, et al. Expression profiling of ependymomas unravels localization and tumor grade-specific tumorigenesis. Cancer. 2009;115:3955–68.

    Article  CAS  PubMed  Google Scholar 

  325. Puget S, Grill J, Valent A, et al. Candidate genes on chromosome 9q33-34 involved in the progression of childhood ependymomas. J Clin Oncol. 2009;27:1884–92.

    Article  CAS  PubMed  Google Scholar 

  326. Villavicencio EH, Walterhouse DO, Iannaccone PM. The Sonic Hedgehog-Patched-Gli pathway in human development and disease. Am J Hum Genet. 2000;67:1047–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  327. Varjosalo M, Taipale J. Hedgehog signaling. J Cell Sci. 2007;120:3–6.

    Article  CAS  PubMed  Google Scholar 

  328. Lee Y, Kawagoe R, Sasai K, et al. Loss of suppressor-of-fused function promotes tumorigenesis. Oncogene. 2007;26:6442–7.

    Article  CAS  PubMed  Google Scholar 

  329. Dahmane N, Sanchez P, Gitton Y, et al. The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development. 2001;128:5201–12.

    CAS  PubMed  Google Scholar 

  330. Shahi MH, Rey JA, Castresana JS. The Sonic Hedgehog-GLI1 signaling pathway in brain tumor development. Expert Opin Ther Targets. 2012;16:1227–38.

    Article  CAS  PubMed  Google Scholar 

  331. Leung C, Lingbeek M, Shakhova O, et al. Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature. 2004;428:337–41.

    Article  CAS  PubMed  Google Scholar 

  332. Wang X, Venugopal C, Manoranjan B, et al. Sonic Hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells. Oncogene. 2012;31:187–99.

    Article  PubMed  CAS  Google Scholar 

  333. Pomeroy SL, Tamayo P, Gaasenbeek M, et al. Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature. 2002;415:436–42.

    Article  CAS  PubMed  Google Scholar 

  334. Bale AE, Yu KP. The hedgehog pathway and basal cell carcinomas. Hum Mol Genet. 2001;10:757–62.

    Article  CAS  PubMed  Google Scholar 

  335. Kool M, Jones DT, Jager N, et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell. 2014;25:393–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  336. Kinzler KW, Bigner SH, Bigner DD, et al. Identification of an amplified, highly expressed gene in a human glioma. Science. 1987;236:70–3.

    Article  CAS  PubMed  Google Scholar 

  337. Yan GN, Yang L, Lv YF, et al. Endothelial cells promote stem-like phenotype of glioma cells through activating the Hedgehog pathway. J Pathol. 2014;234:11–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  338. Takezaki T, Hide T, Takanaga H, et al. Essential role of the Hedgehog signaling pathway in human glioma-initiating cells. Cancer Sci. 2011;102:1306–12.

    Article  CAS  PubMed  Google Scholar 

  339. Hadden MK. Hedgehog pathway inhibitors: a patent review (2009--present). Expert Opin Ther Pat. 2013;23:345–61.

    Article  CAS  PubMed  Google Scholar 

  340. Yauch RL, Dijkgraaf GJ, Alicke B, et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science. 2009;326:572–4.

    Article  CAS  PubMed  Google Scholar 

  341. Buonamici S, Williams J, Morrissey M, et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med. 2010;2:51ra70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  342. Niehrs C. The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol. 2012;13:767–79.

    Article  CAS  PubMed  Google Scholar 

  343. Klaus A, Birchmeier W. Developmental signaling in myocardial progenitor cells: a comprehensive view of Bmp- and Wnt/beta-catenin signaling. Pediatr Cardiol. 2009;30:609–16.

    Article  PubMed  Google Scholar 

  344. Li VS, Ng SS, Boersema PJ, et al. Wnt signaling through inhibition of beta-catenin degradation in an intact Axin1 complex. Cell. 2012;149:1245–56.

    Article  CAS  PubMed  Google Scholar 

  345. Anastas JN, Moon RT. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer. 2013;13:11–26.

    Article  CAS  PubMed  Google Scholar 

  346. Paul I, Bhattacharya S, Chatterjee A, Ghosh MK. Current understanding on EGFR and Wnt/beta-catenin signaling in glioma and their possible crosstalk. Genes Cancer. 2013;4:427–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  347. Holland JD, Klaus A, Garratt AN, Birchmeier W. Wnt signaling in stem and cancer stem cells. Curr Opin Cell Biol. 2013;25:254–64.

    Article  CAS  PubMed  Google Scholar 

  348. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434:843–50.

    Article  CAS  PubMed  Google Scholar 

  349. Baeza N, Masuoka J, Kleihues P, Ohgaki H. AXIN1 mutations but not deletions in cerebellar medulloblastomas. Oncogene. 2003;22:632–6.

    Article  CAS  PubMed  Google Scholar 

  350. Meng X, Poon R, Zhang X, et al. Suppressor of fused negatively regulates beta-catenin signaling. J Biol Chem. 2001;276:40113–9.

    Article  CAS  PubMed  Google Scholar 

  351. Taylor MD, Zhang X, Liu L, et al. Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling. Oncogene. 2004;23:4577–83.

    Article  CAS  PubMed  Google Scholar 

  352. Rathod SS, Rani SB, Khan M, Muzumdar D, Shiras A. Tumor suppressive miRNA-34a suppresses cell proliferation and tumor growth of glioma stem cells by targeting Akt and Wnt signaling pathways. FEBS Open Bio. 2014;4:485–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  353. Cimmino F, Scoppettuolo MN, Carotenuto M, et al. Norcantharidin impairs medulloblastoma growth by inhibition of Wnt/beta-catenin signaling. J Neurooncol. 2012;106:59–70.

    Article  CAS  PubMed  Google Scholar 

  354. Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov. 2014;13:513–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  355. Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells. Cancer Cell. 2007;11:69–82.

    Article  CAS  PubMed  Google Scholar 

  356. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11.

    Article  CAS  PubMed  Google Scholar 

  357. Temple S. Stem cell plasticity—building the brain of our dreams. Nat Rev Neurosci. 2001;2:513–20.

    Article  CAS  PubMed  Google Scholar 

  358. Son MJ, Woolard K, Nam DH, Lee J, Fine HA. SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. Cell Stem Cell. 2009;4:440–52.

    Article  CAS  PubMed  Google Scholar 

  359. Anido J, Saez-Borderias A, Gonzalez-Junca A, et al. TGF-beta receptor inhibitors target the CD44(high)/Id1(high) glioma-initiating cell population in human glioblastoma. Cancer Cell. 2010;18:655–68.

    Article  CAS  PubMed  Google Scholar 

  360. Lathia JD, Gallagher J, Heddleston JM, et al. Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell. 2010;6:421–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  361. Nicolis SK. Cancer stem cells and “stemness” genes in neuro-oncology. Neurobiol Dis. 2007;25:217–29.

    Article  CAS  PubMed  Google Scholar 

  362. Gargiulo G, Cesaroni M, Serresi M, et al. In vivo RNAi screen for BMI1 targets identifies TGF-beta/BMP-ER stress pathways as key regulators of neural- and malignant glioma-stem cell homeostasis. Cancer Cell. 2013;23:660–76.

    Article  CAS  PubMed  Google Scholar 

  363. Dirks PB. Brain tumor stem cells: the cancer stem cell hypothesis writ large. Mol Oncol. 2010;4:420–30.

    Article  PubMed  Google Scholar 

  364. Uchida H, Arita K, Yunoue S, et al. Role of Sonic Hedgehog signaling in migration of cell lines established from CD133-positive malignant glioma cells. J Neurooncol. 2011;104:697–704.

    Article  CAS  PubMed  Google Scholar 

  365. Turchi L, Debruyne DN, Almairac F, et al. Tumorigenic potential of miR-18A* in glioma initiating cells requires NOTCH-1 signaling. Stem Cells. 2013;31:1252–65.

    Article  CAS  PubMed  Google Scholar 

  366. Kim KH, Seol HJ, Kim EH, et al. Wnt/beta-catenin signaling is a key downstream mediator of MET signaling in glioblastoma stem cells. Neuro Oncol. 2013;15:161–71.

    Article  CAS  PubMed  Google Scholar 

  367. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100:3983–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  368. Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004;64:7011–21.

    Article  CAS  PubMed  Google Scholar 

  369. Gregorieff A, Pinto D, Begthel H, et al. Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology. 2005;129:626–38.

    Article  CAS  PubMed  Google Scholar 

  370. Hemmati HD, Nakano I, Lazareff JA, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A. 2003;100:15178–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  371. Singh SK, Clarke ID, Hide T, Dirks PB. Cancer stem cells in nervous system tumors. Oncogene. 2004;23:7267–73.

    Article  CAS  PubMed  Google Scholar 

  372. Tumbar T, Guasch G, Greco V, et al. Defining the epithelial stem cell niche in skin. Science. 2004;303:359–63.

    Article  CAS  PubMed  Google Scholar 

  373. Yuan X, Curtin J, Xiong Y, et al. Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene. 2004;23:9392–400.

    Article  CAS  PubMed  Google Scholar 

  374. Dirks P. Bmi1 and cell of origin determinants of brain tumor phenotype. Cancer Cell. 2007;12:295–7.

    Article  CAS  PubMed  Google Scholar 

  375. Read T-A, Fogarty MP, Markant SL, et al. Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma. Cancer Cell. 2009;15:135–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  376. Ward RJ, Lee L, Graham K, et al. Multipotent CD15+ cancer stem cells in patched-1-deficient mouse medulloblastoma. Cancer Res. 2009;69:4682–90.

    Article  CAS  PubMed  Google Scholar 

  377. Uchida N, Buck DW, He D, et al. Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci U S A. 2000;97:14720–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  378. Prestegarden L, Enger PO. Cancer stem cells in the central nervous system—a critical review. Cancer Res. 2010;70:8255–8.

    Article  CAS  PubMed  Google Scholar 

  379. Passegue E, Jamieson CHM, Ailles LE, Weissman IL. Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci U S A. 2003;100 Suppl 1:11842–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  380. Quintana E, Shackleton M, Sabel MS, et al. Efficient tumour formation by single human melanoma cells. Nature. 2008;456:593–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  381. Diamandis P, Wildenhain J, Clarke ID, et al. Chemical genetics reveals a complex functional ground state of neural stem cells. Nat Chem Biol. 2007;3:268–73.

    Article  CAS  PubMed  Google Scholar 

  382. Shapiro WR, Basler GA, Chernik NL, Posner JB. Human brain tumor transplantation into nude mice. J Natl Cancer Inst. 1979;62:447–53.

    CAS  PubMed  Google Scholar 

  383. Kobayashi N, Allen N, Clendenon NR, Ko LW. An improved rat brain-tumor model. J Neurosurg. 1980;53:808–15.

    Article  CAS  PubMed  Google Scholar 

  384. Finkelstein SD, Black P, Nowak TP, et al. Histological characteristics and expression of acidic and basic fibroblast growth factor genes in intracerebral xenogeneic transplants of human glioma cells. Neurosurgery. 1994;34:136–43.

    Article  CAS  PubMed  Google Scholar 

  385. Li A, Walling J, Kotliarov Y, et al. Genomic changes and gene expression profiles reveal that established glioma cell lines are poorly representative of primary human gliomas. Mol Cancer Res. 2008;6:21–30.

    Article  CAS  PubMed  Google Scholar 

  386. Gunther HS, Schmidt NO, Phillips HS, et al. Glioblastoma-derived stem cell-enriched cultures form distinct subgroups according to molecular and phenotypic criteria. Oncogene. 2008;27:2897–909.

    Article  CAS  PubMed  Google Scholar 

  387. Schulte A, Gunther HS, Phillips HS, et al. A distinct subset of glioma cell lines with stem cell-like properties reflects the transcriptional phenotype of glioblastomas and overexpresses CXCR4 as therapeutic target. Glia. 2011;59:590–602.

    Article  PubMed  Google Scholar 

  388. Bjerkvig R, Tonnesen A, Laerum OD, Backlund EO. Multicellular tumor spheroids from human gliomas maintained in organ culture. J Neurosurg. 1990;72:463–75.

    Article  CAS  PubMed  Google Scholar 

  389. Kleihues P, Lantos PL, Magee PN. Chemical carcinogenesis in the nervous system. Int Rev Exp Pathol. 1976;15:153–232.

    CAS  PubMed  Google Scholar 

  390. Swenberg JA, Koestner A, Wechsler W. The induction of tumors of the nervous system in rats with intravenous methylnitrosourea (MNU). J Neuropathol Exp Neurol. 1971;30:122.

    CAS  PubMed  Google Scholar 

  391. Simeonova I, Huillard E. In vivo models of brain tumors: roles of genetically engineered mouse models in understanding tumor biology and use in preclinical studies. Cell Mol Life Sci. 2014;71:4007–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  392. Aguzzi A, Brandner S, Isenmann S, Steinbach JP, Sure U. Transgenic and gene disruption techniques in the study of neurocarcinogenesis. Glia. 1995;15:348–64.

    Article  CAS  PubMed  Google Scholar 

  393. Hesselager G, Holland EC. Using mice to decipher the molecular genetics of brain tumors. Neurosurgery. 2003;53:685–94.

    Article  PubMed  Google Scholar 

  394. Rajewsky K, Gu H, Kuhn R, et al. Conditional gene targeting. J Clin Invest. 1996;98:600–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  395. Fomchenko EI, Holland EC. Mouse models of brain tumors and their applications in preclinical trials. Clin Cancer Res. 2006;12:5288–97.

    Article  CAS  PubMed  Google Scholar 

  396. Thomas KR, Capecchi MR. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell. 1987;51:503–12.

    Article  CAS  PubMed  Google Scholar 

  397. Uhrbom L, Hesselager G, Nister M, Westermark B. Induction of brain tumors in mice using a recombinant platelet-derived growth factor B-chain retrovirus. Cancer Res. 1998;58:5275–9.

    CAS  PubMed  Google Scholar 

  398. Holland EC, Hively WP, DePinho RA, Varmus HE. A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes Dev. 1998;12:3675–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  399. Srivastava S, Zou ZQ, Pirollo K, Blattner W, Chang EH. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature. 1990;348:747–9.

    Article  CAS  PubMed  Google Scholar 

  400. Ding H, Roncari L, Shannon P, et al. Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. Cancer Res. 2001;61:3826–36.

    CAS  PubMed  Google Scholar 

  401. Reilly KM, Loisel DA, Bronson RT, McLaughlin ME, Jacks T. Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nat Genet. 2000;26:109–13.

    Article  CAS  PubMed  Google Scholar 

  402. Weissenberger J, Steinbach JP, Malin G, et al. Development and malignant progression of astrocytomas in GFAP-v-src transgenic mice. Oncogene. 1997;14:2005–13.

    Article  CAS  PubMed  Google Scholar 

  403. Xiao A, Wu H, Pandolfi PP, Louis DN, Van Dyke T. Astrocyte inactivation of the pRb pathway predisposes mice to malignant astrocytoma development that is accelerated by PTEN mutation. Cancer Cell. 2002;1:157–68.

    Article  CAS  PubMed  Google Scholar 

  404. Holland EC. A mouse model for glioma: biology, pathology, and therapeutic opportunities. Toxicol Pathol. 2000;28:171–7.

    Article  CAS  PubMed  Google Scholar 

  405. Marumoto T, Tashiro A, Friedmann-Morvinski D, et al. Development of a novel mouse glioma model using lentiviral vectors. Nat Med. 2009;15:110–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  406. Klink B, Miletic H, Stieber D, et al. A novel, diffusely infiltrative xenograft model of human anaplastic oligodendroglioma with mutations in FUBP1, CIC, and IDH1. PLoS One. 2013;8:e59773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  407. Dai C, Celestino JC, Okada Y, et al. PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev. 2001;15:1913–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  408. Kelly JJ, Blough MD, Stechishin OD, et al. Oligodendroglioma cell lines containing t(1;19)(q10;p10). Neuro Oncol. 2010;12:745–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  409. Wetmore C, Eberhart DE, Curran T. The normal patched allele is expressed in medulloblastomas from mice with heterozygous germ-line mutation of patched. Cancer Res. 2000;60:2239–46.

    CAS  PubMed  Google Scholar 

  410. Weiner HL, Bakst R, Hurlbert MS, et al. Induction of medulloblastomas in mice by Sonic Hedgehog, independent of Gli1. Cancer Res. 2002;62:6385–9.

    CAS  PubMed  Google Scholar 

  411. Wechsler-Reya RJ, Scott MP. Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron. 1999;22:103–14.

    Article  CAS  PubMed  Google Scholar 

  412. Kawauchi D, Robinson G, Uziel T, et al. A mouse model of the most aggressive subgroup of human medulloblastoma. Cancer Cell. 2012;21:168–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  413. Marino S, Vooijs M, van Der Gulden H, Jonkers J, Berns A. Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev. 2000;14:994–991004.

    CAS  PubMed  PubMed Central  Google Scholar 

  414. Gibson P, Tong Y, Robinson G, et al. Subtypes of medulloblastoma have distinct developmental origins. Nature. 2010;468:1095–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  415. Witt H, Korshunov A, Pfister SM, Milde T. Molecular approaches to ependymoma: the next step(s). Curr Opin Neurol. 2012;25:745–50.

    Article  PubMed  Google Scholar 

  416. Guan S, Shen R, Lafortune T, et al. Establishment and characterization of clinically relevant models of ependymoma: a true challenge for targeted therapy. Neuro Oncol. 2011;13:748–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  417. Milde T, Kleber S, Korshunov A, et al. A novel human high-risk ependymoma stem cell model reveals the differentiation-inducing potential of the histone deacetylase inhibitor Vorinostat. Acta Neuropathol. 2011;122:637–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Neurosurgery, The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

    Daniel Coluccia M.D., Christian Schneider M.D., Christian Smith & James T. Rutka MD, PhD, FRCSC, FACS, FAAP

  2. Department of Neurosurgery, Cantonal Hospital of Aarau, Aarau, Switzerland

    Daniel Coluccia M.D. & Javier Fandino M.D.

  3. Division of Neurosurgery, Dalhousie University, Halifax, NS, Canada

    Adrienne Weeks Ph.D., M.D., F.R.C.S.C.

Authors
  1. Daniel Coluccia M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adrienne Weeks Ph.D., M.D., F.R.C.S.C.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Javier Fandino M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christian Schneider M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christian Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. James T. Rutka MD, PhD, FRCSC, FACS, FAAP
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James T. Rutka MD, PhD, FRCSC, FACS, FAAP .

Editor information

Editors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Curriculum in Toxicology, UNC Program in Translational Medicine, UNC Lineberger Comprehensive Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA

    William B. Coleman

  2. Laboratory for Clinical Genomics and Advanced Technology (CGAT), Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, Hanover, New Hampshire, USA

    Gregory J. Tsongalis

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media New York

About this chapter

Cite this chapter

Coluccia, D., Weeks, A., Fandino, J., Schneider, C., Smith, C., Rutka, J.T. (2017). Molecular Biology of Human Brain Tumors. In: Coleman, W., Tsongalis, G. (eds) The Molecular Basis of Human Cancer. Humana Press, New York, NY. https://doi.org/10.1007/978-1-59745-458-2_35

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-458-2_35

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-934115-18-3

  • Online ISBN: 978-1-59745-458-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation