Advertisement

The Molecular Biology of Diffuse Low-Grade Gliomas

  • Nicholas F. MarkoEmail author
  • Robert J. Weil
Chapter

Abstract

The World Health Organization (WHO) grading scheme for glial neoplasms assigns grade II to three infiltrating (non-circumscribed) gliomas: diffuse astrocytomas, oligodendrogliomas, and oligoastrocytomas. Although commonly referred to collectively as among the “low-grade gliomas”, these three tumors represent molecularly and clinically unique entities. Each is the subject of active basic research aimed at developing a more complete understanding of its molecular biology, and the pace of such research continues to accelerate. Additionally, because prognostication and management of these tumors has historically proven challenging, translational research regarding grade II infiltrating gliomas continues in the hopes of identifying novel molecular features that can better inform diagnostic, prognostic, and therapeutic strategies. Unfortunately, the basic and translational literature regarding the molecular biology of WHO grade II infiltrating gliomas remains nebulous. Our goal for this chapter is to present a comprehensive discussion of current knowledge regarding the molecular characteristics of these three WHO grade II tumors on the chromosomal, genomic, and epigenomic levels. Additionally, we discuss the emerging evidence suggesting molecular differences between adult and pediatric low-grade, infiltrating gliomas. Finally, we present an overview of current strategies for using molecular data to classify low-grade, infiltrating gliomas into clinically relevant categories based on tumor biology.

Keywords

Neuro-oncology Infiltrating Astrocytoma Oligodendroglioma Oligoastrocytoma Molecular biology Genetics Karyotype Epigenetic Epigenomic Classification 

References

  1. 1.
    Louis D, Ohgaki H, Wiestler O, Cavenee W, editors. WHO classification of tumors of the central nervous system. Lyon: IARC; 2007.Google Scholar
  2. 2.
    Schiff D, Brown PD, Giannini C. Outcome in adult low-grade glioma: the impact of prognostic factors and treatment. Neurology. 2007;69:1366–73.PubMedCrossRefGoogle Scholar
  3. 3.
    Reifenberger G, Collins VP. Pathology and molecular genetics of astrocytic gliomas. J Mol Med. 2004;82:656–70.PubMedCrossRefGoogle Scholar
  4. 4.
    (CBTRUS) CBTRotUS. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2004–2007. 2011. Central Brain Tumor Registry of the United States, Hinsdale. 2011. Available at website: http://www.cbtrus.org/2011-NPCR-SEER/WEB-0407-Report-3-3-2011.pdf. Accessed 03 Mars 2011.
  5. 5.
    Inoue R, Isono M, Abe M, Abe T, Kobayashi H. A genotype of the polymorphic DNA repair gene MGMT is associated with de novo glioblastoma. Neurol Res. 2003;25:875–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Bethke L, Webb E, Murray A, Schoemaker M, Johansen C, Christensen HC, et al. Comprehensive analysis of the role of DNA repair gene polymorphisms on risk of glioma. Hum Mol Genet. 2008;17:800–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Barnett GH. High-grade gliomas: diagnosis and treatment. Totowa: Humana Press; 2007.CrossRefGoogle Scholar
  8. 8.
    Rees J, Wen P, editors. Neuro-oncology. Philadelphia: Elsevier; 2010.Google Scholar
  9. 9.
    Marko NF, Prayson RA, Barnett GH, Weil RJ. Integrated molecular analysis suggests a three-class model for low-grade gliomas: a proof-of-concept study. Genomics. 2010;95:16–24.PubMedCrossRefGoogle Scholar
  10. 10.
    Marko NF, Toms SA, Barnett GH, Weil R. Genomic expression patterns distinguish long-term from short-term glioblastoma survivors: a preliminary feasibility study. Genomics. 2008;91:395–406.PubMedCrossRefGoogle Scholar
  11. 11.
    Schrock E, Blume C, Meffert MC, du Manoir S, Bersch W, Kiessling M, et al. Recurrent gain of chromosome arm 7q in low-grade astrocytic tumors studied by comparative genomic hybridization. Genes Chromosomes Cancer. 1996;15:199–205.PubMedCrossRefGoogle Scholar
  12. 12.
    Wessels PH, Twijnstra A, Kessels AG, Krijne-Kubat B, Theunissen PH, Ummelen MI, et al. Gain of chromosome 7, as detected by in situ hybridization, strongly correlates with shorter survival in astrocytoma grade 2. Genes Chromosomes Cancer. 2002;33:279–84.PubMedCrossRefGoogle Scholar
  13. 13.
    Nishizaki T, Ozaki S, Harada K, Ito H, Arai H, Beppu T, et al. Investigation of genetic alterations associated with the grade of astrocytic tumor by comparative genomic hybridization. Genes Chromosomes Cancer. 1998;21:340–6.PubMedCrossRefGoogle Scholar
  14. 14.
    von Deimling A, editor. Gliomas. Heidelberg: Springer; 2009.Google Scholar
  15. 15.
    Watanabe K, Peraud A, Gratas C, Wakai S, Kleihues P, Ohgaki H. p53 and PTEN gene mutations in gemistocytic astrocytomas. Acta Neuropathol. 1998;95:559–64.PubMedCrossRefGoogle Scholar
  16. 16.
    Miyakawa A, Ichimura K, Schmidt EE, Varmeh-Ziaie S, Collins VP. Multiple deleted regions on the long arm of chromosome 6 in astrocytic tumours. Br J Cancer. 2000;82:543–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Reifenberger J, Reifenberger G, Liu L, James CD, Wechsler W, Collins VP. Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol. 1994;145:1175–90.PubMedGoogle Scholar
  18. 18.
    Jeuken JW, von Deimling A, Wesseling P. Molecular pathogenesis of oligodendroglial tumors. J Neurooncol. 2004;70:161–81.PubMedCrossRefGoogle Scholar
  19. 19.
    Okamoto Y, Di Patre PL, Burkhard C, Horstmann S, Jourde B, Fahey M, et al. Population-based study on incidence, survival rates, and genetic alterations of low-grade diffuse astrocytomas and oligodendrogliomas. Acta Neuropathol. 2004;108:49–56.PubMedCrossRefGoogle Scholar
  20. 20.
    Reifenberger G, Louis DN. Oligodendroglioma: toward molecular definitions in diagnostic neuro-oncology. J Neuropathol Exp Neurol. 2003;62:111–26.PubMedGoogle Scholar
  21. 21.
    von Deimling A, Louis DN, von Ammon K, Petersen I, Wiestler OD, Seizinger BR. Evidence for a tumor suppressor gene on chromosome 19q associated with human astrocytomas, oligodendrogliomas, and mixed gliomas. Cancer Res. 1992;52:4277–9.Google Scholar
  22. 22.
    Bello MJ, Vaquero J, de Campos JM, Kusak ME, Sarasa JL, Saez-Castresana J, et al. Molecular analysis of chromosome 1 abnormalities in human gliomas reveals frequent loss of 1p in oligodendroglial tumors. Int J Cancer. 1994;57:172–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Kraus JA, Koopmann J, Kaskel P, Maintz D, Brandner S, Schramm J, et al. Shared allelic losses on chromosomes 1p and 19q suggest a common origin of oligodendroglioma and oligoastrocytoma. J Neuropathol Exp Neurol. 1995;54:91–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Kanner AA, Staugaitis SM, Castilla EA, Chernova O, Prayson RA, Vogelbaum MA, et al. The impact of genotype on outcome in oligodendroglioma: validation of the loss of chromosome arm 1p as an important factor in clinical decision making. J Neurosurg. 2006;104:542–50.PubMedCrossRefGoogle Scholar
  25. 25.
    Griffin CA, Burger P, Morsberger L, Yonescu R, Swierczynski S, Weingart JD, et al. Identification of der(1;19)(q10;p10) in five oligodendrogliomas suggests mechanism of concurrent 1p and 19q loss. J Neuropathol Exp Neurol. 2006;65:988–94.PubMedCrossRefGoogle Scholar
  26. 26.
    Jenkins RB, Blair H, Ballman KV, Giannini C, Arusell RM, Law M, et al. A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res. 2006;66:9852–61.PubMedCrossRefGoogle Scholar
  27. 27.
    Smith JS, Alderete B, Minn Y, Borell TJ, Perry A, Mohapatra G, et al. Localization of common deletion regions on 1p and 19q in human gliomas and their association with histological subtype. Oncogene. 1999;18:4144–52.PubMedCrossRefGoogle Scholar
  28. 28.
    Houillier C, Lejeune J, Benouaich-Amiel A, Laigle-Donadey F, Criniere E, Mokhtari K, et al. Prognostic impact of molecular markers in a series of 220 primary glioblastomas. Cancer. 2006;106:2218–23.PubMedCrossRefGoogle Scholar
  29. 29.
    Maintz D, Fiedler K, Koopmann J, Rollbrocker B, Nechev S, Lenartz D, et al. Molecular genetic evidence for subtypes of oligoastrocytomas. J Neuropathol Exp Neurol. 1997;56:1098–104.PubMedCrossRefGoogle Scholar
  30. 30.
    von Deimling A, Fimmers R, Schmidt MC, Bender B, Fassbender F, Nagel J, et al. Comprehensive allelotype and genetic analysis of 466 human nervous system tumors. J Neuropathol Exp Neurol. 2000;59:544–58.Google Scholar
  31. 31.
    Mueller W, Hartmann C, Hoffmann A, Lanksch W, Kiwit J, Tonn J, et al. Genetic signature of oligoastrocytomas correlates with tumor location and denotes distinct molecular subsets. Am J Pathol. 2002;161:313–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Ueki K, Nishikawa R, Nakazato Y, Hirose T, Hirato J, Funada N, et al. Correlation of histology and molecular genetic analysis of 1p, 19q, 10q, TP53, EGFR, CDK4, and CDKN2A in 91 astrocytic and oligodendroglial tumors. Clin Cancer Res. 2002;8:196–201.PubMedGoogle Scholar
  33. 33.
    Vogazianou AP, Chan R, Backlund LM, Pearson DM, Liu L, Langford CF, et al. Distinct patterns of 1p and 19q alterations identify subtypes of human gliomas that have different prognoses. Neuro Oncol. 2010;12:664–78.PubMedCrossRefGoogle Scholar
  34. 34.
    Rossi MR, Gaile D, Laduca J, Matsui S, Conroy J, McQuaid D, et al. Identification of consistent novel submegabase deletions in low-grade oligodendrogliomas using array-based comparative genomic hybridization. Genes Chromosomes Cancer. 2005;44:85–96.PubMedCrossRefGoogle Scholar
  35. 35.
    Bogler O, Huang HJ, Kleihues P, Cavenee WK. The p53 gene and its role in human brain tumors. Glia. 1995;15:308–27.PubMedCrossRefGoogle Scholar
  36. 36.
    Ohgaki H, Kleihues P. Genetic alterations and signaling pathways in the evolution of gliomas. Cancer Sci. 2009;100:2235–41.PubMedCrossRefGoogle Scholar
  37. 37.
    Ichimura K, Bolin MB, Goike HM, Schmidt EE, Moshref A, Collins VP. Deregulation of the p14ARF/MDM2/p53 pathway is a prerequisite for human astrocytic gliomas with G1-S transition control gene abnormalities. Cancer Res. 2000;60:417–24.PubMedGoogle Scholar
  38. 38.
    Rasheed BK, McLendon RE, Herndon JE, Friedman HS, Friedman AH, Bigner DD, et al. Alterations of the TP53 gene in human gliomas. Cancer Res. 1994;54:1324–30.PubMedGoogle Scholar
  39. 39.
    James CD, Carlbom E, Nordenskjold M, Collins VP, Cavenee WK. Mitotic recombination of chromosome 17 in astrocytomas. Proc Natl Acad Sci USA. 1989;86:2858–62.PubMedCrossRefGoogle Scholar
  40. 40.
    Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol. 2005;64:479–89.PubMedGoogle Scholar
  41. 41.
    Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res. 2004;64:6892–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Sidransky D, Mikkelsen T, Schwechheimer K, Rosenblum ML, Cavanee W, Vogelstein B. Clonal expansion of p53 mutant cells is associated with brain tumour progression. Nature. 1992;355:846–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Watanabe K, Tachibana O, Sata K, Yonekawa Y, Kleihues P, Ohgaki H. 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 223–14.PubMedCrossRefGoogle Scholar
  44. 44.
    Watanabe K, Sato K, Biernat W, Tachibana O, von Ammon K, Ogata N, et al. Incidence and timing of p53 mutations during astrocytoma progression in patients with multiple biopsies. Clin Cancer Res. 1997;3:523–30.PubMedGoogle Scholar
  45. 45.
    von Deimling A, Eibl RH, Ohgaki H, Louis DN, von Ammon K, Petersen I, et al. p53 mutations are associated with 17p allelic loss in grade II and grade III astrocytoma. Cancer Res. 1992;52:2987–90.Google Scholar
  46. 46.
    Peraud A, Kreth FW, Wiestler OD, Kleihues P, Reulen HJ. Prognostic impact of TP53 mutations and P53 protein overexpression in supratentorial WHO grade II astrocytomas and oligoastrocytomas. Clin Cancer Res. 2002;8:1117–24.PubMedGoogle Scholar
  47. 47.
    Geisbrecht BV, Gould SJ. The human PICD gene encodes a cytoplasmic and peroxisomal NADP(+)-dependent isocitrate dehydrogenase. J Biol Chem. 1999;274:30527–33.PubMedCrossRefGoogle Scholar
  48. 48.
    RefSEQ. Isocitrate dehydrogenase. In: National Center for Biotechnology Information. 2008. www.ghr.nlm.nih.gov/gene/IDH1.
  49. 49.
    Narahara K, Kimura S, Kikkawa K, Takahashi Y, Wakita Y, Kasai R, et al. Probable assignment of soluble isocitrate dehydrogenase (IDH1) to 2q33.3. Hum Genet. 1985;71:37–40.PubMedCrossRefGoogle Scholar
  50. 50.
    Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807–12.PubMedCrossRefGoogle Scholar
  51. 51.
    Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360:765–73.PubMedCrossRefGoogle Scholar
  52. 52.
    Ichimura K, Pearson DM, Kocialkowski S, Backlund LM, Chan R, Jones DT, et al. IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro Oncol. 2009;11:341–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 2008;116:597–602.PubMedCrossRefGoogle Scholar
  54. 54.
    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.PubMedCrossRefGoogle Scholar
  55. 55.
    Gravendeel LA, Kloosterhof NK, Bralten LB, van Marion R, Dubbink HJ, Dinjens W, et al. Segregation of non-p.R132H mutations in IDH1 in distinct molecular subtypes of glioma. Hum Mutat. 2010;31:E1186–99.PubMedCrossRefGoogle Scholar
  56. 56.
    Zhao S, Guan KL. IDH1 mutant structures reveal a mechanism of dominant inhibition. Cell Res. 2010;20:1279–81.PubMedCrossRefGoogle Scholar
  57. 57.
    Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 2009;324:261–5.PubMedCrossRefGoogle Scholar
  58. 58.
    Pietrak B, Zhao H, Qi H, Quinn C, Gao E, Boyer JG, et al. A tale of two subunits: how the neom­orphic R132H IDH1 mutation enhances produc­tion of alphaHG. Biochemistry. 2011;50:4804–12.PubMedCrossRefGoogle Scholar
  59. 59.
    Yang B, Zhong C, Peng Y, Lai Z, Ding J. Molecular mechanisms of “off-on switch” of activities of human IDH1 by tumor-associated mutation R132H. Cell Res. 2010;20:1188–200.PubMedCrossRefGoogle Scholar
  60. 60.
    Zhu J, Zuo J, Xu Q, Wang X, Wang Z, Zhou D. Isocitrate dehydrogenase mutations may be a protective mechanism in glioma patients. Med Hypotheses. 2011;76:602–3.PubMedCrossRefGoogle Scholar
  61. 61.
    Metellus P, Coulibaly B, Colin C, de Paula AM, Vasiljevic A, Taieb D, et al. Absence of IDH mutation identifies a novel radiologic and molecular subtype of WHO grade II gliomas with dismal prognosis. Acta Neuropathol. 2010;120:719–29.PubMedCrossRefGoogle Scholar
  62. 62.
    Labussiere M, Idbaih A, Wang XW, Marie Y, Boisselier B, Falet C, et al. All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2. Neurology. 2010;74:1886–90.PubMedCrossRefGoogle Scholar
  63. 63.
    Williams LT. Signal transduction by the platelet-derived growth factor receptor. Science. 1989;243:1564–70.PubMedCrossRefGoogle Scholar
  64. 64.
    Schlessinger J. SH2/SH3 signaling proteins. Curr Opin Genet Dev. 1994;4:25–30.PubMedCrossRefGoogle Scholar
  65. 65.
    di Tomaso E, London N, Fuja D, Logie J, Tyrrell JA, Kamoun W, et al. PDGF-C induces maturation of blood vessels in a model of glioblastoma and attenuates the response to anti-VEGF treatment. PLoS One. 2009;4:e5123.PubMedCrossRefGoogle Scholar
  66. 66.
    Lokker NA, Sullivan CM, Hollenbach SJ, Israel MA, Giese NA. Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. Cancer Res. 2002;62:3729–35.PubMedGoogle Scholar
  67. 67.
    Hermanson M, Funa K, Hartman M, Claesson-Welsh L, Heldin CH, Westermark B, et al. Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. Cancer Res. 1992;52:3213–9.PubMedGoogle Scholar
  68. 68.
    Guha A, Glowacka D, Carroll R, Dashner K, Black PM, Stiles CD. Expression of platelet derived growth factor and platelet derived growth factor receptor mRNA in a glioblastoma from a patient with Li-Fraumeni syndrome. J Neurol Neurosurg Psychiatry. 1995;58:711–4.PubMedCrossRefGoogle Scholar
  69. 69.
    Huang H, Colella S, Kurrer M, Yonekawa Y, Kleihues P, Ohgaki H. Gene expression profiling of low-grade diffuse astrocytomas by cDNA arrays. Cancer Res. 2000;60:6868–74.PubMedGoogle Scholar
  70. 70.
    Varela M, Ranuncolo SM, Morand A, Lastiri J, De Kier Joffe EB, Puricelli LI, et al. EGF-R and PDGF-R, but not bcl-2, overexpression predict overall survival in patients with low-grade astrocytomas. J Surg Oncol. 2004;86:34–40.PubMedCrossRefGoogle Scholar
  71. 71.
    Ekstrand AJ, Sugawa N, James CD, Collins VP. Amplified and rearranged epidermal growth factor receptor genes in human glioblastomas reveal deletions of sequences encoding portions of the N- and/or C-terminal tails. Proc Natl Acad Sci USA. 1992;89:4309–13.PubMedCrossRefGoogle Scholar
  72. 72.
    Liu L, Backlund LM, Nilsson BR, Grander D, Ichimura K, Goike HM, et al. Clinical significance of EGFR amplification and the aberrant EGFRvIII transcript in conventionally treated astrocytic gliomas. J Mol Med. 2005;83:917–26.PubMedCrossRefGoogle Scholar
  73. 73.
    Rorive S, Maris C, Debeir O, Sandras F, Vidaud M, Bieche I, et al. Exploring the distinctive biological characteristics of pilocytic and low-grade diffuse astrocytomas using microarray gene expression profiles. J Neuropathol Exp Neurol. 2006;65:794–807.PubMedCrossRefGoogle Scholar
  74. 74.
    Sallinen SL, Sallinen PK, Haapasalo HK, Helin HJ, Helen PT, Schraml P, et al. Identification of differentially expressed genes in human gliomas by DNA microarray and tissue chip techniques. Cancer Res. 2000;60:6617–22.PubMedGoogle Scholar
  75. 75.
    Godard S, Getz G, Delorenzi M, Farmer P, Kobayashi H, Desbaillets I, et al. Classification of human astrocytic gliomas on the basis of gene expression: a correlated group of genes with angiogenic activity emerges as a strong predictor of subtypes. Cancer Res. 2003;63:6613–25.PubMedGoogle Scholar
  76. 76.
    Hunter S, Young A, Olson J, Brat DJ, Bowers G, Wilcox JN, et al. Differential expression between pilocytic and anaplastic astrocytomas: identification of apolipoprotein D as a marker for low-grade, non-infiltrating primary CNS neoplasms. J Neuropathol Exp Neurol. 2002;61:275–81.PubMedGoogle Scholar
  77. 77.
    Rickman DS, Bobek MP, Misek DE, Kuick R, Blaivas M, Kurnit DM, et al. Distinctive molecular profiles of high-grade and low-grade gliomas based on oligonucleotide microarray analysis. Cancer Res. 2001;61:6885–91.PubMedGoogle Scholar
  78. 78.
    Gutmann DH, Hedrick NM, Li J, Nagarajan R, Perry A, Watson MA. Comparative gene expression profile analysis of neurofibromatosis 1-associated and sporadic pilocytic astrocytomas. Cancer Res. 2002;62:2085–91.PubMedGoogle Scholar
  79. 79.
    Khatua S, Peterson KM, Brown KM, Lawlor C, Santi MR, LaFleur B, et al. Overexpression of the EGFR/FKBP12/HIF-2alpha pathway identified in childhood astrocytomas by angiogenesis gene profiling. Cancer Res. 2003;63:1865–70.PubMedGoogle Scholar
  80. 80.
    Ljubimova JY, Lakhter AJ, Loksh A, Yong WH, Riedinger MS, Miner JH, et al. Overexpression of alpha4 chain-containing laminins in human glial tumors identified by gene microarray analysis. Cancer Res. 2001;61:5601–10.PubMedGoogle Scholar
  81. 81.
    van den Boom J, Wolter M, Kuick R, Misek DE, Youkilis AS, Wechsler DS, et al. Characterization of gene expression profiles associated with glioma ­progression using oligonucleotide-based microarray analysis and real-time reverse transcription-­polymerase chain reaction. Am J Pathol. 2003;163:1033–43.PubMedCrossRefGoogle Scholar
  82. 82.
    Wong KK, Chang YM, Tsang YT, Perlaky L, Su J, Adesina A, et al. Expression analysis of juvenile pilocytic astrocytomas by oligonucleotide microarray reveals two potential subgroups. Cancer Res. 2005;65:76–84.PubMedGoogle Scholar
  83. 83.
    Huang H, Hara A, Homma T, Yonekawa Y, Ohgaki H. Altered expression of immune defense genes in pilocytic astrocytomas. J Neuropathol Exp Neurol. 2005;64:891–901.PubMedCrossRefGoogle Scholar
  84. 84.
    Crawford JR, Santi MR, Thorarinsdottir HK, Cornelison R, Rushing EJ, Zhang H, et al. Detection of human herpesvirus-6 variants in pediatric brain tumors: association of viral antigen in low grade gliomas. J Clin Virol. 2009;46:37–42.PubMedCrossRefGoogle Scholar
  85. 85.
    Besleaga R, Montesinos-Rongen M, Perez-Tur J, Siebert R, Deckert M. Expression of the LGI1 gene product in astrocytic gliomas: downregulation with malignant progression. Virchows Arch. 2003;443:561–4.PubMedCrossRefGoogle Scholar
  86. 86.
    Weil KC, Berge MS, Sehgal A. Molecular characterization of a novel human brain tumor-associated gene BR-3. Anticancer Res. 2002;22:1467–74.PubMedGoogle Scholar
  87. 87.
    Schlierf B, Friedrich RP, Roerig P, Felsberg J, Reifenberger G, Wegner M. Expression of SoxE and SoxD genes in human gliomas. Neuropathol Appl Neurobiol. 2007;33:621–30.PubMedCrossRefGoogle Scholar
  88. 88.
    Boulay JL, Miserez AR, Zweifel C, Sivasankaran B, Kana V, Ghaffari A, et al. Loss of NOTCH2 positively predicts survival in subgroups of human glial brain tumors. PLoS One. 2007;2:e576.PubMedCrossRefGoogle Scholar
  89. 89.
    Yu Y, Xu F, Peng H, Fang X, Zhao S, Li Y, et al. NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas. Proc Natl Acad Sci USA. 1999;96:214–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Husemann K, Wolter M, Buschges R, Bostrom J, Sabel M, Reifenberger G. Identification of two distinct deleted regions on the short arm of chromosome 1 and rare mutation of the CDKN2C gene from 1p32 in oligodendroglial tumors. J Neuropathol Exp Neurol. 1999;58:1041–50.PubMedCrossRefGoogle Scholar
  91. 91.
    Bello MJ, de Campos JM, Vaquero J, Ruiz-Barnes P, Kusak ME, Sarasa JL, et al. hRAD54 gene and 1p high-resolution deletion-mapping analyses in oligodendrogliomas. Cancer Genet Cytogenet. 2000;116:142–7.PubMedCrossRefGoogle Scholar
  92. 92.
    Tews B, Roerig P, Hartmann C, Hahn M, Felsberg J, Blaschke B, et al. Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q. Oncogene. 2007;26:5010–6.PubMedCrossRefGoogle Scholar
  93. 93.
    Barbashina V, Salazar P, Holland EC, Rosenblum MK, Ladanyi M. Allelic losses at 1p36 and 19q13 in gliomas: correlation with histologic classification, definition of a 150-kb minimal deleted region on 1p36, and evaluation of CAMTA1 as a candidate tumor suppressor gene. Clin Cancer Res. 2005;11:1119–28.PubMedGoogle Scholar
  94. 94.
    McDonald JM, Dunmire V, Taylor E, Sawaya R, Bruner J, Fuller GN, et al. Attenuated expression of DFFB is a hallmark of oligodendrogliomas with 1p-allelic loss. Mol Cancer. 2005;4:35.PubMedCrossRefGoogle Scholar
  95. 95.
    Dong S, Pang JC, Hu J, Zhou LF, Ng HK. Transcriptional inactivation of TP73 expression in oligodendroglial tumors. Int J Cancer. 2002;98:370–5.PubMedCrossRefGoogle Scholar
  96. 96.
    McDonald JM, Dunlap S, Cogdell D, Dunmire V, Wei Q, Starzinski-Powitz A, et al. The SHREW1 gene, frequently deleted in oligodendrogliomas, functions to inhibit cell adhesion and migration. Cancer Biol Ther. 2006;5:300–4.PubMedCrossRefGoogle Scholar
  97. 97.
    Hartmann C, Johnk L, Kitange G, Wu Y, Ashworth LK, Jenkins RB, et al. Transcript map of the 3.7-Mb D19S112–S246 candidate tumor suppressor region on the long arm of chromosome 19. Cancer Res. 2002;62:4100–8.PubMedGoogle Scholar
  98. 98.
    Rosenberg JE, Lisle DK, Burwick JA, Ueki K, von Deimling A, Mohrenweiser HW, et al. Refined deletion mapping of the chromosome 19q glioma tumor suppressor gene to the D19S412-STD interval. Oncogene. 1996;13:2483–5.PubMedGoogle Scholar
  99. 99.
    Smith JS, Tachibana I, Pohl U, Lee HK, Thanarajasingam U, Portier BP, et al. A transcript map of the chromosome 19q-arm glioma tumor suppressor region. Genomics. 2000;64:44–50.PubMedCrossRefGoogle Scholar
  100. 100.
    Mora J, Cheung NK, Chen L, Qin J, Gerald W. Loss of heterozygosity at 19q13.3 is associated with locally aggressive neuroblastoma. Clin Cancer Res. 2001;7:1358–61.PubMedGoogle Scholar
  101. 101.
    Hartmann C, Mueller W, von Deimling A. Pathology and molecular genetics of oligodendroglial tumors. J Mol Med. 2004;82:638–55.PubMedCrossRefGoogle Scholar
  102. 102.
    Hong C, Bollen AW, Costello JF. The contribution of genetic and epigenetic mechanisms to gene silencing in oligodendrogliomas. Cancer Res. 2003;63:7600–5.PubMedGoogle Scholar
  103. 103.
    Wolf RM, Draghi N, Liang X, Dai C, Uhrbom L, Eklof C, et al. p190RhoGAP can act to inhibit PDGF-induced gliomas in mice: a putative tumor suppressor encoded on human chromosome 19q13.3. Genes Dev. 2003;17:476–87.PubMedCrossRefGoogle Scholar
  104. 104.
    Tews B, Felsberg J, Hartmann C, Kunitz A, Hahn M, Toedt G, et al. Identification of novel oligodendroglioma-associated candidate tumor suppressor genes in 1p36 and 19q13 using microarray-based expression profiling. Int J Cancer. 2006;119:792–800.PubMedCrossRefGoogle Scholar
  105. 105.
    Trouillard O, Aguirre-Cruz L, Hoang-Xuan K, Marie Y, Delattre JY, Sanson M. Parental 19q loss and PEG3 expression in oligodendrogliomas. Cancer Genet Cytogenet. 2004;151:182–3.PubMedCrossRefGoogle Scholar
  106. 106.
    Jiang X, Yu Y, Yang HW, Agar NY, Frado L, Johnson MD. The imprinted gene PEG3 inhibits Wnt signaling and regulates glioma growth. J Biol Chem. 2010;285:8472–80.PubMedCrossRefGoogle Scholar
  107. 107.
    Schramm J, editor. Low-grade gliomas, vol. 35. New York: Springer; 2010.Google Scholar
  108. 108.
    Reifenberger J, Reifenberger G, Ichimura K, Schmidt EE, Wechsler W, Collins VP. Epidermal growth factor receptor expression in oligodendroglial tumors. Am J Pathol. 1996;149:29–35.PubMedGoogle Scholar
  109. 109.
    Di Rocco F, Carroll RS, Zhang J, Black PM. Platelet-derived growth factor and its receptor expression in human oligodendrogliomas. Neurosurgery. 1998;42:341–6.PubMedCrossRefGoogle Scholar
  110. 110.
    Hagerstrand D, Smits A, Eriksson A, Sigurdardottir S, Olofsson T, Hartman M, et al. Gene expression analyses of grade II gliomas and identification of rPTPbeta/zeta as a candidate oligodendroglioma marker. Neuro Oncol. 2008;10:2–9.PubMedCrossRefGoogle Scholar
  111. 111.
    Nakamura M, Watanabe T, Klangby U, Asker C, Wiman K, Yonekawa Y, et al. p14ARF deletion and methylation in genetic pathways to glioblastomas. Brain Pathol. 2001;11:159–68.PubMedCrossRefGoogle Scholar
  112. 112.
    Watanabe T, Katayama Y, Yoshino A, Yachi K, Ohta T, Ogino A, et al. Aberrant hypermethylation of p14ARF and O6-methylguanine-DNA methyltransferase genes in astrocytoma progression. Brain Pathol. 2007;17:5–10.PubMedCrossRefGoogle Scholar
  113. 113.
    Sherr CJ. Divorcing ARF and p53: an unsettled case. Nat Rev Cancer. 2006;6:663–73.PubMedCrossRefGoogle Scholar
  114. 114.
    Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, et al. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 1998;17:5001–14.PubMedCrossRefGoogle Scholar
  115. 115.
    Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci USA. 1998;95:8292–7.PubMedCrossRefGoogle Scholar
  116. 116.
    Waha A, Guntner S, Huang TH, Yan PS, Arslan B, Pietsch T, et al. Epigenetic silencing of the protocadherin family member PCDH-gamma-A11 in astrocytomas. Neoplasia. 2005;7:193–9.PubMedCrossRefGoogle Scholar
  117. 117.
    Wiencke JK, Zheng S, Jelluma N, Tihan T, Vandenberg S, Tamguney T, et al. Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma. Neuro Oncol. 2007;9:271–9.PubMedCrossRefGoogle Scholar
  118. 118.
    Kunitz A, Wolter M, van den Boom J, Felsberg J, Tews B, Hahn M, et al. DNA hypermethylation and aberrant expression of the EMP3 gene at 19q13.3 in human gliomas. Brain Pathol. 2007;17:363–70.PubMedCrossRefGoogle Scholar
  119. 119.
    Costello JF, Plass C, Cavenee WK. Aberrant methylation of genes in low-grade astrocytomas. Brain Tumor Pathol. 2000;17:49–56.PubMedCrossRefGoogle Scholar
  120. 120.
    Yu J, Zhang H, Gu J, Lin S, Li J, Lu W, et al. Methylation profiles of thirty four promoter-CpG islands and concordant methylation behaviours of sixteen genes that may contribute to carcinogenesis of astrocytoma. BMC Cancer. 2004;4:65.PubMedCrossRefGoogle Scholar
  121. 121.
    Silber JR, Bobola MS, Ghatan S, Blank A, Kolstoe DD, Berger MS. O6-methylguanine-DNA methyltransferase activity in adult gliomas: relation to patient and tumor characteristics. Cancer Res. 1998;58:1068–73.PubMedGoogle Scholar
  122. 122.
    Dong SM, Pang JC, Poon WS, Hu J, To KF, Chang AR, et al. Concurrent hypermethylation of multiple genes is associated with grade of oligodendroglial tumors. J Neuropathol Exp Neurol. 2001;60:808–16.PubMedGoogle Scholar
  123. 123.
    Mollemann M, Wolter M, Felsberg J, Collins VP, Reifenberger G. Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglial tumors. Int J Cancer. 2005;113:379–85.PubMedCrossRefGoogle Scholar
  124. 124.
    Alonso ME, Bello MJ, Gonzalez-Gomez P, Arjona D, Lomas J, de Campos JM, et al. Aberrant promoter methylation of multiple genes in oligodendrogliomas and ependymomas. Cancer Genet Cytogenet. 2003;144:134–42.PubMedCrossRefGoogle Scholar
  125. 125.
    Huang L, Jiang T, Yuan F, Li GL, Cui Y, Liu EZ, et al. Correlation of chromosomes 1p and 19q status and expressions of O6-methylguanine DNA methyltransferase (MGMT), p53 and Ki-67 in diffuse gliomas of World Health Organization (WHO) grades II and III: a clinicopathological study. Neuropathol Appl Neurobiol. 2009;35:367–79.PubMedCrossRefGoogle Scholar
  126. 126.
    Watanabe T, Nakamura M, Kros JM, Burkhard C, Yonekawa Y, Kleihues P, et al. Phenotype versus genotype correlation in oligodendrogliomas and low-grade diffuse astrocytomas. Acta Neuropathol. 2002;103:267–75.PubMedCrossRefGoogle Scholar
  127. 127.
    Levin N, Lavon I, Zelikovitsh B, Fuchs D, Bokstein F, Fellig Y, et al. Progressive low-grade oligodendrogliomas: response to temozolomide and correlation between genetic profile and O6-methylguanine DNA methyltransferase protein expression. Cancer. 2006;106:1759–65.PubMedCrossRefGoogle Scholar
  128. 128.
    Hilton DA, Love S, Barber R, Ellison D, Sandeman DR. Accumulation of p53 and Ki-67 expression do not predict survival in patients with fibrillary ­astrocytomas or the response of these tumors to radiotherapy. Neurosurgery. 1998;42:724–9.PubMedCrossRefGoogle Scholar
  129. 129.
    Ishii N, Tada M, Hamou MF, Janzer RC, Meagher-Villemure K, Wiestler OD, et al. Cells with TP53 mutations in low grade astrocytic tumors evolve clonally to malignancy and are an unfavorable prognostic factor. Oncogene. 1999;18:5870–8.PubMedCrossRefGoogle Scholar
  130. 130.
    Sanson M, Marie Y, Paris S, Idbaih A, Laffaire J, Ducray F, et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol. 2009;27:4150–4.PubMedCrossRefGoogle Scholar
  131. 131.
    Everhard S, Kaloshi G, Criniere E, Benouaich-Amiel A, Lejeune J, Marie Y, et al. MGMT methylation: a marker of response to temozolomide in low-grade gliomas. Ann Neurol. 2006;60:740–3.PubMedCrossRefGoogle Scholar
  132. 132.
    Felsberg J, Erkwoh A, Sabel MC, Kirsch L, Fimmers R, Blaschke B, et al. Oligodendroglial tumors: refinement of candidate regions on chromosome arm 1p and correlation of 1p/19q status with survival. Brain Pathol. 2004;14:121–30.PubMedCrossRefGoogle Scholar
  133. 133.
    Kujas M, Lejeune J, Benouaich-Amiel A, Criniere E, Laigle-Donadey F, Marie Y, et al. Chromosome 1p loss: a favorable prognostic factor in low-grade gliomas. Ann Neurol. 2005;58:322–6.PubMedCrossRefGoogle Scholar
  134. 134.
    Sasaki H, Zlatescu MC, Betensky RA, Johnk LB, Cutone AN, Cairncross JG, et al. Histopatholo­gical-molecular genetic correlations in referral pathologist-diagnosed low-grade “oligodendroglioma”. J Neuropathol Exp Neurol. 2002;61:58–63.PubMedGoogle Scholar
  135. 135.
    Smith JS, Tachibana I, Passe SM, Huntley BK, Borell TJ, Iturria N, et al. PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst. 2001;93:1246–56.PubMedCrossRefGoogle Scholar
  136. 136.
    Ino Y, Zlatescu MC, Sasaki H, Macdonald DR, Stemmer-Rachamimov AO, Jhung S, et al. Long ­survival and therapeutic responses in patients with ­histologically disparate high-grade gliomas demonstrating chromosome 1p loss. J Neurosurg. 2000;92:983–90.PubMedCrossRefGoogle Scholar
  137. 137.
    Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst. 1998;90:1473–9.PubMedCrossRefGoogle Scholar
  138. 138.
    Kaloshi G, Benouaich-Amiel A, Diakite F, Taillibert S, Lejeune J, Laigle-Donadey F, et al. Temozolomide for low-grade gliomas: predictive impact of 1p/19q loss on response and outcome. Neurology. 2007;68:1831–6.PubMedCrossRefGoogle Scholar
  139. 139.
    Hoang-Xuan K, Capelle L, Kujas M, Taillibert S, Duffau H, Lejeune J, et al. Temozolomide as initial treatment for adults with low-grade oligodendrogliomas or oligoastrocytomas and correlation with chromosome 1p deletions. J Clin Oncol. 2004;22:3133–8.PubMedCrossRefGoogle Scholar
  140. 140.
    Bauman GS, Ino Y, Ueki K, Zlatescu MC, Fisher BJ, Macdonald DR, et al. Allelic loss of chromosome 1p and radiotherapy plus chemotherapy in patients with oligodendrogliomas. Int J Radiat Oncol Biol Phys. 2000;48:825–30.PubMedCrossRefGoogle Scholar
  141. 141.
    McLendon RE, Herndon 2nd JE, West B, Reardon D, Wiltshire R, Rasheed BK, et al. Survival analysis of presumptive prognostic markers among oligodendrogliomas. Cancer. 2005;104:1693–9.PubMedCrossRefGoogle Scholar
  142. 142.
    Walker C, du Plessis DG, Joyce KA, Fildes D, Gee A, Haylock B, et al. Molecular pathology and clinical characteristics of oligodendroglial neoplasms. Ann Neurol. 2005;57:855–65.PubMedCrossRefGoogle Scholar
  143. 143.
    Kitange G, Misra A, Law M, Passe S, Kollmeyer TM, Maurer M, et al. Chromosomal imbalances detected by array comparative genomic hybridization in human oligodendrogliomas and mixed ­oligoastrocytomas. Genes Chromosomes Cancer. 2005;42:68–77.PubMedCrossRefGoogle Scholar
  144. 144.
    Jeuken JW, Sprenger SH, Boerman RH, von Deimling A, Teepen HL, van Overbeeke JJ, et al. Subtyping of oligo-astrocytic tumours by comparative genomic hybridization. J Pathol. 2001;194:81–7.PubMedCrossRefGoogle Scholar
  145. 145.
    Eoli M, Bissola L, Bruzzone MG, Pollo B, Maccagnano C, De Simone T, et al. Reclassification of oligoastrocytomas by loss of heterozygosity studies. Int J Cancer. 2006;119:84–90.PubMedCrossRefGoogle Scholar
  146. 146.
    Broniscer A, Baker SJ, West AN, Fraser MM, Proko E, Kocak M, et al. Clinical and molecular characteristics of malignant transformation of low-grade glioma in children. J Clin Oncol. 2007;25:682–9.PubMedCrossRefGoogle Scholar
  147. 147.
    Bhattacharjee MB, Armstrong DD, Vogel H, Cooley LD. Cytogenetic analysis of 120 primary pediatric brain tumors and literature review. Cancer Genet Cytogenet. 1997;97:39–53.PubMedCrossRefGoogle Scholar
  148. 148.
    Ward SJ, Karakoula K, Phipps KP, Harkness W, Hayward R, Thompson D, et al. Cytogenetic ­analysis of paediatric astrocytoma using comparative genomic hybridisation and fluorescence in-situ hybridisation. J Neurooncol. 2010;98:305–18.PubMedCrossRefGoogle Scholar
  149. 149.
    Roberts P, Chumas PD, Picton S, Bridges L, Livingstone JH, Sheridan E. A review of the cytogenetics of 58 pediatric brain tumors. Cancer Genet Cytogenet. 2001;131:1–12.PubMedCrossRefGoogle Scholar
  150. 150.
    Orr LC, Fleitz J, McGavran L, Wyatt-Ashmead J, Handler M, Foreman NK. Cytogenetics in pediatric low-grade astrocytomas. Med Pediatr Oncol. 2002;38:173–7.PubMedCrossRefGoogle Scholar
  151. 151.
    Orellana C, Hernandez-Marti M, Martinez F, Castel V, Millan JM, Alvarez-Garijo JA, et al. Pediatric brain tumors: loss of heterozygosity at 17p and TP53 gene mutations. Cancer Genet Cytogenet. 1998;102:93–9.PubMedCrossRefGoogle Scholar
  152. 152.
    Wong KK, Tsang YT, Chang YM, Su J, Di Francesco AM, Meco D, et al. Genome-wide allelic imbalance analysis of pediatric gliomas by single nucleotide polymorphic allele array. Cancer Res. 2006;66:11172–8.PubMedCrossRefGoogle Scholar
  153. 153.
    Nakamura M, Shimada K, Ishida E, Higuchi T, Nakase H, Sakaki T, et al. Molecular pathogenesis of pediatric astrocytic tumors. Neuro Oncol. 2007;9:113–23.PubMedCrossRefGoogle Scholar
  154. 154.
    Miwa T, Hirose Y, Sasaki H, Ezaki T, Yoshida K, Kawase T. Single-copy gain of chromosome 1q is a negative prognostic marker in pediatric nonependymal, nonpilocytic gliomas. Neurosurgery. 2011;68:206–12.PubMedCrossRefGoogle Scholar
  155. 155.
    Pollack IF, Finkelstein SD, Burnham J, Hamilton RL, Yates AJ, Holmes EJ, et al. Association between chromosome 1p and 19q loss and outcome in pediatric malignant gliomas: results from the CCG-945 cohort. Pediatr Neurosurg. 2003;39:114–21.PubMedCrossRefGoogle Scholar
  156. 156.
    Myal Y, Del Bigio MR, Rhodes RH. Age-related differences in 1p and 19q deletions in oligodendrogliomas. BMC Clin Pathol. 2003;3:6.PubMedCrossRefGoogle Scholar
  157. 157.
    Zhang JG, Kruse CA, Driggers L, Hoa N, Wisoff J, Allen JC, et al. Tumor antigen precursor protein profiles of adult and pediatric brain tumors identify potential targets for immunotherapy. J Neurooncol. 2008;88:65–76.PubMedCrossRefGoogle Scholar
  158. 158.
    Tabori U, Rienstein S, Dromi Y, Leider-Trejo L, Constantini S, Burstein Y, et al. Epidermal growth ­factor receptor gene amplification and expression in disseminated pediatric low-grade gliomas. J Neurosurg. 2005;103:357–61.PubMedGoogle Scholar
  159. 159.
    Otero JJ, Rowitch D, Vandenberg S. OLIG2 is ­differentially expressed in pediatric astrocytic and in ependymal neoplasms. J Neurooncol. 2011;104:423–38.PubMedCrossRefGoogle Scholar
  160. 160.
    Gupta M, Djalilvand A, Brat DJ. Clarifying the diffuse gliomas: an update on the morphologic features and markers that discriminate oligodendroglioma from astrocytoma. Am J Clin Pathol. 2005;124:755–68.PubMedCrossRefGoogle Scholar
  161. 161.
    Fuller GN, Hess KR, Rhee CH, Yung WK, Sawaya RA, Bruner JM, et al. Molecular classification of human diffuse gliomas by multidimensional scaling analysis of gene expression profiles parallels morphology-based classification, correlates with survival, and reveals clinically-relevant novel glioma subsets. Brain Pathol. 2002;12:108–16.PubMedCrossRefGoogle Scholar
  162. 162.
    Kim YH, Nobusawa S, Mittelbronn M, Paulus W, Brokinkel B, Keyvani K, et al. Molecular classification of low-grade diffuse gliomas. Am J Pathol. 2010;177:2708–14.PubMedCrossRefGoogle Scholar
  163. 163.
    Korshunov A, Meyer J, Capper D, Christians A, Remke M, Witt H, et al. Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol. 2009;118:401–5.PubMedCrossRefGoogle Scholar
  164. 164.
    Cooper LA, Gutman DA, Long Q, Johnson BA, Cholleti SR, Kurc T, et al. The proneural molecular signature is enriched in oligodendrogliomas and predicts improved survival among diffuse gliomas. PLoS One. 2010;5:e12548.PubMedCrossRefGoogle Scholar
  165. 165.
    Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17:510–22.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2013

Authors and Affiliations

  1. 1.Department of NeurosurgeryUniversity of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of NeurosurgeryBrain Tumor and Neuro-Oncology Center, Cleveland ClinicClevelandUSA

Personalised recommendations