Glioblastoma: pathology, molecular mechanisms and markers

Acta Neuropathologica

Volumn 129, Issue 6, 2015, Pages 829-848

  Aldape, Kenneth ^a   Zadeh, Gelareh ^a,b   Mansouri, Sheila ^a   Reifenberger, Guido ^c   von Deimling, Andreas ^d  

^a PRINCESS MARGARET HOSPITAL   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

^c HEINRICH HEINE UNIVERSITY   (Germany)

^d GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

Author keywords

G CIMP; Glioblastoma; IDH1 2; MGMT; TCGA

Indexed keywords

B RAF KINASE; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 3; ISOCITRATE DEHYDROGENASE 1; ISOCITRATE DEHYDROGENASE 2; METHYLATED DNA PROTEIN CYSTEINE METHYLTRANSFERASE; PLATELET DERIVED GROWTH FACTOR ALPHA RECEPTOR; TELOMERASE REVERSE TRANSCRIPTASE; TUMOR MARKER;

ADULT DISEASE; ASTROCYTOMA; CANCER CLASSIFICATION; CANCER DIAGNOSIS; CANCER GENETICS; CANCER PATIENT; CHILDHOOD CANCER; CLINICAL FEATURE; DNA METHYLATION; EPIGENETICS; GENE MUTATION; GENETIC ANALYSIS; GENETIC TRANSCRIPTION; GLIOBLASTOMA; HUMAN; MISSENSE MUTATION; MOLECULAR PATHOLOGY; NEUROFIBROMATOSIS TYPE 1; PRIORITY JOURNAL; PROMOTER REGION; REVIEW; SIGNAL TRANSDUCTION; BRAIN TUMOR; GENETICS; PATHOLOGY;

BRAIN NEOPLASMS; GLIOBLASTOMA; HUMANS;

EID: 84929706306     PISSN: 00016322     EISSN: 14320533     Source Type: Journal    
DOI: 10.1007/s00401-015-1432-1     Document Type: Review

References (184)

1. Alcantara Llaguno S, Chen J, Kwon CH, Jackson EL, Li Y, Burns DK, Alvarez-Buylla A, Parada LF (2009) Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell 15:45–56. doi:10.1016/j.ccr.2008.12.006
2. Amatya VJ, Naumann U, Weller M, Ohgaki H (2005) TP53 promoter methylation in human gliomas. Acta Neuropathol 110:178–184. doi:10.1007/s00401-005-1041-5
3. Assanah M, Lochhead R, Ogden A, Bruce J, Goldman J, Canoll P (2006) Glial progenitors in adult white matter are driven to form malignant gliomas by platelet-derived growth factor-expressing retroviruses. J Neurosci Off J Soc Neurosci 26:6781–6790. doi:10.1523/JNEUROSCI.0514-06.2006
4. Assanah MC, Bruce JN, Suzuki SO, Chen A, Goldman JE, Canoll P (2009) PDGF stimulates the massive expansion of glial progenitors in the neonatal forebrain. Glia 57:1835–1847. doi:10.1002/glia.20895
5. Bady P, Sciuscio D, Diserens AC, Bloch J, van den Bent MJ, Marosi C, Dietrich PY, Weller M, Mariani L, Heppner FL et al (2012) MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status. Acta Neuropathol 124:547–560. doi:10.1007/s00401-012-1016-2
6. Baeza N, Weller M, Yonekawa Y, Kleihues P, Ohgaki H (2003) PTEN methylation and expression in glioblastomas. Acta Neuropathol 106:479–485. doi:10.1007/s00401-003-0748-4
7. Bajenaru ML, Hernandez MR, Perry A, Zhu Y, Parada LF, Garbow JR, Gutmann DH (2003) Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. Cancer Res 63:8573–8577
8. Bajenaru ML, Zhu Y, Hedrick NM, Donahoe J, Parada LF, Gutmann DH (2002) Astrocyte-specific inactivation of the neurofibromatosis 1 gene (NF1) is insufficient for astrocytoma formation. Mol Cell Biol 22:5100–5113
9. Banerjee S, Byrd JN, Gianino SM, Harpstrite SE, Rodriguez FJ, Tuskan RG, Reilly KM, Piwnica-Worms DR, Gutmann DH (2010) The neurofibromatosis type 1 tumor suppressor controls cell growth by regulating signal transducer and activator of transcription-3 activity in vitro and in vivo. Cancer Res 70:1356–1366. doi:10.1158/0008-5472.CAN-09-2178
10. Bax DA, Mackay A, Little SE, Carvalho D, Viana-Pereira M, Tamber N, Grigoriadis AE, Ashworth A, Reis RM, Ellison DW et al (2010) A distinct spectrum of copy number aberrations in pediatric high-grade gliomas. Clin Cancer Res Off J Am Assoc Cancer Res 16:3368–3377. doi:10.1158/1078-0432.CCR-10-0438
11. Baylin SB, Esteller M, Rountree MR, Bachman KE, Schuebel K, Herman JG (2001) Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet 10:687–692
12. Baysan M, Bozdag S, Cam MC, Kotliarova S, Ahn S, Walling J, Killian JK, Stevenson H, Meltzer P, Fine HA (2012) G-cimp status prediction of glioblastoma samples using mRNA expression data. PLoS One 7:e47839. doi:10.1371/journal.pone.0047839
13. Beroukhim R, Getz G, Nghiemphu L, Barretina J, Hsueh T, Linhart D, Vivanco I, Lee JC, Huang JH, Alexander S et al (2007) Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proc Natl Acad Sci USA 104:20007–20012. doi:10.1073/pnas.0710052104
14. Bhat KP, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K, Hollingsworth F, Wani K, Heathcock L, James JD, Goodman LD et al (2013) Mesenchymal differentiation mediated by NF-kappaB promotes radiation resistance in glioblastoma. Cancer Cell 24:331–346. doi:10.1016/j.ccr.2013.08.001
15. Bhat KP, Salazar KL, Balasubramaniyan V, Wani K, Heathcock L, Hollingsworth F, James JD, Gumin J, Diefes KL, Kim SH et al (2011) The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes Dev 25:2594–2609. doi:10.1101/gad.176800.111
16. Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession A, Tallini G, Bertorelle R, Bartolini S, Calbucci F, Andreoli A et al (2008) MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol Off J Am Soc Clin Oncol 26:2192–2197. doi:10.1200/JCO.2007.14.8163
17. Brennan C, Momota H, Hambardzumyan D, Ozawa T, Tandon A, Pedraza A, Holland E (2009) Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations. PLoS One 4:e7752. doi:10.1371/journal.pone.0007752
18. Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, Zheng S, Chakravarty D, Sanborn JZ, Berman SH et al (2013) The somatic genomic landscape of glioblastoma. Cell 155:462–477. doi:10.1016/j.cell.2013.09.034
19. Broniscer A, Gajjar A (2004) Supratentorial high-grade astrocytoma and diffuse brainstem glioma: two challenges for the pediatric oncologist. Oncologist 9:197–206
20. Buttarelli FR, Massimino M, Antonelli M, Lauriola L, Nozza P, Donofrio V, Arcella A, Oliva MA, Di Rocco C, Giangaspero F (2010) Evaluation status and prognostic significance of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in pediatric high grade gliomas. Child’s Nervous Sys ChNS Off J Int Soc Pediatr Neurosurg 26:1051–1056. doi:10.1007/s00381-010-1191-1
21. Cairncross G, Wang M, Shaw E, Jenkins R, Brachman D, Buckner J, Fink K, Souhami L, Laperriere N, Curran W et al (2013) Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol Off J Am Soc Clin Oncol 31:337–343. doi:10.1200/JCO.2012.43.2674
22. Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR, Silver JS, Stark PC, Macdonald DR, Ino Y et al (1998) Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90:1473–1479
23. Cancer Genome Atlas Research N (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068. doi:10.1038/nature07385
24. Capper D, Preusser M, Habel A, Sahm F, Ackermann U, Schindler G, Pusch S, Mechtersheimer G, Zentgraf H, von Deimling A (2011) Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody. Acta Neuropathol 122:11–19. doi:10.1007/s00401-011-0841-z
25. Chabner BA (2011) Early accelerated approval for highly targeted cancer drugs. New Engl J Med 364:1087–1089. doi:10.1056/NEJMp1100548
26. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New Eng J Med 364:2507–2516. doi:10.1056/NEJMoa1103782
27. Chung R, Whaley J, Kley N, Anderson K, Louis D, Menon A, Hettlich C, Freiman R, Hedley-Whyte ET, Martuza R et al (1991) TP53 gene mutations and 17p deletions in human astrocytomas. Genes Chromosom Cancer 3:323–331
28. Clarke ID, Dirks PB (2003) A human brain tumor-derived PDGFR-alpha deletion mutant is transforming. Oncogene 22:722–733. doi:10.1038/sj.onc.1206160
29. Costello JF, Berger MS, Huang HS, Cavenee WK (1996) Silencing of p16/CDKN2 expression in human gliomas by methylation and chromatin condensation. Cancer Res 56:2405–2410
30. Costello JF, Plass C, Arap W, Chapman VM, Held WA, Berger MS, Su Huang HJ, Cavenee WK (1997) Cyclin-dependent kinase 6 (CDK6) amplification in human gliomas identified using two-dimensional separation of genomic DNA. Cancer Res 57:1250–1254
31. Dang L, Jin S, Su SM (2010) IDH mutations in glioma and acute myeloid leukemia. Trends Mol Med 16:387–397. doi:10.1016/j.molmed.2010.07.002
32. Danussi C, Akavia UD, Niola F, Jovic A, Lasorella A, Pe’er D, Iavarone A (2013) RHPN2 drives mesenchymal transformation in malignant glioma by triggering RhoA activation. Cancer Res 73:5140–5150. doi:10.1158/0008-5472.CAN-13-1168-T
33. Di Rocco F, Carroll RS, Zhang J, Black PM (1998) Platelet-derived growth factor and its receptor expression in human oligodendrogliomas. Neurosurgery 42:341–346
34. Dias-Santagata D, Akhavanfard S, David SS, Vernovsky K, Kuhlmann G, Boisvert SL, Stubbs H, McDermott U, Settleman J, Kwak EL et al (2010) Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine. EMBO Mol Med 2:146–158. doi:10.1002/emmm.201000070
35. Donson AM, Addo-Yobo SO, Handler MH, Gore L, Foreman NK (2007) MGMT promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric glioblastoma. Pediatr Blood Cancer 48:403–407. doi:10.1002/pbc.20803
36. Druker B (2001) Signal transduction inhibition: results from phase I clinical trials in chronic myeloid leukemia. Semin Hematol 38:9–14
37. Ducrest AL, Szutorisz H, Lingner J, Nabholz M (2002) Regulation of the human telomerase reverse transcriptase gene. Oncogene 21:541–552. doi:10.1038/sj.onc.1205081
38. Dunn GP, Rinne ML, Wykosky J, Genovese G, Quayle SN, Dunn IF, Agarwalla PK, Chheda MG, Campos B, Wang A et al (2012) Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev 26:756–784. doi:10.1101/gad.187922.112
39. Eckel-Passow J, Lachance D, Walsh K, Decker P, Sicotte H, Pekmezci M, Molinaro A, Rice T, Kosel M, Smirnov I et al (2014) TERT promoter mutation, IDH mutation and 1p/19q codeletion define five glioma molecular groups with specific clinical characteristics and germline variant associations. Neuro-Oncology; Abstracts from the 19th Annual Scientific Meeting of the Society for Neuro-Oncology, City
40. Ekstrand AJ, Sugawa N, James CD, Collins VP (1992) 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 89:4309–4313
41. Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. New Eng J Med 343:1350–1354. doi:10.1056/NEJM200011093431901
42. Faury D, Nantel A, Dunn SE, Guiot MC, Haque T, Hauser P, Garami M, Bognar L, Hanzely Z, Liberski PP et al (2007) Molecular profiling identifies prognostic subgroups of pediatric glioblastoma and shows increased YB-1 expression in tumors. J Clin Oncol Off J Am Soc Clin Oncol 25:1196–1208. doi:10.1200/JCO.2006.07.8626
43. Fleming TP, Saxena A, Clark WC, Robertson JT, Oldfield EH, Aaronson SA, Ali IU (1992) Amplification and/or overexpression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumors. Cancer Res 52:4550–4553
44. Fomchenko EI, Dougherty JD, Helmy KY, Katz AM, Pietras A, Brennan C, Huse JT, Milosevic A, Holland EC (2011) Recruited cells can become transformed and overtake PDGF-induced murine gliomas in vivo during tumor progression. PLoS One 6:e20605. doi:10.1371/journal.pone.0020605
45. Frattini V, Trifonov V, Chan JM, Castano A, Lia M, Abate F, Keir ST, Ji AX, Zoppoli P, Niola F et al (2013) The integrated landscape of driver genomic alterations in glioblastoma. Nat Genet 45:1141–1149. doi:10.1038/ng.2734
46. Frederick L, Wang XY, Eley G, James CD (2000) Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res 60:1383–1387
47. Freije WA, Castro-Vargas FE, Fang Z, Horvath S, Cloughesy T, Liau LM, Mischel PS, Nelson SF (2004) Gene expression profiling of gliomas strongly predicts survival. Cancer Res 64:6503–6510. doi:10.1158/0008-5472.CAN-04-0452
48. Fuller GN, Hess KR, Rhee CH, Yung WK, Sawaya RA, Bruner JM, Zhang W (2002) 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 12:108–116
49. Fuller GN, Rhee CH, Hess KR, Caskey LS, Wang R, Bruner JM, Yung WK, Zhang W (1999) Reactivation of insulin-like growth factor binding protein 2 expression in glioblastoma multiforme: a revelation by parallel gene expression profiling. Cancer Res 59:4228–4232
50. Gertler R, Rosenberg R, Stricker D, Friederichs J, Hoos A, Werner M, Ulm K, Holzmann B, Nekarda H, Siewert JR (2004) Telomere length and human telomerase reverse transcriptase expression as markers for progression and prognosis of colorectal carcinoma. J Clin Oncol Off J Am Soc Clin Oncol 22:1807–1814. doi:10.1200/JCO.2004.09.160
51. Godard S, Getz G, Delorenzi M, Farmer P, Kobayashi H, Desbaillets I, Nozaki M, Diserens AC, Hamou MF, Dietrich PY et al (2003) 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 63:6613–6625
52. Gorovets D, Kannan K, Shen R, Kastenhuber ER, Islamdoust N, Campos C, Pentsova E, Heguy A, Jhanwar SC, Mellinghoff IK et al (2012) IDH mutation and neuroglial developmental features define clinically distinct subclasses of lower grade diffuse astrocytic glioma. Clin Cancer Res Off J Am Assoc Cancer Res 18:2490–2501. doi:10.1158/1078-0432.CCR-11-2977
53. Griewank KG, Murali R, Schilling B, Scholz S, Sucker A, Song M, Susskind D, Grabellus F, Zimmer L, Hillen U et al (2013) TERT promoter mutations in ocular melanoma distinguish between conjunctival and uveal tumours. Br J Cancer 109:497–501. doi:10.1038/bjc.2013.312
54. Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG, Sasaki M, Jin S, Schenkein DP, Su SM et al (2010) Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med 207:339–344. doi:10.1084/jem.20092506
55. Gutmann DH, Rasmussen SA, Wolkenstein P, MacCollin MM, Guha A, Inskip PD, North KN, Poyhonen M, Birch PH, Friedman JM (2002) Gliomas presenting after age 10 in individuals with neurofibromatosis type 1 (NF1). Neurology 59:759–761
56. Han SJ, Yang I, Tihan T, Prados MD, Parsa AT (2010) Primary gliosarcoma: key clinical and pathologic distinctions from glioblastoma with implications as a unique oncologic entity. J Neurooncol 96:313–320. doi:10.1007/s11060-009-9973-6
57. Haque T, Faury D, Albrecht S, Lopez-Aguilar E, Hauser P, Garami M, Hanzely Z, Bognar L, Del Maestro RF, Atkinson J et al (2007) Gene expression profiling from formalin-fixed paraffin-embedded tumors of pediatric glioblastoma. Clin Cancer Res Off J Am Assoc Cancer Res 13:6284–6292. doi:10.1158/1078-0432.CCR-07-0525
58. Hartmann C, Meyer J, Balss J, Capper D, Mueller W, Christians A, Felsberg J, Wolter M, Mawrin C, Wick W et al (2009) Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol 118:469–474. doi:10.1007/s00401-009-0561-9
59. Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, Bettegowda C, Rodriguez FJ, Eberhart CG, Hebbar S et al (2011) Altered telomeres in tumors with ATRX and DAXX mutations. Science 333:425. doi:10.1126/science.1207313
60. Hegi ME, Diserens AC, Godard S, Dietrich PY, Regli L, Ostermann S, Otten P, Van Melle G, de Tribolet N, Stupp R (2004) Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res Off J Am Assoc Cancer Res 10:1871–1874
61. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. New Eng J Med 352:997–1003. doi:10.1056/NEJMoa043331
62. Heimberger AB, Hlatky R, Suki D, Yang D, Weinberg J, Gilbert M, Sawaya R, Aldape K (2005) Prognostic effect of epidermal growth factor receptor and EGFRvIII in glioblastoma multiforme patients. Clin Cancer Res Off J Am Assoc Cancer Res 11:1462–1466. doi:10.1158/1078-0432.CCR-04-1737
63. Henson JW, Schnitker BL, Correa KM, von Deimling A, Fassbender F, Xu HJ, Benedict WF, Yandell DW, Louis DN (1994) The retinoblastoma gene is involved in malignant progression of astrocytomas. Annals Neurol 36:714–721. doi:10.1002/ana.410360505
64. Hermanson M, Funa K, Hartman M, Claesson-Welsh L, Heldin CH, Westermark B, Nister M (1992) 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 52:3213–3219
65. Herrlinger U, Rieger J, Koch D, Loeser S, Blaschke B, Kortmann RD, Steinbach JP, Hundsberger T, Wick W, Meyermann R et al (2006) Phase II trial of lomustine plus temozolomide chemotherapy in addition to radiotherapy in newly diagnosed glioblastoma: UKT-03. J Clin Oncol Off J Am Soc Clin Oncol 24:4412–4417. doi:10.1200/JCO.2006.06.9104
66. Hoadley KA, Yau C, Wolf DM, Cherniack AD, Tamborero D, Ng S, Leiserson MD, Niu B, McLellan MD, Uzunangelov V et al (2014) Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 158:929–944. doi:10.1016/j.cell.2014.06.049
67. Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, Kadel S, Moll I, Nagore E, Hemminki K et al (2013) TERT promoter mutations in familial and sporadic melanoma. Science 339:959–961. doi:10.1126/science.1230062
68. Hovestadt V, Remke M, Kool M, Pietsch T, Northcott PA, Fischer R, Cavalli FM, Ramaswamy V, Zapatka M, Reifenberger G et al (2013) Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathol 125:913–916. doi:10.1007/s00401-013-1126-5
69. Huang HS, Nagane M, Klingbeil CK, Lin H, Nishikawa R, Ji XD, Huang CM, Gill GN, Wiley HS, Cavenee WK (1997) The enhanced tumorigenic activity of a mutant epidermal growth factor receptor common in human cancers is mediated by threshold levels of constitutive tyrosine phosphorylation and unattenuated signaling. J Biol Chem 272:2927–2935
70. Hurtt MR, Moossy J, Donovan-Peluso M, Locker J (1992) Amplification of epidermal growth factor receptor gene in gliomas: histopathology and prognosis. J Neuropathol Exp Neurol 51:84–90
71. Huse JT, Brennan C, Hambardzumyan D, Wee B, Pena J, Rouhanifard SH, Sohn-Lee C, le Sage C, Agami R, Tuschl T et al (2009) The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo. Genes Dev 23:1327–1337. doi:10.1101/gad.1777409
72. Ideraabdullah FY, Vigneau S, Bartolomei MS (2008) Genomic imprinting mechanisms in mammals. Mutat Res 647:77–85. doi:10.1016/j.mrfmmm.2008.08.008
73. Inda MM, Bonavia R, Mukasa A, Narita Y, Sah DW, Vandenberg S, Brennan C, Johns TG, Bachoo R, Hadwiger P et al (2010) Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma. Genes Dev 24:1731–1745. doi:10.1101/gad.1890510
74. International Cancer Genome C, Hudson TJ, Anderson W, Artez A, Barker AD, Bell C, Bernabe RR, Bhan MK, Calvo F, Eerola I et al (2010) International network of cancer genome projects. Nature 464:993–998. doi:10.1038/nature08987
75. Janne PA, Engelman JA, Johnson BE (2005) Epidermal growth factor receptor mutations in non-small-cell lung cancer: implications for treatment and tumor biology. J Clin Oncol Off J Am Soc Clin Oncol 23:3227–3234. doi:10.1200/JCO.2005.09.985
76. Jaros E, Perry RH, Adam L, Kelly PJ, Crawford PJ, Kalbag RM, Mendelow AD, Sengupta RP, Pearson AD (1992) Prognostic implications of p53 protein, epidermal growth factor receptor, and Ki-67 labelling in brain tumours. Br J Cancer 66:373–385
77. Jiao Y, Killela PJ, Reitman ZJ, Rasheed AB, Heaphy CM, de Wilde RF, Rodriguez FJ, Rosemberg S, Oba-Shinjo SM, Nagahashi Marie SK et al (2012) Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 3:709–722
78. Jones C, Perryman L, Hargrave D (2012) Paediatric and adult malignant glioma: close relatives or distant cousins? Nature reviews. Clin Oncol 9:400–413. doi:10.1038/nrclinonc.2012.87
79. Karajannis MA, Legault G, Fisher MJ, Milla SS, Cohen KJ, Wisoff JH, Harter DH, Goldberg JD, Hochman T, Merkelson A et al (2014) Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. Neuro-oncology 16:1408–1416. doi:10.1093/neuonc/nou059
80. Karcher S, Steiner HH, Ahmadi R, Zoubaa S, Vasvari G, Bauer H, Unterberg A, Herold-Mende C (2006) Different angiogenic phenotypes in primary and secondary glioblastomas. Int J Cancer J Int Cancer 118:2182–2189. doi:10.1002/ijc.21648
81. Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr, Friedman AH, Friedman H, Gallia GL, Giovanella BC et al (2013) TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci USA 110:6021–6026. doi:10.1073/pnas.1303607110
82. Kim H, Huang W, Jiang X, Pennicooke B, Park PJ, Johnson MD (2010) Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship. Proc Natl Acad Sci USA 107:2183–2188. doi:10.1073/pnas.0909896107
83. Kim S, Dougherty ER, Shmulevich I, Hess KR, Hamilton SR, Trent JM, Fuller GN, Zhang W (2002) Identification of combination gene sets for glioma classification. Mol Cancer Ther 1:1229–1236
84. Kleinschmidt-DeMasters BK, Aisner DL, Birks DK, Foreman NK (2013) Epithelioid GBMs show a high percentage of BRAF V600E mutation. Am J Surg Pathol 37:685–698. doi:10.1097/PAS.0b013e31827f9c5e
85. Knobbe CB, Reifenberger J, Reifenberger G (2004) Mutation analysis of the Ras pathway genes NRAS, HRAS, KRAS and BRAF in glioblastomas. Acta Neuropathol 108:467–470. doi:10.1007/s00401-004-0929-9
86. Koelsche C, Sahm F, Capper D, Reuss D, Sturm D, Jones DT, Kool M, Northcott PA, Wiestler B, Bohmer K et al (2013) Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system. Acta Neuropathol 126:907–915. doi:10.1007/s00401-013-1195-5
87. Korshunov A, Ryzhova M, Hovestadt V, Bender S, Sturm D, Capper D, Meyer J, Schrimpf D, Kool M, Northcott PA et al (2015) Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol 129:669–678. doi:10.1007/s00401-015-1405-4
88. Krex D, Klink B, Hartmann C, von Deimling A, Pietsch T, Simon M, Sabel M, Steinbach JP, Heese O, Reifenberger G et al (2007) Long-term survival with glioblastoma multiforme. Brain J Neurol 130:2596–2606. doi:10.1093/brain/awm204
89. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Janne PA, Costa DB et al (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. New Eng J Med 363:1693–1703. doi:10.1056/NEJMoa1006448
90. Kwon CH, Zhao D, Chen J, Alcantara S, Li Y, Burns DK, Mason RP, Lee EY, Wu H, Parada LF (2008) Pten haploinsufficiency accelerates formation of high-grade astrocytomas. Cancer Res 68:3286–3294. doi:10.1158/0008-5472.CAN-07-6867
91. Labussiere M, Boisselier B, Mokhtari K, Di Stefano AL, Rahimian A, Rossetto M, Ciccarino P, Saulnier O, Paterra R, Marie Y et al (2014) Combined analysis of TERT, EGFR, and IDH status defines distinct prognostic glioblastoma classes. Neurology 83:1200–1206. doi:10.1212/WNL.0000000000000814
92. Lee D, Kang SY, Suh YL, Jeong JY, Lee JI, Nam DH (2012) Clinicopathologic and genomic features of gliosarcomas. J Neurooncol 107:643–650. doi:10.1007/s11060-011-0790-3
93. Lee JC, Vivanco I, Beroukhim R, Huang JH, Feng WL, DeBiasi RM, Yoshimoto K, King JC, Nghiemphu P, Yuza Y et al (2006) Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. PLoS Med 3:e485. doi:10.1371/journal.pmed.0030485
94. Lee JY, Park CK, Park SH, Wang KC, Cho BK, Kim SK (2011) MGMT promoter gene methylation in pediatric glioblastoma: analysis using MS-MLPA. Child’s nervous system: ChNS. Off J Int Soc Pediatr Neurosurg 27:1877–1883. doi:10.1007/s00381-011-1525-7
95. Li A, Walling J, Ahn S, Kotliarov Y, Su Q, Quezado M, Oberholtzer JC, Park J, Zenklusen JC, Fine HA (2009) Unsupervised analysis of transcriptomic profiles reveals six glioma subtypes. Cancer Res 69:2091–2099. doi:10.1158/0008-5472.CAN-08-2100
96. Liang Y, Diehn M, Watson N, Bollen AW, Aldape KD, Nicholas MK, Lamborn KR, Berger MS, Botstein D, Brown PO et al (2005) Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme. Proc Natl Acad Sci USA 102:5814–5819. doi:10.1073/pnas.0402870102
97. Liu XY, Gerges N, Korshunov A, Sabha N, Khuong-Quang DA, Fontebasso AM, Fleming A, Hadjadj D, Schwartzentruber J, Majewski J et al (2012) Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations. Acta Neuropathol 124:615–625. doi:10.1007/s00401-012-1031-3
98. Loenarz C, Schofield CJ (2008) Expanding chemical biology of 2-oxoglutarate oxygenases. Nat Chem Biol 4:152–156. doi:10.1038/nchembio0308-152
99. Lokker NA, Sullivan CM, Hollenbach SJ, Israel MA, Giese NA (2002) 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 62:3729–3735
100. Louis DN (1994) The p53 gene and protein in human brain tumors. J Neuropathol Exp Neurol 53:11–21
101. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109. doi:10.1007/s00401-007-0243-4
102. Lu L, Zhang C, Zhu G, Irwin M, Risch H, Menato G, Mitidieri M, Katsaros D, Yu H (2011) Telomerase expression and telomere length in breast cancer and their associations with adjuvant treatment and disease outcome. Breast Cancer Res BCR 13:R56. doi:10.1186/bcr2893
103. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. New Eng J Med 350:2129–2139. doi:10.1056/NEJMoa040938
104. MacConaill LE, Campbell CD, Kehoe SM, Bass AJ, Hatton C, Niu L, Davis M, Yao K, Hanna M, Mondal C et al (2009) Profiling critical cancer gene mutations in clinical tumor samples. PLoS One 4:e7887. doi:10.1371/journal.pone.0007887
105. Malmstrom A, Gronberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Abacioglu U, Tavelin B, Lhermitte B, Hegi ME et al (2012) Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol 13:916–926. doi:10.1016/S1470-2045(12)70265-6
106. Mashiyama S, Murakami Y, Yoshimoto T, Sekiya T, Hayashi K (1991) Detection of p53 gene mutations in human brain tumors by single-strand conformation polymorphism analysis of polymerase chain reaction products. Oncogene 6:1313–1318
107. Masui K, Cloughesy TF, Mischel PS (2012) Review: molecular pathology in adult high-grade gliomas: from molecular diagnostics to target therapies. Neuropathol Appl Neurobiol 38:271–291. doi:10.1111/j.1365-2990.2011.01238.x
108. McBride SM, Perez DA, Polley MY, Vandenberg SR, Smith JS, Zheng S, Lamborn KR, Wiencke JK, Chang SM, Prados MD et al (2010) Activation of PI3 K/mTOR pathway occurs in most adult low-grade gliomas and predicts patient survival. J Neurooncol 97:33–40. doi:10.1007/s11060-009-0004-4
109. McGillicuddy LT, Fromm JA, Hollstein PE, Kubek S, Beroukhim R, De Raedt T, Johnson BW, Williams SM, Nghiemphu P, Liau LM et al (2009) Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis. Cancer Cell 16:44–54. doi:10.1016/j.ccr.2009.05.009
110. Meyer-Puttlitz B, Hayashi Y, Waha A, Rollbrocker B, Bostrom J, Wiestler OD, Louis DN, Reifenberger G, von Deimling A (1997) Molecular genetic analysis of giant cell glioblastomas. Am J Pathol 151:853–857
111. Nagane M, Levitzki A, Gazit A, Cavenee WK, Huang HJ (1998) Drug resistance of human glioblastoma cells conferred by a tumor-specific mutant epidermal growth factor receptor through modulation of Bcl-XL and caspase-3-like proteases. Proc Natl Acad Sci USA 95:5724–5729
112. Nakamura M, Yonekawa Y, Kleihues P, Ohgaki H (2001) Promoter hypermethylation of the RB1 gene in glioblastomas. Lab Investig J Tech Method Pathol 81:77–82
113. Narita Y, Nagane M, Mishima K, Huang HJ, Furnari FB, Cavenee WK (2002) Mutant epidermal growth factor receptor signaling down-regulates p27 through activation of the phosphatidylinositol 3-kinase/Akt pathway in glioblastomas. Cancer Res 62:6764–6769
114. Network TC (2013) Corrigendum: comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 494:506. doi:10.1038/nature11903
115. Ng HH, Bird A (1999) DNA methylation and chromatin modification. Curr Opin Genet Dev 9:158–163
116. Nishikawa R, Sugiyama T, Narita Y, Furnari F, Cavenee WK, Matsutani M (2004) Immunohistochemical analysis of the mutant epidermal growth factor, deltaEGFR, in glioblastoma. Brain Tumor Pathol 21:53–56
117. Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, Pan F, Pelloski CE, Sulman EP, Bhat KP et al (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17:510–522. doi:10.1016/j.ccr.2010.03.017
118. Ohgaki H, Kleihues P (2013) The definition of primary and secondary glioblastoma. Clin Cancer Res Off J Am Assoc Cancer Res 19:764–772. doi:10.1158/1078-0432.CCR-12-3002
119. Olson RA, Brastianos PK, Palma DA (2011) Prognostic and predictive value of epigenetic silencing of MGMT in patients with high grade gliomas: a systematic review and meta-analysis. J Neurooncol 105:325–335. doi:10.1007/s11060-011-0594-5
120. Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, Wolinsky Y, Kruchko C, Barnholtz-Sloan J (2014) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007–2011. Neuro-oncology 16(Suppl 4):1–63. doi:10.1093/neuonc/nou223
121. Ozawa T, Brennan CW, Wang L, Squatrito M, Sasayama T, Nakada M, Huse JT, Pedraza A, Utsuki S, Yasui Y et al (2010) PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas. Genes Dev 24:2205–2218. doi:10.1101/gad.1972310
122. Ozawa T, Riester M, Cheng YK, Huse JT, Squatrito M, Helmy K, Charles N, Michor F, Holland EC (2014) Most human non-GCIMP glioblastoma subtypes evolve from a common proneural-like precursor glioma. Cancer Cell 26:288–300. doi:10.1016/j.ccr.2014.06.005
123. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812. doi:10.1126/science.1164382
124. Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, Cahill DP, Nahed BV, Curry WT, Martuza RL et al (2014) Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344:1396–1401. doi:10.1126/science.1254257
125. Paugh BS, Broniscer A, Qu C, Miller CP, Zhang J, Tatevossian RG, Olson JM, Geyer JR, Chi SN, da Silva NS et al (2011) Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. J Clin Oncol Off J Am Soc Clin Oncol 29:3999–4006. doi:10.1200/JCO.2011.35.5677
126. Paugh BS, Qu C, Jones C, Liu Z, Adamowicz-Brice M, Zhang J, Bax DA, Coyle B, Barrow J, Hargrave D et al (2010) Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol Off J Am Soc Clin Oncol 28:3061–3068. doi:10.1200/JCO.2009.26.7252
127. Pelloski CE, Ballman KV, Furth AF, Zhang L, Lin E, Sulman EP, Bhat K, McDonald JM, Yung WK, Colman H et al (2007) Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol Off J Am Soc Clin Oncol 25:2288–2294. doi:10.1200/JCO.2006.08.0705
128. Perry A, Aldape KD, George DH, Burger PC (2004) Small cell astrocytoma: an aggressive variant that is clinicopathologically and genetically distinct from anaplastic oligodendroglioma. Cancer 101:2318–2326. doi:10.1002/cncr.20625
129. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L et al (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9:157–173. doi:10.1016/j.ccr.2006.02.019
130. Puget S, Philippe C, Bax DA, Job B, Varlet P, Junier MP, Andreiuolo F, Carvalho D, Reis R, Guerrini-Rousseau L et al (2012) Mesenchymal transition and PDGFRA amplification/mutation are key distinct oncogenic events in pediatric diffuse intrinsic pontine gliomas. PLoS One 7:e30313. doi:10.1371/journal.pone.0030313
131. Reifenberger J, Reifenberger G, Liu L, James CD, Wechsler W, Collins VP (1994) Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol 145:1175–1190
132. Reuss DE, Sahm F, Schrimpf D, Wiestler B, Capper D, Koelsche C, Schweizer L, Korshunov A, Jones DT, Hovestadt V et al (2014) ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an “integrated” diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma. Acta Neuropathol. doi:10.1007/s00401-014-1370-3
133. Rickman DS, Bobek MP, Misek DE, Kuick R, Blaivas M, Kurnit DM, Taylor J, Hanash SM (2001) Distinctive molecular profiles of high-grade and low-grade gliomas based on oligonucleotide microarray analysis. Cancer Res 61:6885–6891
134. Robinson GW, Orr BA, Gajjar A (2014) Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy. BMC Cancer 14:258. doi:10.1186/1471-2407-14-258
135. Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C, Tsoi J, Clark O, Oldrini B, Komisopoulou E et al (2013) An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340:626–630. doi:10.1126/science.1236062
136. Sahm F, Capper D, Jeibmann A, Habel A, Paulus W, Troost D, von Deimling A (2012) Addressing diffuse glioma as a systemic brain disease with single-cell analysis. Arch Neurol 69:523–526. doi:10.1001/archneurol.2011.2910
137. Sallinen SL, Sallinen PK, Haapasalo HK, Helin HJ, Helen PT, Schraml P, Kallioniemi OP, Kononen J (2000) Identification of differentially expressed genes in human gliomas by DNA microarray and tissue chip techniques. Cancer Res 60:6617–6622
138. Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, Gilbert MR, Herndon JE 2nd, McLendon RE, Mitchell DA et al (2010) Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol Off J Am Soc Clin Oncol 28:4722–4729. doi:10.1200/JCO.2010.28.6963
139. Sanders RP, Drissi R, Billups CA, Daw NC, Valentine MB, Dome JS (2004) Telomerase expression predicts unfavorable outcome in osteosarcoma. J Clin Oncol Off J Am Soc Clin Oncol 22:3790–3797. doi:10.1200/JCO.2004.03.043
140. Sandsmark DK, Zhang H, Hegedus B, Pelletier CL, Weber JD, Gutmann DH (2007) Nucleophosmin mediates mammalian target of rapamycin-dependent actin cytoskeleton dynamics and proliferation in neurofibromin-deficient astrocytes. Cancer Res 67:4790–4799. doi:10.1158/0008-5472.CAN-06-4470
141. Sanson M, Marie Y, Paris S, Idbaih A, Laffaire J, Ducray F, El Hallani S, Boisselier B, Mokhtari K, Hoang-Xuan K et al (2009) Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol Off J Am Soc Clin Oncol 27:4150–4154. doi:10.1200/JCO.2009.21.9832
142. Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C, Schmieder K, Wesseling P, Mawrin C, Hasselblatt M et al (2011) Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 121:397–405. doi:10.1007/s00401-011-0802-6
143. Schlegel J, Merdes A, Stumm G, Albert FK, Forsting M, Hynes N, Kiessling M (1994) Amplification of the epidermal-growth-factor-receptor gene correlates with different growth behaviour in human glioblastoma. Int J Cancer J Int Cancer 56:72–77
144. Schumacher T, Bunse L, Pusch S, Sahm F, Wiestler B, Quandt J, Menn O, Osswald M, Oezen I, Ott M et al (2014) A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 512:324–327. doi:10.1038/nature13387
145. Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, Sturm D, Fontebasso AM, Quang DA, Tonjes M et al (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226–231. doi:10.1038/nature10833
146. Shai R, Shi T, Kremen TJ, Horvath S, Liau LM, Cloughesy TF, Mischel PS, Nelson SF (2003) Gene expression profiling identifies molecular subtypes of gliomas. Oncogene 22:4918–4923. doi:10.1038/sj.onc.1206753
147. Shinojima N, Tada K, Shiraishi S, Kamiryo T, Kochi M, Nakamura H, Makino K, Saya H, Hirano H, Kuratsu J et al (2003) Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res 63:6962–6970
148. Simon M, Hosen I, Gousias K, Rachakonda S, Heidenreich B, Gessi M, Schramm J, Hemminki K, Waha A, Kumar R (2014) TERT promoter mutations: a novel independent prognostic factor in primary glioblastomas. Neuro-oncology. doi:10.1093/neuonc/nou158
149. Slamon D, Pegram M (2001) Rationale for trastuzumab (Herceptin) in adjuvant breast cancer trials. Semin Oncol 28:13–19
150. Smith JS, Wang XY, Qian J, Hosek SM, Scheithauer BW, Jenkins RB, James CD (2000) Amplification of the platelet-derived growth factor receptor-A (PDGFRA) gene occurs in oligodendrogliomas with grade IV anaplastic features. J Neuropathol Exp Neurol 59:495–503
151. Snuderl M, Fazlollahi L, Le LP, Nitta M, Zhelyazkova BH, Davidson CJ, Akhavanfard S, Cahill DP, Aldape KD, Betensky RA et al (2011) Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 20:810–817. doi:10.1016/j.ccr.2011.11.005
152. Srivastava A, Jain A, Jha P, Suri V, Sharma MC, Mallick S, Puri T, Gupta DK, Gupta A, Sarkar C (2010) MGMT gene promoter methylation in pediatric glioblastomas. Child’s nervous system: ChNS. Off J Int Soc Pediatr Neurosurg 26:1613–1618. doi:10.1007/s00381-010-1214-y
153. Stockhausen MT, Broholm H, Villingshoj M, Kirchhoff M, Gerdes T, Kristoffersen K, Kosteljanetz M, Spang-Thomsen M, Poulsen HS (2011) Maintenance of EGFR and EGFRvIII expressions in an in vivo and in vitro model of human glioblastoma multiforme. Exp Cell Res 317:1513–1526. doi:10.1016/j.yexcr.2011.04.001
154. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466. doi:10.1016/S1470-2045(09)70025-7
155. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New Eng J Med 352:987–996. doi:10.1056/NEJMoa043330
156. Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DT, Konermann C, Pfaff E, Tonjes M, Sill M, Bender S et al (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22:425–437. doi:10.1016/j.ccr.2012.08.024
157. Suri V, Das P, Pathak P, Jain A, Sharma MC, Borkar SA, Suri A, Gupta D, Sarkar C (2009) Pediatric glioblastomas: a histopathological and molecular genetic study. Neuro-oncology 11:274–280. doi:10.1215/15228517-2008-092
158. Szerlip NJ, Pedraza A, Chakravarty D, Azim M, McGuire J, Fang Y, Ozawa T, Holland EC, Huse JT, Jhanwar S et al (2012) Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc Natl Acad Sci USA 109:3041–3046. doi:10.1073/pnas.1114033109
159. Tabori U, Ma J, Carter M, Zielenska M, Rutka J, Bouffet E, Bartels U, Malkin D, Hawkins C (2006) Human telomere reverse transcriptase expression predicts progression and survival in pediatric intracranial ependymoma. J Clin Oncol Off J Am Soc Clin Oncol 24:1522–1528. doi:10.1200/JCO.2005.04.2127
160. Tanwar MK, Gilbert MR, Holland EC (2002) Gene expression microarray analysis reveals YKL-40 to be a potential serum marker for malignant character in human glioma. Cancer Res 62:4364–4368
161. Thakkar JP, Dolecek TA, Horbinski C, Ostrom QT, Lightner DD, Barnholtz-Sloan JS, Villano JL (2014) Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol Biomark Prevent Pub Am Assoc Cancer Res Cosponsored Am Soc Prevent Oncol 23:1985–1996. doi:10.1158/1055-9965.EPI-14-0275
162. Tso CL, Freije WA, Day A, Chen Z, Merriman B, Perlina A, Lee Y, Dia EQ, Yoshimoto K, Mischel PS et al (2006) Distinct transcription profiles of primary and secondary glioblastoma subgroups. Cancer Res 66:159–167. doi:10.1158/0008-5472.CAN-05-0077
163. Ueki K, Ono Y, Henson JW, Efird JT, von Deimling A, Louis DN (1996) CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer Res 56:150–153
164. van den Bent MJ, Brandes AA, Taphoorn MJ, Kros JM, Kouwenhoven MC, Delattre JY, Bernsen HJ, Frenay M, Tijssen CC, Grisold W et al (2013) 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 Off J Am Soc Clin Oncol 31:344–350. doi:10.1200/JCO.2012.43.2229
165. van den Bent MJ, Erdem-Eraslan L, Idbaih A, de Rooi J, Eilers PH, Spliet WG, den Dunnen WF, Tijssen C, Wesseling P, Sillevis Smitt PA et al (2013) MGMT-STP27 methylation status as predictive marker for response to PCV in anaplastic Oligodendrogliomas and Oligoastrocytomas. A report from EORTC study 26951. Clin Cancer Res Off J Am Assoc Cancer Res 19:5513–5522. doi:10.1158/1078-0432.CCR-13-1157
166. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110. doi:10.1016/j.ccr.2009.12.020
167. Vinagre J, Almeida A, Populo H, Batista R, Lyra J, Pinto V, Coelho R, Celestino R, Prazeres H, Lima L et al (2013) Frequency of TERT promoter mutations in human cancers. Nature Commun 4:2185. doi:10.1038/ncomms3185
168. Wang SC, Hung MC (2009) Nuclear translocation of the epidermal growth factor receptor family membrane tyrosine kinase receptors. Clin Cancer Res Off J Am Assoc Cancer Res 15:6484–6489. doi:10.1158/1078-0432.CCR-08-2813
169. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE et al (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17:225–234. doi:10.1016/j.ccr.2010.01.020
170. Warrington NM, Gianino SM, Jackson E, Goldhoff P, Garbow JR, Piwnica-Worms D, Gutmann DH, Rubin JB (2010) Cyclic AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis-1. Cancer Res 70:5717–5727. doi:10.1158/0008-5472.CAN-09-3769
171. Watanabe T, Yokoo H, Yokoo M, Yonekawa Y, Kleihues P, Ohgaki H (2001) Concurrent inactivation of RB1 and TP53 pathways in anaplastic oligodendrogliomas. J Neuropathol Exp Neurol 60:1181–1189
172. Weller M, Felsberg J, Hartmann C, Berger H, Steinbach JP, Schramm J, Westphal M, Schackert G, Simon M, Tonn JC et al (2009) 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 Off J Am Soc Clin Oncol 27:5743–5750. doi:10.1200/JCO.2009.23.0805
173. Wick W, Meisner C, Hentschel B, Platten M, Schilling A, Wiestler B, Sabel MC, Koeppen S, Ketter R, Weiler M et al (2013) Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation. Neurology 81:1515–1522. doi:10.1212/WNL.0b013e3182a95680
174. Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, Nikkhah G, Papsdorf K, Steinbach JP, Sabel M et al (2012) Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol 13:707–715. doi:10.1016/S1470-2045(12)70164-X
175. Wiencke JK, Zheng S, Jelluma N, Tihan T, Vandenberg S, Tamguney T, Baumber R, Parsons R, Lamborn KR, Berger MS et al (2007) Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma. Neuro-oncology 9:271–279. doi:10.1215/15228517-2007-003
176. Wiestler B, Capper D, Hovestadt V, Sill M, Jones DT, Hartmann C, Felsberg J, Platten M, Feiden W, Keyvani K et al (2014) Assessing CpG island methylator phenotype, 1p/19q codeletion, and MGMT promoter methylation from epigenome-wide data in the biomarker cohort of the NOA-04 trial. Neuro-oncology. doi:10.1093/neuonc/nou138
177. Wiestler B, Capper D, Sill M, Jones DT, Hovestadt V, Sturm D, Koelsche C, Bertoni A, Schweizer L, Korshunov A et al (2014) Integrated DNA methylation and copy-number profiling identify three clinically and biologically relevant groups of anaplastic glioma. Acta Neuropathol 128:561–571. doi:10.1007/s00401-014-1315-x
178. Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, Vogelstein B (1992) Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci USA 89:2965–2969
179. Wong KK, Tsang YT, Chang YM, Su J, Di Francesco AM, Meco D, Riccardi R, Perlaky L, Dauser RC, Adesina A et al (2006) Genome-wide allelic imbalance analysis of pediatric gliomas by single nucleotide polymorphic allele array. Cancer Res 66:11172–11178. doi:10.1158/0008-5472.CAN-06-2438
180. Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, Becksfort J, Qu C, Ding L, Huether R, Parker M et al (2012) Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44:251–253. doi:10.1038/ng.1102
181. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ et al (2009) IDH1 and IDH2 mutations in gliomas. New Eng J Med 360:765–773. doi:10.1056/NEJMoa0808710
182. Zarghooni M, Bartels U, Lee E, Buczkowicz P, Morrison A, Huang A, Bouffet E, Hawkins C (2010) Whole-genome profiling of pediatric diffuse intrinsic pontine gliomas highlights platelet-derived growth factor receptor alpha and poly (ADP-ribose) polymerase as potential therapeutic targets. J Clin Oncol Off J Am Soc Clin Oncol 28:1337–1344. doi:10.1200/JCO.2009.25.5463
183. Zhu Y, Guignard F, Zhao D, Liu L, Burns DK, Mason RP, Messing A, Parada LF (2005) Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8:119–130. doi:10.1016/j.ccr.2005.07.004
184. Zhu Y, Harada T, Liu L, Lush ME, Guignard F, Harada C, Burns DK, Bajenaru ML, Gutmann DH, Parada LF (2005) Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation. Development 132:5577–5588. doi:10.1242/dev.02162