Current Treatment Options in Oncology

, Volume 13, Issue 4, pp 417–436

Biomarkers Classification and Therapeutic Decision-Making for Malignant Gliomas

Neuro-oncology (GJ Lesser, Section Editor)

Opinion statement

Diffuse gliomas are the most common primary brain tumors, with glioblastoma (GBM) encompassing more than 50 % of all cases. Despite aggressive therapy, patients nearly always succumb to their disease and the survival for patients with GBM is approximately 1 year. During past years, numerous scientific contributions have reshaped the field of neuro-oncology and neuropathology. A series of molecular discoveries have shed light on new pathogenic mechanisms, as well as new prognostic and predictive biomarkers with clinical relevance. The current World Health Organization (WHO) classification system is solely based on morphologic criteria; however, there is accumulated evidence that tumors with similar histology have distinct molecular signatures with a clinically significant impact on treatment response and survival. Molecular markers and signatures could be incorporated into the glioma classification and grading system to mirror the clinical outcomes. Additionally, molecular markers could lead to a redefinition of currently controversial entities, such as mixed oligoastrocytomas. Newly discovered molecular alterations also have the potential to become targets for future drug development. Despite tremendous progress in the past decade, therapeutic progress for diffuse gliomas has been slow. A further understanding of glioma biology, in concert with well-designed clinical trials, is necessary to identify more putative molecular biomarkers and unravel the mysteries in the pathogenic mechanisms that trigger this menacing disease.


Diffuse glioma IDH MGMT 1p19q CIC G-CIMP TP53 BRAF BRAF-KIAA1549 BRAFV600E EGFR EGFRvIII Ki-67 MIB-1 pHH3 Proneural Mesenchymal Prognosis Treatment Predictive markers 

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    CBTRUS. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004–2008. 2012; Available from:
  2. 2.
    ACS. The American Cancer Society. Cancer Facts and Figures. 2012; Available from:
  3. 3.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO Classification of tumors of the central nervous system. 4th ed. Lyon: IARC; 2007.Google Scholar
  4. 4.
    Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol. 2007;170(5):1445–53.PubMedCrossRefGoogle Scholar
  5. 5.
    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(19):6892–9.PubMedCrossRefGoogle Scholar
  6. 6.
    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(6):479–89.PubMedGoogle Scholar
  7. 7.•
    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(4):1149–53. This paper was among the first to suggest the major role of the IDH mutations in gliomagenesis.PubMedCrossRefGoogle Scholar
  8. 8.
    Nobusawa S, Watanabe T, Kleihues P, Ohgaki H. IDH1 mutations as molecular signature and predictive factor of secondary glioblastomas. Clin Cancer Res. 2009;15(19):6002–7. Epub 2009/09/17.PubMedCrossRefGoogle Scholar
  9. 9.•
    Ohgaki H, Kleihues P. Genetic profile of astrocytic and oligodendroglial gliomas. Brain Tumor Pathol. 2011;28(3):177–83. This paper provides an excellent overview on the genetic signatures of astrocytomas and oligodendrogliomas.PubMedCrossRefGoogle Scholar
  10. 10.
    Kros JM, Gorlia T, Kouwenhoven MC, Zheng PP, Collins VP, Figarella-Branger D, et al. Panel review of anaplastic oligodendroglioma from European Organization For Research and Treatment of Cancer Trial 26951: assessment of consensus in diagnosis, influence of 1p/19q loss, and correlations with outcome. J Neuropathol Exp Neurol. 2007;66(6):545–51.PubMedCrossRefGoogle Scholar
  11. 11.
    Aldape K, Burger PC, Perry A. Clinicopathologic aspects of 1p/19q loss and the diagnosis of oligodendroglioma. Arch Pathol Lab Med. 2007;131(2):242–51.PubMedGoogle Scholar
  12. 12.
    Stupp R, Hegi ME, van den Bent MJ, Mason WP, Weller M, Mirimanoff RO, et al. Changing paradigms–an update on the multidisciplinary management of malignant glioma. Oncologist. 2006;11(2):165–80.PubMedCrossRefGoogle Scholar
  13. 13.
    Wesolowski JR, Rajdev P, Mukherji SK. Temozolomide (Temodar). AJNR Am J Neuroradiol. 2010;31(8):1383–4.PubMedCrossRefGoogle Scholar
  14. 14.•
    Ichimura K. Molecular pathogenesis of IDH mutations in gliomas. Brain Tumor Pathol. 2012;29(3):131–9. This review paper provides a comprehensive overview on the pathogenesis of IDH mutations in gliomas.Google Scholar
  15. 15.
    Pollack IF, Hamilton RL, Sobol RW, Nikiforova MN, Lyons-Weiler MA, LaFramboise WA, et al. IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children's Oncology Group. Childs Nerv Syst. 2011;27(1):87–94.PubMedCrossRefGoogle Scholar
  16. 16.
    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(5897):1807–12.PubMedCrossRefGoogle Scholar
  17. 17.
    Hartmann C, Meyer J, Balss J, Capper D, Mueller W, Christians A, et al. 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. 2009;118(4):469–74.PubMedCrossRefGoogle Scholar
  18. 18.
    Horbinski C, Kofler J, Kelly LM, Murdoch GH, Nikiforova MN. Diagnostic use of IDH1/2 mutation analysis in routine clinical testing of formalin-fixed, paraffin-embedded glioma tissues. J Neuropathol Exp Neurol. 2009;68(12):1319–25.PubMedCrossRefGoogle Scholar
  19. 19.
    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(8):765–73.PubMedCrossRefGoogle Scholar
  20. 20.
    Sonoda Y, Kumabe T, Nakamura T, Saito R, Kanamori M, Yamashita Y, et al. Analysis of IDH1 and IDH2 mutations in Japanese glioma patients. Cancer Sci. 2009;100(10):1996–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Weller M, Felsberg J, Hartmann C, Berger H, Steinbach JP, Schramm J, 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(34):5743–50.PubMedCrossRefGoogle Scholar
  22. 22.
    Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, 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(35):5874–80.PubMedCrossRefGoogle Scholar
  23. 23.
    van den Bent MJ, Dubbink HJ, Marie Y, Brandes AA, Taphoorn MJ, Wesseling P, 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(5):1597–604.PubMedCrossRefGoogle Scholar
  24. 24.••
    Hartmann C, Hentschel B, Wick W, Capper D, Felsberg J, Simon M, et al. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol. 2010;120(6):707–18. This paper provides evidence on the importance of the genotype over morphology in defining prognosis in selected gliomas.PubMedCrossRefGoogle Scholar
  25. 25.••
    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(6):719–29. Epub 2010/11/17. Another important paper that provides evidence on the importance of the genotype over morphology in selected gliomas.Google Scholar
  26. 26.
    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(25):4150–4.PubMedCrossRefGoogle Scholar
  27. 27.
    Dubbink HJ, Taal W, van Marion R, Kros JM, van Heuvel I, Bromberg JE, et al. IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide. Neurology. 2009;73(21):1792–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Houillier C, Wang X, Kaloshi G, Mokhtari K, Guillevin R, Laffaire J, et al. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology. 2010;75(17):1560–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Ahmadi R, Stockhammer F, Becker N, Hohlen K, Misch M, Christians A, et al. No prognostic value of IDH1 mutations in a series of 100 WHO grade II astrocytomas. J Neurooncol. 2012;109(1):15–22.Google Scholar
  30. 30.
    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(6):2708–14.PubMedCrossRefGoogle Scholar
  31. 31.
    Thon N, Eigenbrod S, Kreth S, Lutz J, Tonn JC, Kretzschmar H, et al. IDH1 mutations in grade II astrocytomas are associated with unfavorable progression-free survival and prolonged postrecurrence survival. Cancer. 2012;118(2):452–60.PubMedCrossRefGoogle Scholar
  32. 32.
    Hartmann C, Hentschel B, Tatagiba M, Schramm J, Schnell O, Seidel C, et al. Molecular markers in low-grade gliomas: predictive or prognostic? Clin Cancer Res. 2011;17(13):4588–99.PubMedCrossRefGoogle Scholar
  33. 33.
    Juratli TA, Kirsch M, Robel K, Soucek S, Geiger K, von Kummer R, et al. IDH mutations as an early and consistent marker in low-grade astrocytomas WHO grade II and their consecutive secondary high-grade gliomas. J Neurooncol. 2012;108(3):403–10.Google Scholar
  34. 34.
    Goze C, Bezzina C, Goze E, Rigau V, Maudelonde T, Bauchet L, et al. 1P19Q loss but not IDH1 mutations influences WHO grade II gliomas spontaneous growth. J Neurooncol. 2012;108(1):69–75.PubMedCrossRefGoogle Scholar
  35. 35.
    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(6):597–602.PubMedCrossRefGoogle Scholar
  36. 36.
    Felsberg J, Wolter M, Seul H, Friedensdorf B, Goppert M, Sabel MC, et al. Rapid and sensitive assessment of the IDH1 and IDH2 mutation status in cerebral gliomas based on DNA pyrosequencing. Acta Neuropathol. 2010;119(4):501–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Capper D, Reuss D, Schittenhelm J, Hartmann C, Bremer J, Sahm F, et al. Mutation-specific IDH1 antibody differentiates oligodendrogliomas and oligoastrocytomas from other brain tumors with oligodendroglioma-like morphology. Acta Neuropathol. 2011;121(2):241–52.PubMedCrossRefGoogle Scholar
  38. 38.
    Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol. 2011;224(3):334–43.PubMedCrossRefGoogle Scholar
  39. 39.
    Boissel N, Nibourel O, Renneville A, Gardin C, Reman O, Contentin N, et al. Prognostic impact of isocitrate dehydrogenase enzyme isoforms 1 and 2 mutations in acute myeloid leukemia: a study by the Acute Leukemia French Association group. J Clin Oncol. 2010;28(23):3717–23.PubMedCrossRefGoogle Scholar
  40. 40.
    Borger DR, Tanabe KK, Fan KC, Lopez HU, Fantin VR, Straley KS, et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist. 2012;17(1):72–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Kang MR, Kim MS, Oh JE, Kim YR, Song SY, Seo SI, et al. Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int J Cancer. 2009;125(2):353–5.PubMedCrossRefGoogle Scholar
  42. 42.••
    Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012;483(7390):479–83. This study demonstrates that the IDH mutations are the foundation of CIMP gliomas.PubMedCrossRefGoogle Scholar
  43. 43.
    Kalinina J, Carroll A, Wang L, Yu Q, Mancheno DE, Wu S, et al. Detection of "oncometabolite" 2-hydroxyglutarate by magnetic resonance analysis as a biomarker of IDH1/2 mutations in glioma. J Mol Med (Berl). 2012. doi:10.1007/s00109-012-0888-x.
  44. 44.
    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-Oncology. 2009;11(4):341–7.PubMedCrossRefGoogle Scholar
  45. 45.•
    Ellezam B, Theeler BJ, Walbert T, Mammoser AG, Horbinski C, Kleinschmidt-Demasters BK, et al. Low rate of R123H IDH1 mutation in infratentorial and spinal cord grade II and III diffuse gliomas. Acta Neuropathol. 2012;124(3):449–51. This study is the first to the best of our knowledge to investigate and report a low rate of IDH protein expression in adult non-supratentorial low grade and intermediate gliomas.Google Scholar
  46. 46.
    Olar A, Raghunathan A, Albarracin CT, Aldape KD, Cahill DP, 3rd, Powell SZ, et al. Absence of IDH1-R132H mutation predicts rapid progression of nonenhancing diffuse glioma in older adults. Ann Diagn Pathol. 2012;16(3):161–70.Google Scholar
  47. 47.
    Bleeker FE, Molenaar RJ, Leenstra S. Recent advances in the molecular understanding of glioblastoma. J Neurooncol. 2012;108(1):11–27.PubMedCrossRefGoogle Scholar
  48. 48.
    Reifenberger G, Louis DN. Oligodendroglioma: toward molecular definitions in diagnostic neuro-oncology. J Neuropathol Exp Neurol. 2003;62(2):111–26.PubMedGoogle Scholar
  49. 49.
    Lassman AB, Iwamoto FM, Cloughesy TF, Aldape KD, Rivera AL, Eichler AF, et al. International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors. Neuro-Oncology. 2011;13(6):649–59.PubMedCrossRefGoogle Scholar
  50. 50.
    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(20):9852–61.PubMedCrossRefGoogle Scholar
  51. 51.
    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(10):988–94.PubMedCrossRefGoogle Scholar
  52. 52.
    Yip S, Butterfield YS, Morozova O, Chittaranjan S, Blough MD, An J, et al. Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers. J Pathol. 2012;226(1):7–16.PubMedCrossRefGoogle Scholar
  53. 53.
    Bettegowda C, Agrawal N, Jiao Y, Sausen M, Wood LD, Hruban RH, et al. Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science. 2011;333(6048):1453–5.PubMedCrossRefGoogle Scholar
  54. 54.
    Sahm F, Koelsche C, Meyer J, Pusch S, Lindenberg K, Mueller W, et al. CIC and FUBP1 mutations in oligodendrogliomas, oligoastrocytomas and astrocytomas. Acta Neuropathol. 2012;123(6):853–60.Google Scholar
  55. 55.
    Scheie D, Cvancarova M, Mork S, Skullerud K, Andresen PA, Benestad I, et al. Can morphology predict 1p/19q loss in oligodendroglial tumours? Histopathology. 2008;53(5):578–87.PubMedCrossRefGoogle Scholar
  56. 56.
    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(19):1473–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Cairncross G, Jenkins R. Gliomas with 1p/19q codeletion: a.k.a. oligodendroglioma. Cancer J. 2008;14(6):352–7.PubMedCrossRefGoogle Scholar
  58. 58.
    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(21):1831–6.PubMedCrossRefGoogle Scholar
  59. 59.
    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(23):1886–90.PubMedCrossRefGoogle Scholar
  60. 60.
    Xiong J, Liu Y, Wang Y, Ke RH, Mao Y, Ye ZR. Chromosome 1p/19q status combined with expression of p53 protein improves the diagnostic and prognostic evaluation of oligodendrogliomas. Chin Med J (Engl). 2010;123(24):3566–73.Google Scholar
  61. 61.
    van den Bent MJ, Gravendeel LA, Gorlia T, Kros JM, Lapre L, Wesseling P, 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(22):7148–55.PubMedCrossRefGoogle Scholar
  62. 62.
    Ducray F, Idbaih A, de Reynies A, Bieche I, Thillet J, Mokhtari K, et al. Anaplastic oligodendrogliomas with 1p19q codeletion have a proneural gene expression profile. Mol Cancer. 2008;7:41.PubMedCrossRefGoogle Scholar
  63. 63.
    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(9):e12548.PubMedCrossRefGoogle Scholar
  64. 64.
    Jansen M, Yip S, Louis DN. Molecular pathology in adult gliomas: diagnostic, prognostic, and predictive markers. Lancet Neurol. 2010;9(7):717–26.PubMedCrossRefGoogle Scholar
  65. 65.
    Lee CJ, Chan WI, Cheung M, Cheng YC, Appleby VJ, Orme AT, et al. CIC, a member of a novel subfamily of the HMG-box superfamily, is transiently expressed in developing granule neurons. Brain Res Mol Brain Res. 2002;106(1–2):151–6.PubMedCrossRefGoogle Scholar
  66. 66.
    McBride OW, Merry D, Givol D. The gene for human p53 cellular tumor antigen is located on chromosome 17 short arm (17p13). Proc Natl Acad Sci U S A. 1986;83(1):130–4.PubMedCrossRefGoogle Scholar
  67. 67.
    Mendrysa SM, Ghassemifar S, Malek R. p53 in the CNS: perspectives on development, stem cells, and cancer. Genes Cancer. 2011;2(4):431–42.PubMedCrossRefGoogle Scholar
  68. 68.
    Stander M, Peraud A, Leroch B, Kreth FW. Prognostic impact of TP53 mutation status for adult patients with supratentorial World Health Organization Grade II astrocytoma or oligoastrocytoma: a long-term analysis. Cancer. 2004;101(5):1028–35.PubMedCrossRefGoogle Scholar
  69. 69.••
    Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110. This study provides a molecular classification of gliomas based on gene-expression profiles.PubMedCrossRefGoogle Scholar
  70. 70.
    Levidou G, El-Habr E, Saetta AA, Bamias C, Katsouyanni K, Patsouris E, et al. P53 immunoexpression as a prognostic marker for human astrocytomas: a meta-analysis and review of the literature. J Neurooncol. 2010;100(3):363–71.PubMedCrossRefGoogle Scholar
  71. 71.
    Weller M, Stupp R, Reifenberger G, Brandes AA, van den Bent MJ, Wick W, et al. MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol. 2010;6(1):39–51.PubMedCrossRefGoogle Scholar
  72. 72.
    Nakagawachi T, Soejima H, Urano T, Zhao W, Higashimoto K, Satoh Y, et al. Silencing effect of CpG island hypermethylation and histone modifications on O6-methylguanine-DNA methyltransferase (MGMT) gene expression in human cancer. Oncogene. 2003;22(55):8835–44.PubMedGoogle Scholar
  73. 73.
    Kaina B, Christmann M, Naumann S, Roos WP. MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents. DNA Repair. 2007;6(8):1079–99.PubMedCrossRefGoogle Scholar
  74. 74.
    Mellai M, Monzeglio O, Piazzi A, Caldera V, Annovazzi L, Cassoni P, et al. MGMT promoter hypermethylation and its associations with genetic alterations in a series of 350 brain tumors. J Neurooncol. 2012;107(3):617–31.PubMedCrossRefGoogle Scholar
  75. 75.
    van den Bent MJ, Dubbink HJ, Sanson M, van der Lee-Haarloo CR, Hegi M, Jeuken JW, et al. MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC Brain Tumor Group Study 26951. J Clin Oncol. 2009;27(35):5881–6.PubMedCrossRefGoogle Scholar
  76. 76.
    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(6):740–3.PubMedCrossRefGoogle Scholar
  77. 77.
    Rivera AL, Pelloski CE, Gilbert MR, Colman H, De La Cruz C, Sulman EP, et al. MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro-Oncology. 2010;12(2):116–21.PubMedCrossRefGoogle Scholar
  78. 78.
    Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997–1003.PubMedCrossRefGoogle Scholar
  79. 79.
    Olson RA, Brastianos PK, Palma DA. Prognostic and predictive value of epigenetic silencing of MGMT in patients with high grade gliomas: a systematic review and meta-analysis. J Neurooncol. 2011;105(2):325–35.PubMedCrossRefGoogle Scholar
  80. 80.•
    Reifenberger G, Hentschel B, Felsberg J, Schackert G, Simon M, Schnell O, et al. Predictive impact of MGMT promoter methylation in glioblastoma of the elderly. Int J Cancer. 2012;131(6):1342–50. This study on older glioblastoma patients, a less investigated population, shows the predictive role of the MGMT methylation status.Google Scholar
  81. 81.
    Brandes AA, Franceschi E, Tosoni A, Bartolini S, Bacci A, Agati R, et al. O(6)-methylguanine DNA-methyltransferase methylation status can change between first surgery for newly diagnosed glioblastoma and second surgery for recurrence: clinical implications. Neuro-Oncology. 2010;12(3):283–8.PubMedCrossRefGoogle Scholar
  82. 82.
    Felsberg J, Thon N, Eigenbrod S, Hentschel B, Sabel MC, Westphal M, et al. Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas. Int J Cancer. 2011;129(3):659–70.PubMedCrossRefGoogle Scholar
  83. 83.
    Cancer Genome Atlas Research Network (CGARN). Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061–8.Google Scholar
  84. 84.
    Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession A, Tallini G, et al. MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol. 2008;26(13):2192–7.PubMedCrossRefGoogle Scholar
  85. 85.
    Preusser M, Charles Janzer R, Felsberg J, Reifenberger G, Hamou MF, Diserens AC, et al. Anti-O6-methylguanine-methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association with patient survival impede its use as clinical biomarker. Brain Pathol. 2008;18(4):520–32.PubMedGoogle Scholar
  86. 86.
    Rodriguez FJ, Thibodeau SN, Jenkins RB, Schowalter KV, Caron BL, O'Neill BP, et al. MGMT immunohistochemical expression and promoter methylation in human glioblastoma. Appl Immunohistochem Mol Morphol. 2008;16(1):59–65.PubMedGoogle Scholar
  87. 87.••
    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(5):510–22. Another important study that identifies the G-CIMP glioma phenotype.PubMedCrossRefGoogle Scholar
  88. 88.
    Holbro T, Civenni G, Hynes NE. The ErbB receptors and their role in cancer progression. Exp Cell Res. 2003;284(1):99–110.PubMedCrossRefGoogle Scholar
  89. 89.
    Gan HK, Kaye AH, Luwor RB. The EGFRvIII variant in glioblastoma multiforme. J Clin Neurosci: Off J Neurosurg Soc Australas. 2009;16(6):748–54.Google Scholar
  90. 90.
    Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, 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(3):157–73.PubMedCrossRefGoogle Scholar
  91. 91.
    Gao G, Ren S, Li A, Xu J, Xu Q, Su C, et al. Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR: A meta-analysis from six phase III randomized controlled trials. Int J Cancer. 2012;131(5):E822–9.Google Scholar
  92. 92.
    van den Bent MJ, Brandes AA, Rampling R, Kouwenhoven MC, Kros JM, Carpentier AF, et al. Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol. 2009;27(8):1268–74.PubMedCrossRefGoogle Scholar
  93. 93.
    Uhm JH, Ballman KV, Wu W, Giannini C, Krauss JC, Buckner JC, et al. Phase II evaluation of gefitinib in patients with newly diagnosed Grade 4 astrocytoma: Mayo/North Central Cancer Treatment Group Study N0074. Int J Radiat Oncol Biol Phys. 2011;80(2):347–53.PubMedCrossRefGoogle Scholar
  94. 94.
    Brown PD, Krishnan S, Sarkaria JN, Wu W, Jaeckle KA, Uhm JH, et al. Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177. J Clin Oncol. 2008;26(34):5603–9.PubMedCrossRefGoogle Scholar
  95. 95.
    Hegi ME, Diserens AC, Bady P, Kamoshima Y, Kouwenhoven MC, Delorenzi M, et al. Pathway analysis of glioblastoma tissue after preoperative treatment with the EGFR tyrosine kinase inhibitor gefitinib–a phase II trial. Mol Cancer Ther. 2011;10(6):1102–12.PubMedCrossRefGoogle Scholar
  96. 96.
    Dhomen N, Marais R. New insight into BRAF mutations in cancer. Curr Opin Genet Dev. 2007;17(1):31–9.PubMedCrossRefGoogle Scholar
  97. 97.
    Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008;68(21):8673–7.PubMedCrossRefGoogle Scholar
  98. 98.
    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(3):401–5.PubMedCrossRefGoogle Scholar
  99. 99.
    Jacob K, Albrecht S, Sollier C, Faury D, Sader E, Montpetit A, et al. Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. Br J Cancer. 2009;101(4):722–33.PubMedCrossRefGoogle Scholar
  100. 100.
    Tran NH, Wu X, Frost JA. B-Raf and Raf-1 are regulated by distinct autoregulatory mechanisms. J Biol Chem. 2005;280(16):16244–53.PubMedCrossRefGoogle Scholar
  101. 101.
    Raabe EH, Lim KS, Kim JM, Meeker A, Mao XG, Nikkhah G, et al. BRAF activation induces transformation and then senescence in human neural stem cells: a pilocytic astrocytoma model. Clin Cancer Res. 2011;17(11):3590–9.PubMedCrossRefGoogle Scholar
  102. 102.
    Jacob K, Quang-Khuong DA, Jones DT, Witt H, Lambert S, Albrecht S, et al. Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. Clin Cancer Res. 2011;17(14):4650–60.PubMedCrossRefGoogle Scholar
  103. 103.
    Hasselblatt M, Riesmeier B, Lechtape B, Brentrup A, Stummer W, Albert FK, et al. BRAF-KIAA1549 fusion transcripts are less frequent in pilocytic astrocytomas diagnosed in adults. Neuropathol Appl Neurobiol. 2011;37(7):803–6.PubMedCrossRefGoogle Scholar
  104. 104.
    Lin A, Rodriguez FJ, Karajannis MA, Williams SC, Legault G, Zagzag D, et al. BRAF alterations in primary glial and glioneuronal neoplasms of the central nervous system with identification of 2 novel KIAA1549:BRAF fusion variants. J Neuropathol Exp Neurol. 2012;71(1):66–72.PubMedCrossRefGoogle Scholar
  105. 105.
    Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 2011;121(3):397–405.PubMedCrossRefGoogle Scholar
  106. 106.
    Dias-Santagata D, Lam Q, Vernovsky K, Vena N, Lennerz JK, Borger DR, et al. BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: diagnostic and therapeutic implications. PLoS One. 2011;6(3):e17948.PubMedCrossRefGoogle Scholar
  107. 107.
    Badiali M, Gleize V, Paris S, Moi L, Elhouadani S, Arcella A, et al. KIAA1549-BRAF fusions and IDH mutations can coexist in diffuse gliomas of adults. Brain Pathol. 2012. doi:10.1111/j.1750-3639.2012.00603.x.
  108. 108.
    Jeuken J, van den Broecke C, Gijsen S, Boots-Sprenger S, Wesseling P. RAS/RAF pathway activation in gliomas: the result of copy number gains rather than activating mutations. Acta Neuropathol. 2007;114(2):121–33.PubMedCrossRefGoogle Scholar
  109. 109.
    Kim YH, Nonoguchi N, Paulus W, Brokinkel B, Keyvani K, Sure U, et al. Frequent BRAF Gain in Low-grade Diffuse Gliomas with 1p/19q Loss. Brain Pathol. 2012. doi:10.1111/j.1750-3639.2012.00601.x.
  110. 110.
    Horbinski C, Hamilton RL, Nikiforov Y, Pollack IF. Association of molecular alterations, including BRAF, with biology and outcome in pilocytic astrocytomas. Acta Neuropathol. 2010;119(5):641–9.PubMedCrossRefGoogle Scholar
  111. 111.
    Hawkins C, Walker E, Mohamed N, Zhang C, Jacob K, Shirinian M, et al. BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin Cancer Res. 2011;17(14):4790–8.PubMedCrossRefGoogle Scholar
  112. 112.
    Ascierto PA, Kirkwood JM, Grob JJ, Simeone E, Grimaldi AM, Maio M, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10(1):85.PubMedCrossRefGoogle Scholar
  113. 113.
    Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000;182(3):311–22.PubMedCrossRefGoogle Scholar
  114. 114.
    Hendzel MJ, Wei Y, Mancini MA, Van Hooser A, Ranalli T, Brinkley BR, et al. Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation. Chromosoma. 1997;106(6):348–60.PubMedCrossRefGoogle Scholar
  115. 115.
    Habberstad AH, Gulati S, Torp SH. Evaluation of the proliferation markers Ki-67/MIB-1, mitosin, survivin, pHH3, and DNA topoisomerase IIalpha in human anaplastic astrocytomas–an immunohistochemical study. Diagn Pathol. 2011;6:43.PubMedCrossRefGoogle Scholar
  116. 116.
    Colman H, Giannini C, Huang L, Gonzalez J, Hess K, Bruner J, et al. Assessment and prognostic significance of mitotic index using the mitosis marker phospho-histone H3 in low and intermediate-grade infiltrating astrocytomas. Am J Surg Pathol. 2006;30(5):657–64.PubMedCrossRefGoogle Scholar
  117. 117.
    Preusser M, Hoeftberger R, Woehrer A, Gelpi E, Kouwenhoven M, Kros JM, et al. Prognostic value of Ki67 index in anaplastic oligodendroglial tumours - a translational study of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Histopathology. 2012;60(6):885–94.PubMedCrossRefGoogle Scholar
  118. 118.
    Zheng S, Chheda MG, Verhaak RG. Studying a complex tumor: potential and pitfalls. Cancer J. 2012;18(1):107–14.PubMedCrossRefGoogle Scholar
  119. 119.
    Walker C, Haylock B, Husband D, Joyce KA, Fildes D, Jenkinson MD, et al. Clinical use of genotype to predict chemosensitivity in oligodendroglial tumors. Neurology. 2006;66(11):1661–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Pathology and Genomic MedicineThe Methodist HospitalHoustonUSA
  2. 2.Department of PathologyUniversity of Texas MD Anderson Cancer CenterHoustonUSA

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