Skip to main content

Advertisement

Log in

Applicable advances in the molecular pathology of glioblastoma

  • Review Article
  • Published:
Brain Tumor Pathology Aims and scope Submit manuscript

Abstract

Comprising more than 80 % of malignant brain tumors, glioma has proven to be a daunting cause of mortality in a vast majority of the human population. Progressive and extensive research on malignant glioma has substantially enhanced our understanding of glioma cell biology and molecular pathology. Subtypes of glioma such as astrocytoma and oligodendroglioma are currently grouped together into one pathological class, where they show many differences in histology and molecular etiology. This indicates that it may be beneficial to consider a new and radical subclassification. Thus, we summarize recent developments in glioblastoma multiforme (GBM) subtypes, immunohistochemical analyses useful for diagnoses and the biological evaluation and therapeutic implications of gliomas in this review.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996

    Article  CAS  PubMed  Google Scholar 

  2. Chin L, Meyerson M, Aldape K, Bigner D, Mikkelsen T, VandenBerg S et al (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068

    Article  Google Scholar 

  3. Parsons DW, Jones S, Zhang XS, Lin JCH, Leary RJ, Angenendt P et al (2008) An integrated genomic analysis of human glioblastoma Multiforme. Science 321(5897):1807–1812

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Kim TM, Huang W, Park R, Park PJ, Johnson MD (2011) A developmental taxonomy of glioblastoma defined and maintained by MicroRNAs. Cancer Res 71(9):3387–3399

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17(1):98–110

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109

    Article  PubMed Central  PubMed  Google Scholar 

  7. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD 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(3):157–173

    Article  CAS  PubMed  Google Scholar 

  8. Brennan C, Momota H, Hambardzumyan D, Ozawa T, Tandon A, Pedraza A et al (2009) Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations. PLoS ONE 4(11):e7752

    Article  PubMed Central  PubMed  Google Scholar 

  9. Brown KE, Chagoya G, Kwatra SG, Yen T, Keir ST, Cooter M et al (2015) Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development. J Neurochem 133(5):730–738

  10. Motomura K, Natsume A, Watanabe R, Ito I, Kato Y, Momota H et al (2012) Immunohistochemical analysis-based proteomic subclassification of newly diagnosed glioblastomas. Cancer Sci 103(10):1871–1879

    Article  CAS  PubMed  Google Scholar 

  11. Nicolay DJ, Doucette JR, Nazarali AJ (2007) Transcriptional control of oligodendrogenesis. Glia 55(13):1287–1299

    Article  PubMed  Google Scholar 

  12. Hu BY, Du ZW, Li XJ, Ayala M, Zhang SC (2009) Human oligodendrocytes from embryonic stem cells: conserved SHH signaling networks and divergent FGF effects. Development 136(9):1443–1452

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Levine JM, Reynolds R, Fawcett JW (2001) The oligodendrocyte precursor cell in health and disease. Trends Neurosci 24(1):39–47

    Article  CAS  PubMed  Google Scholar 

  14. Nishiyama A, Lin XH, Giese N, Heldin CH, Stallcup WB (1996) Interaction between NG2 proteoglycan and PDGF alpha-receptor on O2A progenitor cells is required for optimal response to PDGF. J Neurosci Res 43(3):315–330

    Article  CAS  PubMed  Google Scholar 

  15. Rao RC, Boyd J, Padmanabhan R, Chenoweth JG, McKay RD (2009) Efficient serum-free derivation of oligodendrocyte precursors from neural stem cell-enriched cultures. Stem Cells 27(1):116–125

    Article  CAS  PubMed  Google Scholar 

  16. Kato Y, Kaneko M, Sata M, Fujita N, Tsuruo T, Osawa M (2005) Enhanced expression of Aggrus (T1alpha/podoplanin), a platelet-aggregation-inducing factor in lung squamous cell carcinoma. Tumour Biol 26(4):195–200

    Article  CAS  PubMed  Google Scholar 

  17. Kato Y, Sasagawa I, Kaneko M, Osawa M, Fujita N, Tsuruo T (2004) Aggrus: a diagnostic marker that distinguishes seminoma from embryonal carcinoma in testicular germ cell tumors. Oncogene 23(52):8552–8556

    Article  CAS  PubMed  Google Scholar 

  18. Kato Y, Kaneko MK, Kuno A, Uchiyama N, Amano K, Chiba Y et al (2006) Inhibition of tumor cell-induced platelet aggregation using a novel anti-podoplanin antibody reacting with its platelet-aggregation-stimulating domain. Biochem Biophys Res Commun 349(4):1301–1307

    Article  CAS  PubMed  Google Scholar 

  19. Hantusch B, Kalt R, Krieger S, Puri C, Kerjaschki D (2007) Sp1/Sp3 and DNA-methylation contribute to basal transcriptional activation of human podoplanin in MG63 versus Saos-2 osteoblastic cells. BMC Mol Biol 8:20

    Article  PubMed Central  PubMed  Google Scholar 

  20. Stamenkovic I, Yu Q (2009) Shedding light on proteolytic cleavage of CD44: the responsible sheddase and functional significance of shedding. J Invest Dermatol 129(6):1321–1324

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Xu Y, Stamenkovic I, Yu Q (2010) CD44 attenuates activation of the hippo signaling pathway and is a prime therapeutic target for glioblastoma. Cancer Res 70(6):2455–2464

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Martin-Villar E, Fernandez-Munoz B, Parsons M, Yurrita MM, Megias D, Perez-Gomez E et al (2010) Podoplanin associates with CD44 to promote directional cell migration. Mol Biol Cell 21(24):4387–4399

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Le Mercier M, Hastir D, Moles Lopez X, De Neve N, Maris C, Trepant AL et al (2012) A simplified approach for the molecular classification of glioblastomas. PLoS ONE 7:e45475

    Article  PubMed Central  PubMed  Google Scholar 

  24. Popova SN, Bergqvist M, Dimberg A, Edqvist PH, Ekman S, Hesselager G et al (2014) Subtyping of gliomas of various WHO grades by the application of immunohistochemistry. Histopathology 64(3):365–379

    Article  PubMed  Google Scholar 

  25. Conroy S, Kruyt FA, Joseph JV, Balasubramaniyan V, Bhat KP, Wagemakers M et al (2014) Subclassification of newly diagnosed glioblastomas through an immunohistochemical approach. PLoS ONE 9:e115687

    Article  PubMed Central  PubMed  Google Scholar 

  26. Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408(6810):307–310

    Article  CAS  PubMed  Google Scholar 

  27. Louis DN (1994) The p53 gene and protein in human brain tumors. J Neuropathol Exp Neurol 53(1):11–21

    Article  CAS  PubMed  Google Scholar 

  28. Jenkins RB, Blair H, Ballman KV, Giannini C, Arusell RM, Law M et al (2006) 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 66:9852–9861

    Article  CAS  PubMed  Google Scholar 

  29. 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(5):1175–1190

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Kim YH, Nobusawa S, Mittelbronn M, Paulus W, Brokinkel B, Keyvani K et al (2010) Molecular classification of low-grade diffuse gliomas. Am J Pathol 177(6):2708–2714

    Article  PubMed Central  PubMed  Google Scholar 

  31. Suzuki A, Nobusawa S, Natsume A, Suzuki H, Kim YH, Yokoo H et al (2014) Olig2 labeling index is correlated with histological and molecular classifications in low-grade diffuse gliomas. J Neurooncol 120(2):283–291

    Article  CAS  PubMed  Google Scholar 

  32. Schmidt EE, Ichimura K, Reifenberger G, Collins VP (1994) CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas. Cancer Res 54(24):6321–6324

    CAS  PubMed  Google Scholar 

  33. Ruas M, Peters G (1998) The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim Biophys Acta 1378(2):F115–F177

    CAS  PubMed  Google Scholar 

  34. Wakabayashi T, Natsume A, Hatano H, Fujii M, Shimato S, Ito M et al (2009) p16 promoter methylation in the serum as a basis for the molecular diagnosis of gliomas. Neurosurgery 64(3):455–461 (discussion 61–62)

    Article  PubMed  Google Scholar 

  35. Ohgaki H, Kleihues P (2007) Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170(5):1445–1453

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Doetsch F, Petreanu L, Caille I, Garcia-Verdugo JM, Alvarez-Buylla A (2002) EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36(6):1021–1034

    Article  CAS  PubMed  Google Scholar 

  37. Ivkovic S, Canoll P, Goldman JE (2008) Constitutive EGFR signaling in oligodendrocyte progenitors leads to diffuse hyperplasia in postnatal white matter. J Neurosci 28(4):914–922

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Jansen M, Yip S, Louis DN (2010) Molecular pathology in adult gliomas: diagnostic, prognostic, and predictive markers. Lancet Neurol 9(7):717–726

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Weickert CS, Webster MJ, Colvin SM, Herman MM, Hyde TM, Weinberger DR et al (2000) Localization of epidermal growth factor receptors and putative neuroblasts in human subependymal zone. J Comp Neurol 423(3):359–372

    Article  CAS  PubMed  Google Scholar 

  40. Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H et al (1985) Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 313(5998):144–147

    Article  CAS  PubMed  Google Scholar 

  41. Frederick L, Wang XY, Eley G, James CD (2000) Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res 60(5):1383–1387

    CAS  PubMed  Google Scholar 

  42. Ohno M, Natsume A, Ichiro Iwami K, Iwamizu H, Noritake K, Ito D et al (2010) Retrovirally engineered T-cell-based immunotherapy targeting type III variant epidermal growth factor receptor, a glioma-associated antigen. Cancer Sci 101(12):2518–2524

    Article  CAS  PubMed  Google Scholar 

  43. Li GH, Wei H, Lv SQ, Ji H, Wang DL (2010) Knockdown of STAT3 expression by RNAi suppresses growth and induces apoptosis and differentiation in glioblastoma stem cells. Int J Oncol 37(1):103–110

    Article  PubMed  Google Scholar 

  44. Choi BD, Archer GE, Mitchell DA, Heimberger AB, McLendon RE, Bigner DD et al (2009) EGFRvIII-targeted vaccination therapy of malignant glioma. Brain Pathol 19(4):713–723

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Gerson SL, Trey JE, Miller K, Berger NA (1986) Comparison of O6-alkylguanine-DNA alkyltransferase activity based on cellular DNA content in human, rat and mouse tissues. Carcinogenesis 7(5):745–749

    Article  CAS  PubMed  Google Scholar 

  46. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352(10):997–1003

    Article  CAS  PubMed  Google Scholar 

  47. Mikeska T, Bock C, El-Maarri O, Hubner A, Ehrentraut D, Schramm J et al (2007) Optimization of quantitative MGMT promoter methylation analysis using pyrosequencing and combined bisulfite restriction analysis. J Mol Diagn 9(3):368–381

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Felsberg J, Thon N, Eigenbrod S, Hentschel B, Sabel MC, Westphal M et al (2011) 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 129(3):659–670

    Article  CAS  PubMed  Google Scholar 

  49. Wick W, Weller M, van den Bent M, Sanson M, Weiler M, von Deimling A et al (2014) MGMT testing–the challenges for biomarker-based glioma treatment. Nat Rev Neurol 10(7):372–385

    Article  CAS  PubMed  Google Scholar 

  50. Kato T, Natsume A, Toda H, Iwamizu H, Sugita T, Hachisu R et al (2010) Efficient delivery of liposome-mediated MGMT-siRNA reinforces the cytotoxity of temozolomide in GBM-initiating cells. Gene Ther 17(11):1363–1371

    Article  CAS  PubMed  Google Scholar 

  51. Tsujiuchi T, Natsume A, Motomura K, Kondo G, Ranjit M, Hachisu R et al (2014) Preclinical evaluation of an O(6)-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains. Am J Transl Res 6(2):169–178

    PubMed Central  PubMed  Google Scholar 

  52. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM et al (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462(7274):739–744

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360(8):765–773

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321(5897):1807–1812

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Huse JT, Holland EC (2010) Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma. Nat Rev Cancer 10(5):319–331

    Article  CAS  PubMed  Google Scholar 

  56. Tsankova NM, Canoll P (2014) Advances in genetic and epigenetic analyses of gliomas: a neuropathological perspective. J Neurooncol 119(3):481–490

    Article  CAS  PubMed  Google Scholar 

  57. Kato Y, Natsume A, Kaneko MK (2013) A novel monoclonal antibody GMab-m1 specifically recognizes IDH1-R132G mutation. Biochem Biophys Res Commun 432(4):564–567

    Article  CAS  PubMed  Google Scholar 

  58. Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K et al (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226–231

    Article  CAS  PubMed  Google Scholar 

  59. Abedalthagafi M, Phillips JJ, Kim GE, Mueller S, Haas-Kogen DA, Marshall RE et al (2013) The alternative lengthening of telomere phenotype is significantly associated with loss of ATRX expression in high-grade pediatric and adult astrocytomas: a multi-institutional study of 214 astrocytomas. Mod Pathol 26:1425–1432

    Article  CAS  PubMed  Google Scholar 

  60. Clynes D, Jelinska C, Xella B, Ayyub H, Taylor S, Mitson M et al (2014) ATRX dysfunction induces replication defects in primary mouse cells. PLoS ONE 9:e92915

    Article  PubMed Central  PubMed  Google Scholar 

  61. Liu XY, Gerges N, Korshunov A, Sabha N, Khuong-Quang DA, Fontebasso AM et al (2012) Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations. Acta Neuropathol 124(5):615–625

    Article  CAS  PubMed  Google Scholar 

  62. Reuss DE, Sahm F, Schrimpf D, Wiestler B, Capper D, Koelsche C et al (2015) 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 129(1):133–146

    Article  CAS  PubMed  Google Scholar 

  63. Shay JW, Wright WE (2011) Role of telomeres and telomerase in cancer. Semin Cancer Biol 21:349–353

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Arita H, Narita Y, Fukushima S, Tateishi K, Matsushita Y, Yoshida A et al (2013) Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathol 126(2):267–276

    Article  CAS  PubMed  Google Scholar 

  65. Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA, Jr 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR et al (2013) The somatic genomic landscape of glioblastoma. Cell 155(2):462–477

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Aubert G, Lansdorp PM (2008) Telomeres and aging. Physiol Rev 88:557–579

    Article  CAS  PubMed  Google Scholar 

  68. Reitman ZJ, Pirozzi CJ, Yan H (2013) Promoting a new brain tumor mutation: tERT promoter mutations in CNS tumors. Acta Neuropathol 126(6):789–792

    Article  PubMed Central  PubMed  Google Scholar 

  69. Talbert PB, Henikoff S (2010) Histone variants–ancient wrap artists of the epigenome. Nat Rev Mol Cell Biol 11:264–275

    Article  CAS  PubMed  Google Scholar 

  70. Aihara K, Mukasa A, Gotoh K, Saito K, Nagae G, Tsuji S et al (2014) H3F3A K27 M mutations in thalamic gliomas from young adult patients. Neuro Oncol 16:140–146

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Zhou Q, Wang S, Anderson DJ (2000) Identification of a novel family of oligodendrocyte lineage-specific basic helix-loop-helix transcription factors. Neuron 25:331–343

    Article  CAS  PubMed  Google Scholar 

  72. Lu QR, Park JK, Noll E, Chan JA, Alberta J, Yuk D et al (2001) Oligodendrocyte lineage genes (OLIG) as molecular markers for human glial brain tumors. Proc Natl Acad Sci USA 98:10851–10856

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Williams LT (1989) Signal transduction by the platelet-derived growth factor receptor. Science 243(4898):1564–1570

    Article  CAS  PubMed  Google Scholar 

  74. Nister M, Libermann TA, Betsholtz C, Pettersson M, Claesson-Welsh L, Heldin CH et al (1988) Expression of messenger RNAs for platelet-derived growth factor and transforming growth factor-alpha and their receptors in human malignant glioma cell lines. Cancer Res 48(14):3910–3918

    CAS  PubMed  Google Scholar 

  75. Ozerdem U, Stallcup WB (2000) Early contribution of pericytes to angiogenic sprouting and tube formation. Angiogenesis 6:241–249

    Article  Google Scholar 

  76. Calzolari F, Malatesta P (2010) Recent insights into PDGF-induced gliomagenesis. Brain Pathol 20:527–538

    Article  CAS  PubMed  Google Scholar 

  77. Jiao Y, Killela PJ, Reitman ZJ, Rasheed AB, Heaphy CM, de Wilde RF et al (2012) Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 3(7):709–722

    PubMed Central  PubMed  Google Scholar 

  78. Sahm F, Koelsche C, Meyer J, Pusch S, Lindenberg K, Mueller W et al (2012) CIC and FUBP1 mutations in oligodendrogliomas, oligoastrocytomas and astrocytomas. Acta Neuropathol 123(6):853–860

    Article  CAS  PubMed  Google Scholar 

  79. Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG, Ferraris DV et al (2010) Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res 70(22):8981–8987

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Ohka F, Ito M, Ranjit M, Senga T, Motomura A, Motomura K et al (2014) Quantitative metabolome analysis profiles activation of glutaminolysis in glioma with IDH1 mutation. Tumour Biol 35(6):5911–5920

    Article  CAS  PubMed  Google Scholar 

  81. Komori T, Hirose T, Shibuya M, Suzuki H, Tanaka S, Sasaki A (2013) Controversies over the diagnosis of oligodendroglioma: a report from the satellite workshop at the 4th international symposium of brain tumor pathology, Nagoya Congress Center, May 23, 2012. Brain Tumor Pathol 30(4):253–261

    Article  PubMed  Google Scholar 

  82. Sampetrean O, Saya H (2013) Characteristics of glioma stem cells. Brain Tumor Pathol 30(4):209–214

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

We have no conflict of interest to disclose.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Atsushi Natsume.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ranjit, M., Motomura, K., Ohka, F. et al. Applicable advances in the molecular pathology of glioblastoma. Brain Tumor Pathol 32, 153–162 (2015). https://doi.org/10.1007/s10014-015-0224-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10014-015-0224-6

Keywords

Navigation