Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Advances in the molecular genetics of gliomas — implications for classification and therapy

Nature Reviews Clinical Oncology volume 14, pages 434–452 (2017)Cite this article

Subjects

Key Points

  • The 2016 WHO Classification of Tumours of the Central Nervous System reflects a paradigm shift, replacing traditional histology-based glioma diagnostics with an integrated histological and molecular classification system that enables more-precise tumour categorization

  • The requisite diagnostic biomarkers in the 2016 WHO classification of gliomas are IDH1/2 (IDH) mutations, 1p/19q codeletion, H3F3A or HIST1H3B/C K27M (H3-K27M) mutations and C11orf95–RELA fusions

  • Additional diagnostically relevant biomarkers include loss of nuclear ATRX expression, TERT-promoter mutations, KIAA1549–BRAF fusions, BRAF-V600E mutation, H3F3A-G34 mutation, and several other alterations associated with rare glioma entities

  • MGMT-promoter methylation is predictive of benefit from alkylating chemotherapy in patients with IDH-wild-type glioblastoma; predictive biomarkers for targeted therapies, such as IDH1 and BRAF mutations, are also emerging

  • Novel methods for large-scale DNA-methylation, copy-number and mutational profiling will further advance the assessment of glioma-associated molecular biomarkers

  • Clinical trials require assessment of molecular biomarkers as criteria for study entry and/or patient stratification; predictive DNA sequencing followed by targeted therapy will support the implementation of precision medicine in neuro-oncology

Abstract

Genome-wide molecular-profiling studies have revealed the characteristic genetic alterations and epigenetic profiles associated with different types of gliomas. These molecular characteristics can be used to refine glioma classification, to improve prediction of patient outcomes, and to guide individualized treatment. Thus, the WHO Classification of Tumours of the Central Nervous System was revised in 2016 to incorporate molecular biomarkers — together with classic histological features — in an integrated diagnosis, in order to define distinct glioma entities as precisely as possible. This paradigm shift is markedly changing how glioma is diagnosed, and has important implications for future clinical trials and patient management in daily practice. Herein, we highlight the developments in our understanding of the molecular genetics of gliomas, and review the current landscape of clinically relevant molecular biomarkers for use in classification of the disease subtypes. Novel approaches to the genetic characterization of gliomas based on large-scale DNA-methylation profiling and next-generation sequencing are also discussed. In addition, we illustrate how advances in the molecular genetics of gliomas can promote the development and clinical translation of novel pathogenesis-based therapeutic approaches, thereby paving the way towards precision medicine in neuro-oncology.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Diagnostic approach for integrated histological and molecular classification of diffuse gliomas according to the 2016 WHO Classification of Tumours of the Central Nervous System22.
Figure 2: Histological and molecular features of selected glioma entities.
Figure 3: Molecular subgroups of glioblastoma, as defined by distinct genetic and epigenetic profiles8,21,40.
Figure 4: Current post-surgery treatment strategies for major glioma entities classified according to the 2016 WHO Classification of Tumours of the Central Nervous System22.
Figure 5: Schematic illustration of different clinical trial designs.

Similar content being viewed by others

References

  1. Rouse, C., Gittleman, H., Ostrom, Q. T., Kruchko, C. & Barnholtz-Sloan, J. S. Years of potential life lost for brain and CNS tumours relative to other cancers in adults in the United States, 2010. Neuro Oncol. 18, 70–77 (2016).

    PubMed  Google Scholar 

  2. Ostrom, Q. T. et al. CBTRUS statistical report: primary brain and central nervous system tumours diagnosed in the United States in 2008–2012. Neuro Oncol. 17, (Suppl. 4) iv1–iv62 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gilbert, M. R. et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomised phase III clinical trial. J. Clin. Oncol. 31, 4085–4091 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Chinot, O. L. et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 709–722 (2014).

    CAS  PubMed  Google Scholar 

  5. Gilbert, M. R. et al. A randomised trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 699–708 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Gramatzki, D. et al. Glioblastoma in the Canton of Zurich, Switzerland revisited: 2005 to 2009. Cancer 122, 2206–2215 (2016).

    CAS  PubMed  Google Scholar 

  7. Zong, H., Parada, L. F. & Baker, S. J. Cell of origin for malignant gliomas and its implication in therapeutic development. Cold Spring Harb. Perspect. Biol. 29, 7 (2015).

    Google Scholar 

  8. Sturm, D. et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22, 425–437 (2012).

    CAS  PubMed  Google Scholar 

  9. Brennan, C. W. et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Cancer Genome Atlas Research Network. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N. Engl. J. Med. 372, 2481–2498 (2015).

  11. Suzuki, H. et al. Mutational landscape and clonal architecture in grade II and III gliomas. Nat. Genet. 47, 458–468 (2015).

    CAS  PubMed  Google Scholar 

  12. Ceccarelli, M. et al. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164, 550–563 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012).

    CAS  PubMed  Google Scholar 

  14. Wu, G. et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat. Genet. 44, 251–253 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Jones, D. T. et al. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat. Genet. 45, 927–932 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang, J. et al. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat. Genet. 45, 602–612 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Wu, G. et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat. Genet. 46, 444–450 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Buczkowicz, P. et al. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat. Genet. 46, 451–456 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Parker, M. et al. C11orf95–RELA fusions drive oncogenic NF-κB signalling in ependymoma. Nature 506, 451–455 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Pajtler, K. W. et al. Molecular classification of ependymal tumours across all CNS compartments, histopathological grades, and age groups. Cancer Cell 27, 728–743 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Korshunov, A. et al. Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumours with associated molecular prognostic markers. Acta Neuropathol. 129, 669–678 (2015).

    CAS  PubMed  Google Scholar 

  22. Louis, D. N., Ohgaki, H., Wiestler, O. D. & Cavenee, W. K. (Eds). WHO Classification of Tumours of the Central Nervous System, Revised 4th edn 10–122 (IARC, 2016).

    Google Scholar 

  23. Louis, D. N., Ohgaki, H., Wiestler, O. D. & Cavenee, W. K. (Eds). WHO Classification of Tumours of the Central Nervous System, 4th edn 10–80 (IARC, 2007).

    Google Scholar 

  24. van den Bent, M. J. Interobserver variation of the histopathological diagnosis in clinical trials on glioma: a clinician's perspective. Acta Neuropathol. 120, 297–304 (2010).

    PubMed  PubMed Central  Google Scholar 

  25. Wiestler, B. et al. Integrated DNA methylation and copy-number profiling identify three clinically and biologically relevant groups of anaplastic glioma. Acta Neuropathol. 128, 561–571 (2014).

    CAS  PubMed  Google Scholar 

  26. Weller, M. et al. Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups. Acta Neuropathol. 129, 679–693 (2015).

    CAS  PubMed  Google Scholar 

  27. Sahm, F. et al. Farewell to oligoastrocytoma: in situ molecular genetics favor classification as either oligodendroglioma or astrocytoma. Acta Neuropathol. 128, 551–559 (2014).

    CAS  PubMed  Google Scholar 

  28. Herrlinger, U. et al. Gliomatosis cerebri: no evidence for a separate brain tumour entity. Acta Neuropathol. 131, 309–319 (2016).

    CAS  PubMed  Google Scholar 

  29. Louis, D. N. et al. International Society of Neuropathology—Haarlem consensus guidelines for nervous system tumour classification and grading. Brain Pathol. 24, 429–435 (2014).

    PubMed  PubMed Central  Google Scholar 

  30. Louis, D. N. et al. The 2016 World Health Organization Classification of Tumours of the Central Nervous System: a summary. Acta Neuropathol. 131, 803–820 (2016).

    PubMed  Google Scholar 

  31. Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Balss, J. et al. Analysis of the IDH1 codon 132 mutation in brain tumours. Acta Neuropathol. 116, 597–602 (2008).

    CAS  PubMed  Google Scholar 

  34. Weller, M. et al. Glioma. Nat. Rev. Dis. Primers 1, 15017 (2015).

    PubMed  Google Scholar 

  35. Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Noushmehr, H. et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510–522 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Capper, D. et al. Monoclonal antibody specific for IDH1 R132H mutation. Acta Neuropathol. 118, 599–601 (2009).

    CAS  PubMed  Google Scholar 

  38. van den Bent, M. J. et al. Interlaboratory comparison of IDH mutation detection. J. Neurooncol. 112, 173–178 (2013).

    PubMed  Google Scholar 

  39. Reuss, D. E. et al. Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities. Acta Neuropathol. 130, 407–417 (2015).

    CAS  PubMed  Google Scholar 

  40. Masui, K., Mischel, P. S. & Reifenberger, G. Molecular classification of gliomas. Handb. Clin. Neurol. 134, 97–120 (2016).

    PubMed  Google Scholar 

  41. Sasaki, M. et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488, 656–659 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Watson, L. A., Goldberg, H. & Bérubé, N. G. Emerging roles of ATRX in cancer. Epigenomics 7, 1365–1378 (2015).

    CAS  PubMed  Google Scholar 

  43. Bai, H. et al. Integrated genomic characterization of IDH1-mutant glioma malignant progression. Nat. Genet. 48, 59–66 (2016).

    CAS  PubMed  Google Scholar 

  44. Mazor, T. et al. DNA methylation and somatic mutations converge on the cell cycle and define similar evolutionary histories in brain tumours. Cancer Cell 28, 307–317 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Griffin, C. A. et al. Identification of der(1;19)(q10;p10) in five oligodendrogliomas suggests mechanism of concurrent 1p and 19q loss. J. Neuropathol. Exp. Neurol. 65, 988–994 (2006).

    PubMed  Google Scholar 

  46. Jenkins, R. B. 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. 66, 9852–9856 (2006).

    CAS  PubMed  Google Scholar 

  47. Arita, H. et al. Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathol. 126, 267–276 (2013).

    CAS  PubMed  Google Scholar 

  48. Bettegowda, C. et al. Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science 333, 1453–1455 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Alentorn, A. et al. Allelic loss of 9p21.3 is a prognostic factor in 1p/19q codeleted anaplastic gliomas. Neurology 85, 1325–1331 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Labreche, K. et al. TCF12 is mutated in anaplastic oligodendroglioma. Nat. Commun. 6, 7207 (2015).

    CAS  PubMed  Google Scholar 

  51. Kamoun, A. et al. Integrated multi-omics analysis of oligodendroglial tumours identifies three subgroups of 1p/19q co-deleted gliomas. Nat. Commun. 7, 11263 (2016).

    PubMed  PubMed Central  Google Scholar 

  52. Huse, J. T., Diamond, E. L., Wang, L. & Rosenblum, M. K. Mixed glioma with molecular features of composite oligodendroglioma and astrocytoma: a true “oligoastrocytoma”? Acta Neuropathol. 129, 151–153 (2015).

    PubMed  Google Scholar 

  53. Aldape, K., Zadeh, G., Mansouri, S., Reifenberger, G. & von Deimling, A. Glioblastoma: pathology, molecular mechanisms and markers. Acta Neuropathol. 129, 829–848 (2015).

    CAS  PubMed  Google Scholar 

  54. Kleinschmidt-DeMasters, B. K., Aisner, D. L., Birks, D. K. & Foreman, N. K. Epithelioid GBMs show a high percentage of BRAF V600E mutation. Am. J. Surg. Pathol. 37, 685–698 (2013).

    PubMed  PubMed Central  Google Scholar 

  55. Verhaak, R. G. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterised by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98–110 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Bhat, K. P. et al. Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma. Cancer Cell. 24, 331–346 (2013).

    CAS  PubMed  Google Scholar 

  57. Patel, A. P. et al. Single-cell RNA-seq highlights intratumoural heterogeneity in primary glioblastoma. Science 344, 1396–1401 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Sandmann, T. et al. Patients with proneural glioblastoma may derive overall survival benefit from the addition of bevacizumab to first-line radiotherapy and temozolomide: retrospective analysis of the AVAglio trial. J. Clin. Oncol. 33, 2735–2744 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Hawkins, C. et al. BRAF–KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin. Cancer Res. 17, 4790–4798 (2011).

    CAS  PubMed  Google Scholar 

  60. Weber, R. G. et al. Frequent loss of chromosome 9, homozygous CDKN2A/p14ARF/CDKN2B deletion and low TSC1 mRNA expression in pleomorphic xanthoastrocytomas. Oncogene 26, 1088–1097 (2007).

    CAS  PubMed  Google Scholar 

  61. Schindler, G. et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumours reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 121, 397–405 (2011).

    CAS  PubMed  Google Scholar 

  62. Koelsche, C. et al. BRAF-mutated pleomorphic xanthoastrocytoma is associated with temporal location, reticulin fiber deposition and CD34 expression. Brain Pathol. 24, 221–229 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Alexandrescu, S. et al. Epithelioid glioblastomas and anaplastic epithelioid pleomorphic xanthoastrocytomas — same entity or first cousins? Brain Pathol. 26, 215–223 (2016).

    CAS  PubMed  Google Scholar 

  64. Chan, J. A. et al. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J. Neuropathol. Exp. Neurol. 63, 1236–1242 (2004).

    CAS  PubMed  Google Scholar 

  65. Nauen, D. et al. Molecular analysis of pediatric oligodendrogliomas highlights genetic differences with adult counterparts and other pediatric gliomas. Brain Pathol. 26, 206–214 (2016).

    CAS  PubMed  Google Scholar 

  66. Qaddoumi, I. et al. Genetic alterations in uncommon low-grade neuroepithelial tumours: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol. 131, 833–845 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Bandopadhayay, P. et al. MYB–QKI rearrangements in angiocentric glioma drive tumourigenicity through a tripartite mechanism. Nat. Genet. 48, 273–282 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Bender, S. et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 24, 660–672 (2013).

    CAS  PubMed  Google Scholar 

  69. Lewis, P. W. et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340, 857–861 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Hashizume, R. et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat. Med. 20, 1394–1396 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Grasso, C. S. et al. Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat. Med. 21, 555–559 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Castel, D. et al. Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol. 130, 815–827 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Mack, S. C. et al. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506, 445–450 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Weller, M. et al. EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. Lancet Oncol. 15, e395–403 (2014).

    PubMed  Google Scholar 

  75. Wick, W. et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 13, 707–715 (2012).

    CAS  PubMed  Google Scholar 

  76. Malmström, A. et al. 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 (2012).

    PubMed  Google Scholar 

  77. van den Bent, M. J. et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumour group study 26951. J. Clin. Oncol. 31, 344–350 (2013).

    CAS  PubMed  Google Scholar 

  78. Cairncross, G. et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J. Clin. Oncol. 31, 337–343 (2013).

    CAS  PubMed  Google Scholar 

  79. Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005).

    CAS  PubMed  Google Scholar 

  80. Wick, W. et al. MGMT testing — the challenges for biomarker-based glioma treatment. Nat. Rev. Neurol. 10, 372–385 (2014).

    CAS  PubMed  Google Scholar 

  81. Hegi, M. E. et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352, 997–1003 (2005).

    CAS  PubMed  Google Scholar 

  82. Wick, W. et al. Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation. Neurology 81, 1515–1522 (2013).

    CAS  PubMed  Google Scholar 

  83. Grasbon-Frodl, E. et al. Intratumoural homogeneity of MGMT promoter hypermethylation as demonstrated in serial stereotactic specimens from anaplastic astrocytomas and glioblastomas. Int. J. Cancer 121, 2458–2464 (2007).

    CAS  PubMed  Google Scholar 

  84. Felsberg, J. 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 129, 659–670 (2011).

    CAS  PubMed  Google Scholar 

  85. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  86. Vogazianou, A. P. et al. Distinct patterns of 1p and 19q alterations identify subtypes of human gliomas that have different prognoses. Neuro Oncol. 12, 664–678 (2010).

    PubMed  PubMed Central  Google Scholar 

  87. Preusser, M., Bienkowski, M. & Birner, P. BRAF inhibitors in BRAF-V600 mutated primary neuroepithelial brain tumours. Expert Opin. Investig. Drugs 25, 7–14 (2016).

    CAS  PubMed  Google Scholar 

  88. Rohle, D. et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340, 626–630 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Schumacher, T. et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 512, 324–327 (2014).

    CAS  PubMed  Google Scholar 

  90. Sampson, J. H. et al. 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. 28, 4722–4729 (2010).

    PubMed  PubMed Central  Google Scholar 

  91. Schuster, J. et al. A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. Neuro Oncol. 17, 854–861 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Phillips, A. C. et al. ABT-414, an antibody–drug conjugate targeting a tumor-selective EGFR epitope. Mol. Cancer Ther. 15, 661–669 (2016).

    CAS  PubMed  Google Scholar 

  93. Zahonero, C. et al. Preclinical test of dacomitinib, an irreversible EGFR inhibitor, confirms its effectiveness for glioblastoma. Mol. Cancer Ther. 14, 1548–1558 (2015).

    CAS  PubMed  Google Scholar 

  94. Reardon, D. A. et al. ReACT: overall survival from a randomised phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma. J. Clin. Oncol. 33 (Suppl.), abstr 2009 (2015).

    Google Scholar 

  95. Singh, D. et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 337, 1231–1235 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Di Stefano, A. L. et al. Detection, characterization, and inhibition of FGFR–TACC fusions in IDH wild-type glioma. Clin. Cancer Res. 21, 3307–3317 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Worst, B. C. et al. Next-generation personalised medicine for high-risk paediatric cancer patients — the INFORM pilot study. Eur. J. Cancer 65, 91–101 (2016).

    PubMed  Google Scholar 

  98. Hertenstein, A. et al. Umbrella protocol for phase I/IIa trials of molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed glioblastoma without MGMT promoter methylation - Neuro Master Match (N2M2). J. Clin. Oncol. 34, TPS2084 (2016).

    Google Scholar 

  99. US National Institutes of Health. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02465060 (2016).

  100. Dubbink, H. J. et al. Molecular classification of anaplastic oligodendroglioma using next-generation sequencing: a report of the prospective randomised EORTC Brain Tumour Group 26951 phase III trial. Neuro Oncol. 18, 388–400 (2016).

    CAS  PubMed  Google Scholar 

  101. Nikiforova, M. N. et al. Targeted next-generation sequencing panel (GlioSeq) provides comprehensive genetic profiling of central nervous system tumours. Neuro Oncol. 18, 379–387 (2016).

    CAS  PubMed  Google Scholar 

  102. Sahm, F. et al. Next-generation sequencing in routine brain tumour diagnostics enables an integrated diagnosis and identifies actionable targets. Acta Neuropathol. 131, 903–910 (2016).

    CAS  PubMed  Google Scholar 

  103. Zacher, A. et al. Molecular diagnostics of gliomas using next generation sequencing of a glioma-tailored gene panel. Brain Pathol. http://dx.doi.org/10.1111/bpa.12367 (2016).

  104. Bady, P., Delorenzi, M. & Hegi, M. E. Sensitivity analysis of the MGMT-STP27 model and impact of genetic and epigenetic context to predict the MGMT methylation status in gliomas and other tumours. J. Mol. Diagn. 18, 350–361 (2016).

    CAS  PubMed  Google Scholar 

  105. Bettegowda, C. et al. Detection of circulating tumour DNA in early- and late-stage human malignancies. Sci. Transl. Med. 6, 224ra24 (2014).

    PubMed  PubMed Central  Google Scholar 

  106. De Mattos-Arruda, L. et al. Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma. Nat. Commun. 6, 8839 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Wang, Y. et al. Detection of tumour-derived DNA in cerebrospinal fluid of patients with primary tumours of the brain and spinal cord. Proc. Natl Acad. Sci. USA 112, 9704–9709 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Drusco, A. et al. A differentially expressed set of microRNAs in cerebro-spinal fluid (CSF) can diagnose CNS malignancies. Oncotarget 6, 20829–20839 (2015).

    PubMed  PubMed Central  Google Scholar 

  109. Shi, R. et al. Exosomal levels of miRNA-21 from cerebrospinal fluids associated with poor prognosis and tumor recurrence of glioma patients. Oncotarget 6, 26971–26981 (2015).

    PubMed  PubMed Central  Google Scholar 

  110. Rudà, R., Gilbert, M. & Soffietti, R. Ependymomas of the adult: molecular biology and treatment. Curr. Opin. Neurol. 21, 754–761 (2008).

    PubMed  Google Scholar 

  111. Stummer, W. et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 7, 392–401 (2006).

    CAS  PubMed  Google Scholar 

  112. Senft, C. et al. Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial. Lancet Oncol. 12, 997–1003 (2011).

    PubMed  Google Scholar 

  113. Vuorinen, V., Hinkka, S., Farkkila, M. & Jaaskelainen, J. Debulking or biopsy of malignant glioma in elderly people — a randomised study. Acta Neurochir. (Wien) 145, 5–10 (2003).

    CAS  Google Scholar 

  114. van den Bent, M. J. et al. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 366, 985–990 (2005).

    CAS  PubMed  Google Scholar 

  115. Daniels, T. B. et al. Validation of EORTC prognostic factors for adults with low-grade glioma: a report using intergroup 86-72-51. Int. J. Radiat. Oncol. Biol. Phys. 81, 218–224 (2011).

    PubMed  PubMed Central  Google Scholar 

  116. Pignatti, F. et al. Prognostic factors for survival in adult patients with cerebral low-grade glioma. J. Clin. Oncol. 20, 2076–2084 (2002).

    PubMed  Google Scholar 

  117. Buckner, J. C. et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N. Engl. J. Med. 374, 1344–1355 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Baumert, B. G. et al. Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033–26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 17, 1521–1532 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. US National Institutes of Health. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00887146 (2016).

  120. Cairncross, J. G. et al. Benefit from procarbazine, lomustine, and vincristine in oligodendroglial tumors is associated with mutation of IDH. J. Clin. Oncol. 32, 783–790 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. van den Bent, M. J. et al. 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. 19, 5513–5522 (2013).

    CAS  PubMed  Google Scholar 

  122. van den Bent, M. J. et al. Results of the interim analysis of the EORTC randomized phase III CATNON trial on concurrent and adjuvant temozolomide in anaplastic glioma without 1p/19q co-deletion, an intergroup trial [abstract]. J. Clin. Oncol. 34, LBA2000 (2016).

    Google Scholar 

  123. Laperriere, N. et al. Optimal management of elderly patients with glioblastoma. Cancer Treat. Rev. 39, 350–357 (2013).

    PubMed  Google Scholar 

  124. Roa, W. et al. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomised clinical trial. J. Clin. Oncol. 22, 1583–1588 (2004).

    CAS  PubMed  Google Scholar 

  125. Perry, J. R. et al. A phase III randomised controlled trial of short-course radiotherapy with or without concomitant and adjuvant temozolomide in elderly patients with glioblastoma (CCTG CE.6, EORTC 26062–22061, TROG 08.02, NCT00482677). J. Clin. Oncol. 34, LBA2 (2016).

    Google Scholar 

  126. Suchorska, B. et al. Complete resection of contrast-enhancing tumour volume is associated with improved survival in recurrent glioblastoma-results from the DIRECTOR trial. Neuro Oncol. 18, 549–556 (2016).

    PubMed  PubMed Central  Google Scholar 

  127. Mayer, R. & Sminia, P. Reirradiation tolerance of the human brain. Int. J. Radiat. Oncol. Biol. Phys. 70, 1350–1360 (2008).

    CAS  PubMed  Google Scholar 

  128. Batchelor, T. T. et al. Phase III randomised trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J. Clin. Oncol. 31, 3212–3218 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Wick, W. et al. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J. Clin. Oncol. 28, 1168–1174 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Perry, J. R. et al. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J. Clin. Oncol. 28, 2051–2057 (2010).

    CAS  PubMed  Google Scholar 

  131. Weller, M. et al. MGMT promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: the DIRECTOR trial. Clin. Cancer Res. 21, 2057–2064 (2015).

    CAS  PubMed  Google Scholar 

  132. Friedman, H. S. et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J. Clin. Oncol. 27, 4733–4740 (2009).

    CAS  PubMed  Google Scholar 

  133. Kreisl, T. N. et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumour progression in recurrent glioblastoma. J. Clin. Oncol. 27, 740–745 (2009).

    CAS  PubMed  Google Scholar 

  134. Wick, W. et al. Phase III trial exploring the combination of bevacizumab and lomustine in patients with first recurrence of a glioblastoma: the EORTC 26101 trial [abstract LB-05]. Neuro Oncol. 17 (Suppl. 5), v1 (2015).

    Google Scholar 

  135. Stupp, R. et al. Maintenance therapy with tumour-treating fields plus temozolomide versus temozolomide alone for glioblastoma: a randomised clinical trial. JAMA 314, 2535–2543 (2015).

    CAS  PubMed  Google Scholar 

  136. Wick, W. TTFields: where does all the skepticism come from? Neuro Oncol. 18, 303–305 (2016).

    PubMed  PubMed Central  Google Scholar 

  137. Johnson, B. E. et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 343, 189–193 (2014).

    CAS  PubMed  Google Scholar 

  138. Singh, S. K. et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004).

    CAS  PubMed  Google Scholar 

  139. Bao, S. et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760 (2006).

    CAS  PubMed  Google Scholar 

  140. Chen, J. et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488, 522–526 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Lathia, J. D., Mack, S. C., Mulkearns-Hubert, E. E., Valentim, C. L. & Rich, J. N. Cancer stem cells in glioblastoma. Genes Dev. 29, 1203–1217 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Gallo, M. et al. MLL5 orchestrates a cancer self-renewal state by repressing the histone variant H3.3 and globally reorganizing chromatin. Cancer Cell 28, 715–729 (2015).

    CAS  PubMed  Google Scholar 

  143. Pietras, A. et al. Osteopontin–CD44 signaling in the glioma perivascular niche enhances cancer stem cell phenotypes and promotes aggressive tumour growth. Cell Stem Cell 14, 357–369 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Zhu, Z. et al. Targeting self-renewal in high-grade brain tumours leads to loss of brain tumour stem cells and prolonged survival. Cell Stem Cell 15, 185–198 (2014).

    CAS  PubMed  Google Scholar 

  145. Xu, R. et al. Molecular and clinical effects of Notch inhibition in glioma patients: a phase 0/I trial. Clin. Cancer Res. 22, 4786–4796 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Sloan, A. E. et al. Targeting glioma-initiating cells in GBM: ABTC-0904, a randomized phase 0/II study targeting the Sonic Hedgehog-signaling pathway. J. Clin. Oncol. 32, (2014).

  147. van Thuijl, H. F. et al. Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment. Acta Neuropathol. 129, 597–607 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Squatrito, M. et al. Loss of ATM/Chk2/p53 pathway components accelerates tumour development and contributes to radiation resistance in gliomas. Cancer Cell 18, 619–629 (2010).

    CAS  PubMed  Google Scholar 

  149. Halliday, J. et al. In vivo radiation response of proneural glioma characterised by protective p53 transcriptional program and proneural–mesenchymal shift. Proc. Natl Acad. Sci. USA 111, 5248–5253 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Osswald, M. et al. Brain tumour cells interconnect to a functional and resistant network. Nature 528, 93–98 (2015).

    CAS  PubMed  Google Scholar 

  151. Krueger, D. A. et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N. Engl. J. Med. 363, 1801–1811 (2010).

    CAS  PubMed  Google Scholar 

  152. Franz, D. N. et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 381, 125–132 (2013).

    CAS  PubMed  Google Scholar 

  153. Chamberlain, M. C. Salvage therapy with BRAF inhibitors for recurrent pleomorphic xanthoastrocytoma: a retrospective case series. J. Neurooncol. 114, 237–240 (2013).

    CAS  PubMed  Google Scholar 

  154. Lee, E. Q., Ruland, S., LeBoeuf, N. R., Wen, P. Y. & Santagata, S. Successful treatment of a progressive BRAF V600E-mutated anaplastic pleomorphic xanthoastrocytoma with vemurafenib monotherapy. J. Clin. Oncol. 34, e87–89 (2016).

    CAS  PubMed  Google Scholar 

  155. US National Institutes of Health. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01748149 (2016).

  156. Kieran, M. W. et al. The first study of dabrafenib in pediatric patients with BRAF V600–mutant relapsed or refractory low-grade gliomas. Ann. Oncol. 27 (Suppl. 6), abstr LBA19_PR (2016).

    Google Scholar 

  157. Sievert, A. J. et al. Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas. Proc. Natl Acad. Sci. USA 110, 5957–5962 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Karajannis, M. A. et al. Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. Neuro Oncol. 16, 1408–1416 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. US National Institutes of Health. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01089101 (2016).

  160. Robinson, G. W., Orr, B. A. & Gajjar, A. Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy. BMC Cancer 14, 258 (2014).

    PubMed  PubMed Central  Google Scholar 

  161. Galanis, E. et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J. Clin. Oncol. 23, 5294–5304 (2005).

    CAS  PubMed  Google Scholar 

  162. Wick, W. et al. Phase II study of radiotherapy and temsirolimus versus radiochemotherapy with temozolomide in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation (EORTC 26082). Clin. Cancer Res. 22, 4797–4806 (2016).

    CAS  PubMed  Google Scholar 

  163. Van den Bent, M. J. et al. Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J. Clin. Oncol. 27, 1268–1274 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Stupp, R. et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071–22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 15, 1100–1108 (2014).

    CAS  PubMed  Google Scholar 

  165. Hegi, M. E., Rajakannu, P. & Weller, M. Epidermal growth factor receptor: a re-emerging target in glioblastoma. Curr. Opin. Neurol. 25, 774–779 (2012).

    CAS  PubMed  Google Scholar 

  166. Van den Bent, M. J. et al. Efficacy of a novel antibody-drug conjugate (ADC), ABT-414, as monotherapy in epidermal growth factor receptor (EGFR) amplified, recurrent glioblastoma (GBM). J. Clin. Oncol. 34, 2542 (2016).

    Google Scholar 

  167. US National Institutes of Health. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02073994 (2016).

  168. US National Institutes of Health. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02481154 (2016).

  169. US National Institutes of Health. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02381886 (2016).

  170. Liu, F. et al. EGFR mutation promotes glioblastoma through epigenome and transcription factor network remodeling. Mol. Cell. 60, 307–318 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Vivanco, I. et al. Differential sensitivity of glioma-versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors. Cancer Discov. 2, 458–471 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Snuderl, M. et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 20, 810–817 (2011).

    CAS  PubMed  Google Scholar 

  173. Prados, M. D. et al. Toward precision medicine in glioblastoma: the promise and the challenges. Neuro Oncol. 17, 1051–1063 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Nduom, E. K., Weller, M. & Heimberger, A. B. Immunosuppressive mechanisms in glioblastoma. Neuro Oncol. 17, vii9–vii14 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Engelhardt, B. et al. Vascular, glial, and lymphatic immune gateways of the central nervous system. Acta Neuropathol. 132, 317–338 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Reardon, D. A. et al. Immunotherapy advances for glioblastoma. Neuro Oncol. 16, 1441–1458 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Weller, M. et al. ACT IV: An international, double-blind, phase 3 trial of rindopepimut in newly diagnosed, EGFRvIII-expressing glioblastoma. Neuro Oncol. 18, (Suppl. 6): vi17–vi18 (2016).

    Google Scholar 

  178. Mitchell, D. A. et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature 519, 366–369 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Wen, P. et al. A randomised double blind placebo-controlled phase 2 trial of dendritic cell (DC) vaccine ICT-107 following standard treatment in newly diagnosed patients with GBM. Neuro Oncol. 16, v8–v22 (2014).

    Google Scholar 

  180. US National Institutes of Health. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02546102 (2016).

  181. US National Institutes of Health. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00045968 (2016).

  182. Preusser, M., Lim, M., Hafler, D. A., Reardon, D. A. & Sampson, J. H. Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nat. Rev. Neurol. 11, 504–514 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Ribas, A. et al. Phase III randomised clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J. Clin. Oncol. 31, 616–622 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Rizvi, N. A. et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 16, 257–265 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Reardon, D. A. et al. Glioblastoma eradication following immune checkpoint blockade in an orthotopic, immunocompetent model. Cancer Immunol. Res. 4, 124–135 (2016).

    CAS  PubMed  Google Scholar 

  188. Bouffet, E. et al. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J. Clin. Oncol. 34, 2206–2211 (2016).

    CAS  PubMed  Google Scholar 

  189. US National Institutes of Health. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02017717 (2016).

  190. US National Institutes of Health. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02667587 (2016).

  191. US National Institutes of Health. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02617589 (2016).

  192. Jena, B., Dotti, G. & Cooper, L. J. Redirecting T-cell specificity by introducing a tumour-specific chimeric antigen receptor. Blood 116, 1035–1044 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Davila, M. L. et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6, 224ra25 (2014).

    PubMed  PubMed Central  Google Scholar 

  194. Morgan, R. A. et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J. Immunother. 36, 133–151 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Sampson, J. H. et al. EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss. Clin. Cancer Res. 20, 972–984 (2014).

    CAS  PubMed  Google Scholar 

  196. Shiina, S. et al. CAR T cells targeting podoplanin reduce orthotopic glioblastomas in mouse brains. Cancer Immunol. Res. 4, 259–268 (2016).

    CAS  PubMed  Google Scholar 

  197. US National Institutes of Health. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01454596 (2016).

  198. US National Institutes of Health. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01109095 (2016).

  199. Ahmed, N. et al. Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J. Clin. Oncol. 33, 1688–1696 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Billingham, L., Malottki, K. & Steven, N. Research methods to change clinical practice for patients with rare cancers. Lancet Oncol. 17, e70–80 (2016).

    PubMed  Google Scholar 

  201. Galanis, E. et al. Phase 2 trial design in neuro-oncology revisited: a report from the RANO group. Lancet Oncol. 13, e196–204 (2012).

    PubMed  Google Scholar 

  202. US National Institutes of Health. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02343406 (2016).

  203. US National Institutes of Health. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02573324 (2016).

  204. US National Institutes of Health. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01112527 (2016).

  205. US National Institutes of Health. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01975701 (2016).

  206. Simon, R. & Roychowdhury, S. Implementing personalised cancer genomics in clinical trials. Nat. Rev. Drug Discov. 12, 358–369 (2013).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge funding of their research by the Brain Tumour Funders Collaborative for the EORTC 1419 study (G.R. and M.W.), German Cancer Aid (grant 111537 to G.R.), the German Ministry of Research and Education (grant 031A425B to G.R., and grant 01ZX1401B to C.B.K.-T.), the Max-Eder programme of German Cancer Aid (grant 110663 to C.B.K.-T.), the Highly Specialized Medicine programme of the Canton of Zurich, Switzerland (M.W.), and the Swiss National Science Foundation (grant 31OO3O-1462L3 to M.W.).

Author information

Author notes

  1. Hans-Georg Wirsching

    Present address: Present address: Human Biology Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, C3-111, PO Box 19024, Seattle, Washington 98109–1024, USA.,

Authors and Affiliations

  1. Department of Neuropathology, Heinrich Heine University Düsseldorf, Moorenstrasse. 5, D-40225, Düsseldorf, Germany

    Guido Reifenberger & Christiane B. Knobbe-Thomsen

  2. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Heidelberg, partner site Essen/Düsseldorf, Moorenstrasse 5, D-40225, Düsseldorf, Germany

    Guido Reifenberger

  3. Department of Neurology and Brain Tumour Centre, Cancer Centre Zürich, University Hospital and University of Zürich, Frauenklinikstrasse 26, CH-8091, Zürich, Switzerland

    Hans-Georg Wirsching & Michael Weller

Authors
  1. Guido Reifenberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hans-Georg Wirsching
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christiane B. Knobbe-Thomsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Weller
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The concept of the article was developed by G.R. and M.W. All authors researched data for the article, made substantial contributions to discussions of content, wrote parts of the manuscript, designed figures or tables, and reviewed and edited the final manuscript before submission for publication.

Corresponding author

Correspondence to Guido Reifenberger.

Ethics declarations

Competing interests

G.R. has received research grants from Merck Serono and Roche, as well as honoraria for advisory boards or lectures from Amgen and Celldex. M.W. has received research funding from Merck Serono, MSD and Novocure, as well as honoraria from Merck Serono and MSD, and has consultancy relationships with BMS, Celldex, Genentech/Roche, Merck Serono, MSD, and Novocure. H.-G.W. and C.B.K.-T. declare no competing interests.

Related links

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Reifenberger, G., Wirsching, HG., Knobbe-Thomsen, C. et al. Advances in the molecular genetics of gliomas — implications for classification and therapy. Nat Rev Clin Oncol 14, 434–452 (2017). https://doi.org/10.1038/nrclinonc.2016.204

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2016.204

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer