Download PDF
J Neurol Surg A Cent Eur Neurosurg 2020; 81(01): 064-070
DOI: 10.1055/s-0039-1688911
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Glioblastoma Multiforme and Genetic Mutations: The Issue Is Not Over Yet. An Overview of the Current Literature

Nicola Montemurro 
1   Unit of Neurosurgery, “Di Venere” City Hospital, ASL Bari, Bari, Italy
2   Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Aldo Moro, Bari, Italy
› Author Affiliations
Further Information

Publication History

24 June 2018

06 February 2019

Publication Date:
24 September 2019 (online)

   Permissions and Reprints

Abstract

Background and Objective Glioblastoma multiforme (GBM) is still a deadly disease with a poor prognosis and high mortality, despite the discovery of new biomarkers and new innovative targeted therapies. The role of genetic mutations in GBM is still not at all clear; however, molecular markers are an integral part of tumor assessment in modern neuro-oncology.

Material and Methods We performed a Medline search for the key words “glioblastoma,” “glioblastoma multiforme,” and “genetic” or “genetics” from 1990 to the present, finding an exponential increase in the number of published articles, especially in the past 7 years.

Results The understanding of molecular subtypes of gliomas recently led to a revision of the World Health Organization classification criteria for these tumors, introducing the concept of primary and secondary GBMs based on genetic alterations and gene or protein expression profiles. Some of these genetic alterations are currently believed to have clinical significance and are more related to secondary GBMs: TP53 mutations, detectable in the early stages of secondary GBM (found in 65%), isocitrate dehydrogenase 1/2 mutations (50% of secondary GBMs), and also O6-methylguanine-DNA methyltransferase promoter methylation (75% of secondary GBMs).

Conclusion From the introduction of the first standard of care (SOC) established in 2005 in patients with a new diagnosis of GBM, a great number of trials have been conducted to improve the actual SOC, but the real turning point has never been achieved or is yet to come. Surgical gross total resection, with at least one more reoperation, radiation therapy plus concomitant and adjuvant temozolomide chemotherapy currently remains the current SOC for patients with GBM.

Keywords

glioblastoma multiforme - prognostic biomarker - genetics - isocitrate dehydrogenase 1/2 - O6-methylguanine-DNA methyltransferase (MGMT)
 

  • References

  • 1 Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review. JAMA 2013; 310 (17) 1842-1850
    CrossrefPubMedGoogle Scholar
  • 2 Wann A, Tully PA, Barnes EH. , et al. Outcomes after second surgery for recurrent glioblastoma: a retrospective case-control study. J Neurooncol 2018; 137 (02) 409-415
    CrossrefPubMedGoogle Scholar
  • 3 Montemurro N, Perrini P, Blanco MO, Vannozzi R. Second surgery for recurrent glioblastoma: a concise overview of the current literature. Clin Neurol Neurosurg 2016; 142: 60-64
    CrossrefPubMedGoogle Scholar
  • 4 deSouza RM, Shaweis H, Han C. , et al. Has the survival of patients with glioblastoma changed over the years?. Br J Cancer 2016; 114 (02) 146-150
    CrossrefPubMedGoogle Scholar
  • 5 Ohba S, Hirose Y. Current and future drug treatments for glioblastomas. Curr Med Chem 2016; 23 (38) 4309-4316
    CrossrefPubMedGoogle Scholar
  • 6 Soomro SH, Ting LR, Qing YY, Ren M. Molecular biology of glioblastoma: classification and mutational locations. J Pak Med Assoc 2017; 67 (09) 1410-1414
    PubMedGoogle Scholar
  • 7 Siegal T. Clinical relevance of prognostic and predictive molecular markers in gliomas. Adv Tech Stand Neurosurg 2016; (43) 91-108
    PubMedGoogle Scholar
  • 8 Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008; 455 (7216(: 1061-1068
    PubMedGoogle Scholar
  • 9 Louis DN, Perry A, Reifenberger G. , et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 2016; 131 (06) 803-820
    CrossrefPubMedGoogle Scholar
  • 10 Malzkorn B, Reifenberger G. Practical implications of integrated glioma classification according to the World Health Organization classification of tumors of the central nervous system 2016. Curr Opin Oncol 2016; 28 (06) 494-501
    CrossrefPubMedGoogle Scholar
  • 11 Sturm D, Orr BA, Toprak UH. , et al. New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 2016; 164 (05) 1060-1072
    CrossrefPubMedGoogle Scholar
  • 12 Li R, Li H, Yan W. , et al. Genetic and clinical characteristics of primary and secondary glioblastoma is associated with differential molecular subtype distribution. Oncotarget 2015; 6 (09) 7318-7324
    CrossrefPubMedGoogle Scholar
  • 13 Crisman TJ, Zelaya I, Laks DR. , et al. Identification of an efficient gene expression panel for glioblastoma classification. PLoS One 2016; 11 (11) e0164649
    CrossrefPubMedGoogle Scholar
  • 14 Karsy M, Guan J, Cohen AL, Jensen RL, Colman H. New molecular considerations for glioma: IDH, ATRX, BRAF, TERT, H3 K27M. Curr Neurol Neurosci Rep 2017; 17 (02) 19
    CrossrefPubMedGoogle Scholar
  • 15 Karsy M, Neil JA, Guan J, Mahan MA, Colman H, Jensen RL. A practical review of prognostic correlations of molecular biomarkers in glioblastoma. Neurosurg Focus 2015; 38 (03) E4
    PubMedGoogle Scholar
  • 16 Liu A, Hou C, Chen H, Zong X, Zong P. Genetics and epigenetics of glioblastoma: applications and overall incidence of IDH1 mutation. Front Oncol 2016; 6: 16
    PubMedGoogle Scholar
  • 17 Lombardi MY, Assem M. Glioblastoma genomics: a very complicated story. In: De Vleeschouwer S. , ed. Glioblastoma. Brisbane, Australia: Codon Publications; 2017: 3-25
    CrossrefGoogle Scholar
  • 18 Rao SK, Edwards J, Joshi AD, Siu IM, Riggins GJ. A survey of glioblastoma genomic amplifications and deletions. J Neurooncol 2010; 96 (02) 169-179
    CrossrefPubMedGoogle Scholar
  • 19 Roth P, Weller M. Challenges to targeting epidermal growth factor receptor in glioblastoma: escape mechanisms and combinatorial treatment strategies. Neuro Oncol 2014; 16 (Suppl. 08) viii14-9
    PubMedGoogle Scholar
  • 20 Wee CW, Kim E, Kim N. , et al. Novel recursive partitioning analysis classification for newly diagnosed glioblastoma: A multi-institutional study highlighting the MGMT promoter methylation and IDH1 gene mutation status. Radiother Oncol 2017; 123 (01) 106-111
    CrossrefPubMedGoogle Scholar
  • 21 Brennan CW, Verhaak RG, McKenna A. , et al; TCGA Research Network. The somatic genomic landscape of glioblastoma. Cell 2013; 155 (02) 462-477
    CrossrefPubMedGoogle Scholar
  • 22 Brat DJ, Verhaak RG, Aldape KD. , et al; Cancer Genome Atlas Research Network. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 2015; 372 (26) 2481-2498
    CrossrefPubMedGoogle Scholar
  • 23 Ceccarelli M, Barthel FP, Malta TM. , et al; TCGA Research Network. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 2016; 164 (03) 550-563
    CrossrefPubMedGoogle Scholar
  • 24 Colman H. Toward more informative biomarker-based clinical trials in glioblastoma. Neuro Oncol 2017; 19 (07) 880-881
    CrossrefPubMedGoogle Scholar
  • 25 Eckel-Passow JE, Lachance DH, Molinaro AM. , et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 2015; 372 (26) 2499-2508
    CrossrefPubMedGoogle Scholar
  • 26 Jiao Y, Killela PJ, Reitman ZJ. , et al. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 2012; 3 (07) 709-722
    CrossrefPubMedGoogle Scholar
  • 27 Nakamura M, Watanabe T, Yonekawa Y, Kleihues P, Ohgaki H. Promoter methylation of the DNA repair gene MGMT in astrocytomas is frequently associated with G:C --> A:T mutations of the TP53 tumor suppressor gene. Carcinogenesis 2001; 22 (10) 1715-1719
    CrossrefPubMedGoogle Scholar
  • 28 Parsons DW, Jones S, Zhang X. , et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008; 321 (5897): 1807-1812
    CrossrefPubMedGoogle Scholar
  • 29 Costello JF, Plass C, Arap W. , et al. Cyclin-dependent kinase 6 (CDK6) amplification in human gliomas identified using two-dimensional separation of genomic DNA. Cancer Res 1997; 57 (07) 1250-1254
    PubMedGoogle Scholar
  • 30 Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res 2013; 19 (04) 764-772
    CrossrefPubMedGoogle Scholar
  • 31 Richardson TE, Snuderl M, Serrano J. , et al. Rapid progression to glioblastoma in a subset of IDH-mutated astrocytomas: a genome-wide analysis. J Neurooncol 2017; 133 (01) 183-192
    CrossrefPubMedGoogle Scholar
  • 32 Szopa W, Burley TA, Kramer-Marek G, Kaspera W. Diagnostic and therapeutic biomarkers in glioblastoma: current status and future perspectives. BioMed Res Int 2017; 2017: 8013575
    PubMedGoogle Scholar
  • 33 Suzuki H, Aoki K, Chiba K. , et al. Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet 2015; 47 (05) 458-468
    CrossrefPubMedGoogle Scholar
  • 34 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) 6002-6007
    CrossrefPubMedGoogle Scholar
  • 35 Aldape K, Zadeh G, Mansouri S, Reifenberger G, von Deimling A. Glioblastoma: pathology, molecular mechanisms and markers. Acta Neuropathol 2015; 129 (06) 829-848
    CrossrefPubMedGoogle Scholar
  • 36 Jordan JT, Gerstner ER, Batchelor TT, Cahill DP, Plotkin SR. Glioblastoma care in the elderly. Cancer 2016; 122 (02) 189-197
    CrossrefPubMedGoogle Scholar
  • 37 Roth P, Gramatzki D, Weller M. Management of elderly patients with glioblastoma. Curr Neurol Neurosci Rep 2017; 17 (04) 35
    CrossrefPubMedGoogle Scholar
  • 38 Zawlik I, Vaccarella S, Kita D, Mittelbronn M, Franceschi S, Ohgaki H. Promoter methylation and polymorphisms of the MGMT gene in glioblastomas: a population-based study. Neuroepidemiology 2009; 32 (01) 21-29
    CrossrefPubMedGoogle Scholar
  • 39 Sanson M, Marie Y, Paris S. , et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 2009; 27 (25) 4150-4154
    CrossrefPubMedGoogle Scholar
  • 40 Wick W, Hartmann C, Engel C. , 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) 5874-5880
    CrossrefPubMedGoogle Scholar
  • 41 Yan H, Parsons DW, Jin G. , et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360 (08) 765-773
    CrossrefPubMedGoogle Scholar
  • 42 Weller M, Weber RG, Willscher E. , 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 2015; 129 (05) 679-693
    CrossrefPubMedGoogle Scholar
  • 43 Pekmezci M, Rice T, Molinaro AM. , et al. Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT. Acta Neuropathol 2017; 133 (06) 1001-1016
    CrossrefPubMedGoogle Scholar
  • 44 Dali R, Verginelli F, Pramatarova A, Sladek R, Stifani S. Characterization of a FOXG1:TLE1 transcriptional network in glioblastoma-initiating cells. Mol Oncol 2018; 12 (06) 775-787
    CrossrefPubMedGoogle Scholar
  • 45 Han F, Hu R, Yang H. , et al. PTEN gene mutations correlate to poor prognosis in glioma patients: a meta-analysis. OncoTargets Ther 2016; 9 (09) 3485-3492
    PubMedGoogle Scholar
  • 46 Mosrati MA, Malmström A, Lysiak M. , et al. TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma. Oncotarget 2015; 6 (18) 16663-16673
    CrossrefPubMedGoogle Scholar
  • 47 Labussière M, Di Stefano AL, Gleize V. , et al. TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations. Br J Cancer 2014; 111 (10) 2024-2032
    CrossrefPubMedGoogle Scholar
  • 48 Fan X, Wang Y, Liu Y. , et al. Brain regions associated with telomerase reverse transcriptase promoter mutations in primary glioblastomas. J Neurooncol 2016; 128 (03) 455-462
    CrossrefPubMedGoogle Scholar
  • 49 Fan X, Wang Y, Wang K. , et al. Anatomical specificity of vascular endothelial growth factor expression in glioblastomas: a voxel-based mapping analysis. Neuroradiology 2016; 58 (01) 69-75
    CrossrefPubMedGoogle Scholar
  • 50 Reich TR, Switzeny OJ, Renovanz M. , et al. Epigenetic silencing of XAF1 in high-grade gliomas is associated with IDH1 status and improved clinical outcome. Oncotarget 2017; 8 (09) 15071-15084
    CrossrefPubMedGoogle Scholar
  • 51 Mansouri A, Karamchandani J, Das S. Molecular Genetics of Secondary Glioblastoma. In: De Vleeschouwer S. , ed. Glioblastoma. Brisbane, Australia: Codon Publications; 2017: 27-42
    CrossrefGoogle Scholar
  • 52 Schindler G, Capper D, Meyer J. , 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 (03) 397-405
    CrossrefPubMedGoogle Scholar
  • 53 Verhaak RG, Hoadley KA, Purdom E. , et al; Cancer Genome Atlas Research Network. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 2010; 17 (01) 98-110
    CrossrefPubMedGoogle Scholar
  • 54 Phillips HS, Kharbanda S, Chen R. , 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 (03) 157-173
    CrossrefPubMedGoogle Scholar
  • 55 Turcan S, Rohle D, Goenka A. , et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 2012; 483 (7390): 479-483
    PubMedGoogle Scholar
  • 56 Stupp R, Mason WP, van den Bent MJ. , et al; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352 (10) 987-996
    CrossrefPubMedGoogle Scholar
  • 57 Chen R, Cohen AL, Colman H. Targeted therapeutics in patients with high-grade gliomas: past, present, and future. Curr Treat Options Oncol 2016; 17 (08) 42
    CrossrefPubMedGoogle Scholar
  • 58 Chinot OL, Wick W, Mason W. , et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 2014; 370 (08) 709-722
    CrossrefPubMedGoogle Scholar
  • 59 Gilbert MR, Dignam JJ, Armstrong TS. , et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 2014; 370 (08) 699-708
    CrossrefPubMedGoogle Scholar
  • 60 Gilbert MR, Wang M, Aldape KD. , et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol 2013; 31 (32) 4085-4091
    CrossrefPubMedGoogle Scholar
  • 61 Marosi C, Preusser M. Milestones of the last 10 years: CNS cancer. Memo 2017; 10 (01) 18-21
    CrossrefPubMedGoogle Scholar
  • 62 Nabors LB, Fink KL, Mikkelsen T. , et al. Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study. Neuro Oncol 2015; 17 (05) 708-717
    CrossrefPubMedGoogle Scholar
  • 63 Sampson JH, Aldape KD, Archer GE. , et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol 2011; 13 (03) 324-333
    CrossrefPubMedGoogle Scholar
  • 64 Schulte A, Liffers K, Kathagen A. , et al. Erlotinib resistance in EGFR-amplified glioblastoma cells is associated with upregulation of EGFRvIII and PI3Kp110δ. Neuro Oncol 2013; 15 (10) 1289-1301
    CrossrefPubMedGoogle Scholar
  • 65 Stupp R, Hegi ME, Gorlia T. , et al; European Organisation for Research and Treatment of Cancer (EORTC); Canadian Brain Tumor Consortium; CENTRIC study team. 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 2014; 15 (10) 1100-1108
    CrossrefPubMedGoogle Scholar
  • 66 van den Bent MJ, Brandes AA, Rampling R. , 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 (08) 1268-1274
    CrossrefPubMedGoogle Scholar
  • 67 Taylor JW, Schiff D. Treatment considerations for MGMT-unmethylated glioblastoma. Curr Neurol Neurosci Rep 2015; 15 (01) 507
    CrossrefPubMedGoogle Scholar
  • 68 Binabaj MM, Bahrami A, ShahidSales S. , et al. The prognostic value of MGMT promoter methylation in glioblastoma: a meta-analysis of clinical trials. J Cell Physiol 2018; 233 (01) 378-386
    CrossrefPubMedGoogle Scholar
  • 69 Azoulay M, Santos F, Shenouda G. , et al. Benefit of re-operation and salvage therapies for recurrent glioblastoma multiforme: results from a single institution. J Neurooncol 2017; 132 (03) 419-426
    CrossrefPubMedGoogle Scholar
  • 70 Franceschi E, Bartolotti M, Tosoni A. , et al. The effect of re-operation on survival in patients with recurrent glioblastoma. Anticancer Res 2015; 35 (03) 1743-1748
    PubMedGoogle Scholar
  • 71 Roth P, Preusser M, Weller M. Immunotherapy of brain cancer. Oncol Res Treat 2016; 39 (06) 326-334
    CrossrefPubMedGoogle Scholar
  • 72 Weller M, Butowski N, Tran DD. , et al; ACT IV trial investigators. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol 2017; 18 (10) 1373-1385
    CrossrefPubMedGoogle Scholar
  • 73 Felsberg J, Hentschel B, Kaulich K. , et al; German Glioma Network. Epidermal growth factor receptor variant III (EGFRvIII) positivity in EGFR-amplified glioblastomas: prognostic role and comparison between primary and recurrent tumors. Clin Cancer Res 2017; 23 (22) 6846-6855
    CrossrefPubMedGoogle Scholar
  • 74 Tanguturi SK, Trippa L, Ramkissoon SH. , et al. Leveraging molecular datasets for biomarker-based clinical trial design in glioblastoma. Neuro Oncol 2017; 19 (07) 908-917
    CrossrefPubMedGoogle Scholar
  • 75 Ghosh D, Nandi S, Bhattacharjee S. Combination therapy to checkmate Glioblastoma: clinical challenges and advances. Clin Transl Med 2018; 7 (01) 33
    CrossrefPubMedGoogle Scholar
  • 76 Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12 (04) 252-264
    CrossrefPubMedGoogle Scholar
  • 77 Zeng J, See AP, Phallen J. , et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys 2013; 86 (02) 343-349
    CrossrefPubMedGoogle Scholar
  • 78 Jenkinson MD, Barone DG, Bryant A. , et al. Intraoperative imaging technology to maximise extent of resection for glioma. Cochrane Database Syst Rev 2018; 1: CD012788
    PubMedGoogle Scholar
  • 79 Lin CA, Rhodes CT, Lin C, Phillips JJ, Berger MS. Comparative analyses identify molecular signature of MRI-classified SVZ-associated glioblastoma. Cell Cycle 2017; 16 (08) 765-775
    CrossrefPubMedGoogle Scholar