Genetic secrets of long-term glioblastoma survivors

Keywords: Glioblastoma, genetics, IDH, MGMT, chromosome 1p/19q, long term survival, extreme survivors


Glioblastomas account for the majority of primary brain tumors. Although glioblastomas are considered as rare diseases, they represent 60%-70% of all gliomas and in most cases have fatal consequences. Genetic analyses show great heterogeneity both intratumor and intertumor. This notion opens up debates about glioblastoma origin. Different brain cells including astrocytes, neural stem cells, oligodendrocyte precursor cells and glioblastoma stem cells are proposed as capable of initiation and reseeding a tumor; however data is still inconclusive. Due to high mortality rate, long term glioblastoma survivors are defined as patients who live longer than 2 years post diagnosis. Extreme survivors, living 10 years or more after diagnosis, comprise less than 1% of all patients. Molecular testing suggests differences in the genetic profiles of glioblastoma between short and long term survivors. The most informative indicators are IDH mutations and MGMT promotor methylation. Other genes like FBLN4, EMP3, IGFBP-2, IGFBP-3, LGALS3, MAOB, PDPN, SERPING1 and TIMP1 have also been associated with glioblastoma prolonged survival. Emerging evidence proposes roles of different microRNAs in predicting patient survival. Moreover, clinical features like seizures as a symptom at presentation, age at diagnosis, and the extent of the surgical resection are also factors that influence the length of survival. Because of the small number of long term survivors, it is difficult to examine these samples and draw conclusions about the genetics of glioblastoma longevity. To aid in the clinical care, a thorough “omics” approach is necessary for identifying differences between short and long term glioblastoma survivors.


Download data is not yet available.

Author Biography

Ivana Jovčevska, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Institute of Biochemistry


Jiang Y, Uhrbom L. On the origin of glioma. Upsala journal of medical sciences. 2012;117(2):113-21.

Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta neuropathologica. 2016;131(6):803-20.

Zhang C, Bao Z, Zhang W, Jiang T. Progress on molecular biomarkers and classification of malignant gliomas. Front Med. 2013;7(2):150-6.

Noroxe DS, Poulsen HS, Lassen U. Hallmarks of glioblastoma: a systematic review. ESMO open. 2016;1(6):e000144.

Zong H, Verhaak RG, Canoll P. The cellular origin for malignant glioma and prospects for clinical advancements. Expert Rev Mol Diagn. 2012;12(4):383-94.

Chaurasia A, Park SH, Seo JW, Park CK. Immunohistochemical Analysis of ATRX, IDH1 and p53 in Glioblastoma and Their Correlations with Patient Survival. Journal of Korean medical science. 2016;31(8):1208-14.

Barthel FP, Wesseling P, Verhaak RGW. Reconstructing the molecular life history of gliomas. Acta Neuropathol. 2018;135(5):649-70.

Cahill D, Turcan S. Origin of Gliomas. Semin Neurol. 2018;38(1):5-10.

Agnihotri S, Aldape KD, Zadeh G. Isocitrate dehydrogenase status and molecular subclasses of glioma and glioblastoma. Neurosurg Focus. 2014;37(6):E13.

Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, et al. Genetic pathways to glioblastoma: a population-based study. Cancer research. 2004;64(19):6892-9.

Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. The American journal of pathology. 2007;170(5):1445-53.

Olar A, Aldape KD. Using the molecular classification of glioblastoma to inform personalized treatment. J Pathol. 2014;232(2):165-77.

Jovčevska I. Sequencing the next generation of glioblastomas. Critical Reviews in Clinical Laboratory Sciences. 2018:1-19.

Reuss DE, Sahm F, Schrimpf D, Wiestler B, Capper D, Koelsche C, et al. 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 neuropathologica. 2015;129(1):133-46.

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.

Friedmann-Morvinski D. Glioblastoma heterogeneity and cancer cell plasticity. Crit Rev Oncog. 2014;19(5):327-36.

Li R, Li H, Yan W, Yang P, Bao Z, Zhang C, et al. Genetic and clinical characteristics of primary and secondary glioblastoma is associated with differential molecular subtype distribution. Oncotarget. 2015;6(9):7318-24.

Parker NR, Hudson AL, Khong P, Parkinson JF, Dwight T, Ikin RJ, et al. Intratumoral heterogeneity identified at the epigenetic, genetic and transcriptional level in glioblastoma. Scientific reports. 2016;6:22477.

Mooney KL, Choy W, Sidhu S, Pelargos P, Bui TT, Voth B, et al. The role of CD44 in glioblastoma multiforme. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2016;34:1-5.

Cancer Genome Atlas Research N. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061-8.

Wang R, Wei J, Li Z, Tian Y, Du C. Bioinformatical analysis of gene expression signatures of different glioma subtypes. Oncology letters. 2018;15(3):2807-14.

Zuccarini M, Giuliani P, Ziberi S, Carluccio M, Iorio PD, Caciagli F, et al. The Role of Wnt Signal in Glioblastoma Development and Progression: A Possible New Pharmacological Target for the Therapy of This Tumor. Genes (Basel). 2018;9(2).

Pecina-Slaus N, Kafka A, Tomas D, Markovic L, Okstajner PK, Sukser V, et al. Wnt signaling transcription factors TCF-1 and LEF-1 are upregulated in malignant astrocytic brain tumors. Histol Histopathol. 2014;29(12):1557-64.

Lee Y, Lee JK, Ahn SH, Lee J, Nam DH. WNT signaling in glioblastoma and therapeutic opportunities. Laboratory investigation; a journal of technical methods and pathology. 2016;96(2):137-50.

Chowdhury FA, Hossain MK, Mostofa AGM, Akbor MM, Bin Sayeed MS. Therapeutic Potential of Thymoquinone in Glioblastoma Treatment: Targeting Major Gliomagenesis Signaling Pathways. BioMed research international. 2018;2018:4010629.

Aum DJ, Kim DH, Beaumont TL, Leuthardt EC, Dunn GP, Kim AH. Molecular and cellular heterogeneity: the hallmark of glioblastoma. Neurosurg Focus. 2014;37(6):E11.

Soeda A, Hara A, Kunisada T, Yoshimura S, Iwama T, Park DM. The evidence of glioblastoma heterogeneity. Sci Rep. 2015;5:7979.

Eder K, Kalman B. Molecular heterogeneity of glioblastoma and its clinical relevance. Pathol Oncol Res. 2014;20(4):777-87.

Meyer M, Reimand J, Lan X, Head R, Zhu X, Kushida M, et al. Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity. Proc Natl Acad Sci U S A. 2015;112(3):851-6.

Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344(6190):1396-401.

Kim H, Zheng S, Amini SS, Virk SM, Mikkelsen T, Brat DJ, et al. Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution. Genome Res. 2015;25(3):316-27.

Driessens G, Beck B, Caauwe A, Simons BD, Blanpain C. Defining the mode of tumour growth by clonal analysis. Nature. 2012;488(7412):527-30.

Vermeulen L, Sprick MR, Kemper K, Stassi G, Medema JP. Cancer stem cells--old concepts, new insights. Cell death and differentiation. 2008;15(6):947-58.

Borovski T, De Sousa EMF, Vermeulen L, Medema JP. Cancer stem cell niche: the place to be. Cancer research. 2011;71(3):634-9.

Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, et al. Neurogenesis in the adult human hippocampus. Nature medicine. 1998;4(11):1313-7.

Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al. Identification of a cancer stem cell in human brain tumors. Cancer research. 2003;63(18):5821-8.

Zong H, Parada LF, Baker SJ. Cell of origin for malignant gliomas and its implication in therapeutic development. Cold Spring Harb Perspect Biol. 2015;7(5).

Borovski T, Vermeulen L, Sprick MR, Medema JP. One renegade cancer stem cell? Cell Cycle. 2009;8(6):803-8.

Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756-60.

Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Molecular cancer. 2006;5:67.

Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature. 2004;432(7015):396-401.

Ailles LE, Weissman IL. Cancer stem cells in solid tumors. Current opinion in biotechnology. 2007;18(5):460-6.

Welte Y, Adjaye J, Lehrach HR, Regenbrecht CR. Cancer stem cells in solid tumors: elusive or illusive? Cell communication and signaling : CCS. 2010;8(1):6.

Azzarelli R, Simons BD, Philpott A. The developmental origin of brain tumours: a cellular and molecular framework. Development. 2018;145(10).

Kim KH, Seol HJ, Kim EH, Rheey J, Jin HJ, Lee Y, et al. Wnt/beta-catenin signaling is a key downstream mediator of MET signaling in glioblastoma stem cells. Neuro-oncology. 2013;15(2):161-71.

Yamanaka R. Cell- and peptide-based immunotherapeutic approaches for glioma. Trends in molecular medicine. 2008;14(5):228-35.

Zacher A, Kaulich K, Stepanow S, Wolter M, Kohrer K, Felsberg J, et al. Molecular Diagnostics of Gliomas Using Next Generation Sequencing of a Glioma-Tailored Gene Panel. Brain Pathol. 2017;27(2):146-59.

Aldape K, Zadeh G, Mansouri S, Reifenberger G, von Deimling A. Glioblastoma: pathology, molecular mechanisms and markers. Acta neuropathologica. 2015;129(6):829-48.

Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review. JAMA : the journal of the American Medical Association. 2013;310(17):1842-50.

Ho VK, Reijneveld JC, Enting RH, Bienfait HP, Robe P, Baumert BG, et al. Changing incidence and improved survival of gliomas. Eur J Cancer. 2014;50(13):2309-18.

Czapski B, Baluszek S, Herold-Mende C, Kaminska B. Clinical and immunological correlates of long term survival in glioblastoma. Contemp Oncol (Pozn). 2018;22(1A):81-5.

Monticelli M, Zeppa P, Zenga F, Altieri R, Mammi M, Bertero L, et al. The post-surgical era of GBM: How molecular biology has impacted on our clinical management. A review. Clin Neurol Neurosurg. 2018;170:120-6.

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.

Thomas L, Di Stefano AL, Ducray F. Predictive biomarkers in adult gliomas: the present and the future. Current opinion in oncology. 2013;25(6):689-94.

Dunn GP, Rinne ML, Wykosky J, Genovese G, Quayle SN, Dunn IF, et al. Emerging insights into the molecular and cellular basis of glioblastoma. Genes & development. 2012;26(8):756-84.

Kitambi SS, Toledo EM, Usoskin D, Wee S, Harisankar A, Svensson R, et al. Vulnerability of glioblastoma cells to catastrophic vacuolization and death induced by a small molecule. Cell. 2014;157(2):313-28.

Yuan GQ, Wei NL, Mu LY, Wang XQ, Zhang YN, Zhou WN, et al. A 4-miRNAs signature predicts survival in glioblastoma multiforme patients. Cancer Biomark. 2017;20(4):443-52.

Gately L, McLachlan SA, Philip J, Ruben J, Dowling A. Long-term survivors of glioblastoma: a closer look. J Neurooncol. 2018;136(1):155-62.

Tykocki T, Eltayeb M. Ten-year survival in glioblastoma. A systematic review. J Clin Neurosci. 2018.

Fan X, Li Y, Shan X, You G, Wu Z, Li Z, et al. Seizures at presentation are correlated with better survival outcomes in adult diffuse glioma: A systematic review and meta-analysis. Seizure. 2018;59:16-23.

Berendsen S, Varkila M, Kroonen J, Seute T, Snijders TJ, Kauw F, et al. Prognostic relevance of epilepsy at presentation in glioblastoma patients. Neuro Oncol. 2016;18(5):700-6.

Dobran M, Nasi D, Chiriatti S, Gladi M, Somma LD, Iacoangeli M, et al. Prognostic Factors in Glioblastoma: Is There a Role for Epilepsy? Neurol Med Chir (Tokyo). 2018;58(3):110-5.

Flanigan PM, Jahangiri A, Kuang R, Truong A, Choi S, Chou A, et al. Improved Survival with Decreased Wait Time to Surgery in Glioblastoma Patients Presenting with Seizure. Neurosurgery. 2017;81(5):824-33.

Reifenberger G, Weber RG, Riehmer V, Kaulich K, Willscher E, Wirth H, et al. Molecular characterization of long-term survivors of glioblastoma using genome- and transcriptome-wide profiling. Int J Cancer. 2014;135(8):1822-31.

Michaelsen SR, Urup T, Olsen LR, Broholm H, Lassen U, Poulsen HS. Molecular profiling of short-term and long-term surviving patients identifies CD34 mRNA level as prognostic for glioblastoma survival. J Neurooncol. 2018;137(3):533-42.

Gerber NK, Goenka A, Turcan S, Reyngold M, Makarov V, Kannan K, et al. Transcriptional diversity of long-term glioblastoma survivors. Neuro Oncol. 2014;16(9):1186-95.

Hartmann C, Hentschel B, Simon M, Westphal M, Schackert G, Tonn JC, et al. Long-term survival in primary glioblastoma with versus without isocitrate dehydrogenase mutations. Clin Cancer Res. 2013;19(18):5146-57.

Li F, Li Y, Zhang K, Li Y, He P, Liu Y, et al. FBLN4 as candidate gene associated with long-term and short-term survival with primary glioblastoma. Onco Targets Ther. 2017;10:387-95.

Sandmann T, Bourgon R, Garcia J, Li C, Cloughesy T, Chinot OL, 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. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015;33(25):2735-44.

Cantero D, Rodriguez de Lope A, Moreno de la Presa R, Sepulveda JM, Borras JM, Castresana JS, et al. Molecular Study of Long-Term Survivors of Glioblastoma by Gene-Targeted Next-Generation Sequencing. Journal of neuropathology and experimental neurology. 2018;77(8):710-6.

Niyazi M, Zehentmayr F, Niemoller OM, Eigenbrod S, Kretzschmar H, Schulze-Osthoff K, et al. MiRNA expression patterns predict survival in glioblastoma. Radiat Oncol. 2011;6:153.

Srinivasan S, Patric IR, Somasundaram K. A ten-microRNA expression signature predicts survival in glioblastoma. PLoS One. 2011;6(3):e17438.

Zhang W, Zhang J, Yan W, You G, Bao Z, Li S, et al. Whole-genome microRNA expression profiling identifies a 5-microRNA signature as a prognostic biomarker in Chinese patients with primary glioblastoma multiforme. Cancer. 2013;119(4):814-24.

Hermansen SK, Sorensen MD, Hansen A, Knudsen S, Alvarado AG, Lathia JD, et al. A 4-miRNA signature to predict survival in glioblastomas. PLoS One. 2017;12(11):e0188090.

Sperduto CM, Chakravarti A, Aldape K, Burger P, Papermaster GB, Sperduto P. Twenty-year survival in glioblastoma: a case report and molecular profile. Int J Radiat Oncol Biol Phys. 2009;75(4):1162-5.

Smoll NR, Schaller K, Gautschi OP. The cure fraction of glioblastoma multiforme. Neuroepidemiology. 2012;39(1):63-9.

Walid MS. Prognostic factors for long-term survival after glioblastoma. Perm J. 2008;12(4):45-8.

Genetics of glioblastoma
How to Cite
Jovčevska I. Genetic secrets of long-term glioblastoma survivors. BJBMS [Internet]. 14Aug.2018 [cited 21Feb.2019];. Available from: