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Molecular Heterogeneity of Glioblastoma and its Clinical Relevance

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Pathology & Oncology Research

Abstract

Glioblastoma is the most common intracranial malignancy and constitutes about 50 % of all gliomas. Both inter-tumor and intra-tumor histological heterogeneity had been recognized by the early 1980-ies. Recent works using novel molecular platforms provided molecular definitions of these tumors. Based on comprehensive genomic sequence analyses, The Cancer Genome Atlas Research Network (TCGA) cataloged somatic mutations and recurrent copy number alterations in glioblastoma. Robust transcriptome and epigenome studies also revealed inter-tumor heterogeneity. Integration and cluster analyses of multi-dimensional genomic data lead to a new classification of glioblastoma tumors into subtypes with distinct biological features and clinical correlates. However, multiple observations also revealed tumor area-specific patterns of genomic imbalance. In addition, genetic alterations have been identified that were common to all areas analyzed and other alterations that were area specific. Analyses of intra-tumor transcriptome variations revealed that in more than half of the examined cases, fragments from the same tumor mass could be classified into at least two different glioblastoma molecular subgroups. Intra-tumor heterogeneity of molecular genetic profiles in glioblastoma may explain the difficulties encountered in the validation of oncologic biomarkers, and contribute to a biased selection of patients for single target therapies, treatment failure or drug resistance. In this paper, we summarize the currently available literature concerning inter- and intra-tumor molecular heterogeneity of glioblastomas, and call attention to the importance of this topic in relation to the growing efforts in routine molecular diagnostics and personalized therapy.

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References

  1. Dolecek TA, Propp JM, Stroup NE, Kruchko C (2012) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro-Oncol 14(suppl 5):v1–v49

    Article  PubMed  PubMed Central  Google Scholar 

  2. Olar A, Aldape KD (2014) Using the molecular classification of glioblastoma to inform personalized treatment. J Pathol 232(2):165–177

    Article  PubMed  Google Scholar 

  3. Burger PC, Green SB (1987) Patient age, histologic features, and length of survival in patients with glioblastoma multiforme. Cancer 59(9):1617–1625

    Article  PubMed  CAS  Google Scholar 

  4. Shapiro JR, Yung WK, Shapiro WR (1981) Isolation, karyotype, and clonal growth of heterogeneous subpopulations of human malignant gliomas. Cancer Res 41(6):2349–2359

    PubMed  CAS  Google Scholar 

  5. Loeper S, Romeike B, Heckmann N, Jung V, Henn W, Feiden W, Zang K, Urbschat S (2001) Frequent mitotic errors in tumor cells of genetically micro-heterogeneous glioblastomas. Cytogenet Genome Res 94(1–2):1–8

    Article  CAS  Google Scholar 

  6. Coons SW, Johnson PC, Shapiro JR (1995) Cytogenetic and flow cytometry DNA analysis of regional heterogeneity in a low grade human glioma. Cancer Res 55(7):1569–1577

    PubMed  CAS  Google Scholar 

  7. Misra A, Chattopadhyay P, Dinda AK, Sarkar C, Mahapatra AK, Hasnain SE, Sinha S (2000) Extensive intra-tumor heterogeneity in primary human glial tumors as a result of locus non-specific genomic alterations. J Neuro-Oncol 48(1):1–12

    Article  CAS  Google Scholar 

  8. Harada K, Nishizaki T, Ozaki S, Kubota H, Ito H, Sasaki K (1998) Intratumoral cytogenetic heterogeneity detected by comparative genomic hybridization and laser scanning cytometry in human gliomas. Cancer Res 58(20):4694–4700

    PubMed  CAS  Google Scholar 

  9. Walker C, du Plessis DG, Joyce KA, Machell Y, Thomson-Hehir J, Al Haddad SA, Broome JC, Warnke PC (2003) Phenotype versus genotype in gliomas displaying inter-or intratumoral histological heterogeneity. Clin Cancer Res 9(13):4841–4851

    PubMed  CAS  Google Scholar 

  10. Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C (2007) Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21(21):2683–2710

    Article  PubMed  CAS  Google Scholar 

  11. McLendon R, Friedman A, Bigner D, Van Meir EG, Brat DJ, Mastrogianakis GM, Olson JJ, Mikkelsen T, Lehman N, Aldape K (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nat 455(7216):1061–1068

    Article  CAS  Google Scholar 

  12. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Sci 321(5897):1807–1812. doi:10.1126/science.1164382

    Article  CAS  Google Scholar 

  13. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN (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. doi:10.1016/j.ccr.2009.12.020

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Masica DL, Karchin R (2011) Correlation of somatic mutation and expression identifies genes important in human glioblastoma progression and survival. Cancer Res 71(13):4550–4561

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Cerami E, Demir E, Schultz N, Taylor BS, Sander C (2010) Automated network analysis identifies core pathways in glioblastoma. PLoS One 5(2):e8918

    Article  PubMed  PubMed Central  Google Scholar 

  16. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C (2007) Patterns of somatic mutation in human cancer genomes. Nat 446(7132):153–158

    Article  CAS  Google Scholar 

  17. Stratton MR, Campbell PJ, Futreal PA (2009) The cancer genome. Nat 458(7239):719–724

    Article  CAS  Google Scholar 

  18. Ahn J-Y, Hu Y, Kroll TG, Allard P, Ye K (2004) PIKE-A is amplified in human cancers and prevents apoptosis by up-regulating Akt. Proc Natl Acad Sci U S A 101(18):6993–6998

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Qi Q, He K, Liu X, Pham C, Meyerkord C, Fu H, Ye K (2013) Disrupting the PIKE-A/Akt interaction inhibits glioblastoma cell survival, migration, invasion and colony formation. Oncog 32(8):1030–1040

    Article  CAS  Google Scholar 

  20. Frattini V, Trifonov V, Chan JM, Castano A, Lia M, Abate F, Keir ST, Ji AX, Zoppoli P, Niola F (2013) The integrated landscape of driver genomic alterations in glioblastoma. Nat Genet 45(10):1141–1149

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Pugh TJ, Weeraratne SD, Archer TC, Krummel DAP, Auclair D, Bochicchio J, Carneiro MO, Carter SL, Cibulskis K, Erlich RL (2012) Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nat 488(7409):106–110

    Article  CAS  Google Scholar 

  22. Zhang J, Benavente CA, McEvoy J, Flores-Otero J, Ding L, Chen X, Ulyanov A, Wu G, Wilson M, Wang J (2012) A novel retinoblastoma therapy from genomic and epigenetic analyses. Nat 481(7381):329–334

    CAS  Google Scholar 

  23. Network CGAR (2013) Integrated genomic characterization of endometrial carcinoma. Nat 497(7447):67–73

    Article  Google Scholar 

  24. Freije WA, Castro-Vargas FE, Fang Z, Horvath S, Cloughesy T, Liau LM, Mischel PS, Nelson SF (2004) Gene expression profiling of gliomas strongly predicts survival. Cancer Res 64(18):6503–6510

    Article  PubMed  CAS  Google Scholar 

  25. Liang Y, Diehn M, Watson N, Bollen AW, Aldape KD, Nicholas MK, Lamborn KR, Berger MS, Botstein D, Brown PO (2005) Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme. Proc Natl Acad Sci U S A 102(16):5814–5819

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L (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  PubMed  CAS  Google Scholar 

  27. Kong J, Cooper LA, Wang F, Gutman DA, Gao J, Chisolm C, Sharma A, Pan T, Van Meir EG, Kurc TM (2011) Integrative, multimodal analysis of glioblastoma using TCGA molecular data, pathology images, and clinical outcomes. Biomed Eng, IEEE Trans on 58(12):3469–3474

    Article  Google Scholar 

  28. Kim Y-W, Koul D, Kim SH, Lucio-Eterovic AK, Freire PR, Yao J, Wang J, Almeida JS, Aldape K, Yung WA (2013) Identification of prognostic gene signatures of glioblastoma: a study based on TCGA data analysis. Neuro-Oncol 15(7):829–839

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Doucette T, Rao G, Rao A, Shen L, Aldape K, Wei J, Dziurzynski K, Gilbert M, Heimberger AB (2013) Immune heterogeneity of glioblastoma subtypes: extrapolation from the cancer genome atlas. Cancer Immunol Res 1(2):112–122

    Article  PubMed  CAS  Google Scholar 

  30. Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128(4):683–692

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, Pan F, Pelloski CE, Sulman EP, Bhat KP, Verhaak RG, Hoadley KA, Hayes DN, Perou CM, Schmidt HK, Ding L, Wilson RK, Van Den Berg D, Shen H, Bengtsson H, Neuvial P, Cope LM, Buckley J, Herman JG, Baylin SB, Laird PW, Aldape K (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17(5):510–522. doi:10.1016/j.ccr.2010.03.017

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, Zheng S, Chakravarty D, Sanborn JZ, Berman SH (2013) The somatic genomic landscape of glioblastoma. Cell 155(2):462–477

    Article  PubMed  CAS  Google Scholar 

  33. Li B, Senbabaoglu Y, Peng W, Yang M-L, Xu J, Li JZ (2012) Genomic estimates of aneuploid content in glioblastoma multiforme and improved classification. Clin Cancer Res 18(20):5595–5605

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. Iorio MV, Croce CM (2012) MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med 4(3):143–159

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Kim T-M, 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  PubMed  CAS  PubMed Central  Google Scholar 

  36. Li R, Gao K, Luo H, Wang X, Shi Y, Dong Q, Luan W, You Y (2014) Identification of intrinsic subtype-specific prognostic microRNAs in primary glioblastoma. J Exp Clin Cancer Res 33(1):9

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Godlewski J, Newton H, Chiocca E, Lawler S (2010) MicroRNAs and glioblastoma; the stem cell connection. Cell Death Differ 17(2):221–228

    Article  PubMed  CAS  Google Scholar 

  38. Hermansen SK, Kristensen BW (2013) MicroRNA biomarkers in glioblastoma. J Neuro-Oncol 114(1):13–23

    Article  CAS  Google Scholar 

  39. Dirks PB (2010) Brain tumor stem cells: the cancer stem cell hypothesis writ large. Mol Oncol 4(5):420–430

    Article  PubMed  Google Scholar 

  40. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nat 432(7015):396–401

    Article  CAS  Google Scholar 

  41. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F, Vescovi A (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64(19):7011–7021

    Article  PubMed  CAS  Google Scholar 

  42. Lottaz C, Beier D, Meyer K, Kumar P, Hermann A, Schwarz J, Junker M, Oefner PJ, Bogdahn U, Wischhusen J (2010) Transcriptional profiles of CD133+ and CD133− glioblastoma-derived cancer stem cell lines suggest different cells of origin. Cancer Res 70(5):2030–2040

    Article  PubMed  CAS  Google Scholar 

  43. De Bacco F, Casanova E, Medico E, Pellegatta S, Orzan F, Albano R, Luraghi P, Reato G, D’Ambrosio A, Porrati P (2012) The MET oncogene is a functional marker of a glioblastoma stem cell subtype. Cancer Res 72(17):4537–4550

    Article  PubMed  Google Scholar 

  44. Weller M, Stupp R, Hegi ME, van den Bent M, Tonn JC, Sanson M, Wick W, Reifenberger G (2012) Personalized care in neuro-oncology coming of age: why we need MGMT and 1p/19q testing for malignant glioma patients in clinical practice. Neuro-Oncol 14(suppl 4):iv100–iv108

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  45. Marko NF, Quackenbush J, Weil RJ (2011) Why is there a lack of consensus on molecular subgroups of glioblastoma? Understanding the nature of biological and statistical variability in glioblastoma expression data. PLoS One 6(7):e20826

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  46. Nobusawa S, Lachuer J, Wierinckx A, Kim YH, Huang J, Legras C, Kleihues P, Ohgaki H (2010) Intratumoral patterns of genomic imbalance in glioblastomas. Brain Pathol 20(5):936–944. doi:10.1111/j.1750-3639.2010.00395.x

    PubMed  CAS  Google Scholar 

  47. Snuderl M, Fazlollahi L, Le LP, Nitta M, Zhelyazkova BH, Davidson CJ, Akhavanfard S, Cahill DP, Aldape KD, Betensky RA (2011) Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 20(6):810–817

    Article  PubMed  CAS  Google Scholar 

  48. Little SE, Popov S, Jury A, Bax DA, Doey L, Al-Sarraj S, Jurgensmeier JM, Jones C (2012) Receptor tyrosine kinase genes amplified in glioblastoma exhibit a mutual exclusivity in variable proportions reflective of individual tumor heterogeneity. Cancer Res 72(7):1614–1620

    Article  PubMed  CAS  Google Scholar 

  49. Szerlip NJ, Pedraza A, Chakravarty D, Azim M, McGuire J, Fang Y, Ozawa T, Holland EC, Huse JT, Jhanwar S (2012) Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc Natl Acad Sci 109(8):3041–3046

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  50. Sottoriva A, Spiteri I, Piccirillo SG, Touloumis A, Collins VP, Marioni JC, Curtis C, Watts C, Tavare S (2013) Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci U S A 110(10):4009–4014. doi:10.1073/pnas.1219747110

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  51. Purow B, Schiff D (2009) Advances in the genetics of glioblastoma: are we reaching critical mass? Nat Rev Neurol 5(8):419–426

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  52. Ikediobi O (2008) Somatic pharmacogenomics in cancer. Pharmacogenomics J 8(5):305–314

    Article  PubMed  CAS  Google Scholar 

  53. Inda M-d-M, Bonavia R, Seoane J (2014) Glioblastoma multiforme: a look inside its heterogeneous nature. Cancers 6(1):226–239

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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Acknowledgments

The authors’ academic activities are supported by the Markusovszky University Teaching Hospital and the University of Pecs.

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  1. Markusovszky University Teaching Hospital, Markusovszky Street 5, 9700, Szombathely, Hungary

    Katalin Eder & Bernadette Kalman

  2. University of Pecs, Pecs, Hungary

    Bernadette Kalman

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  1. Katalin Eder
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Correspondence to Katalin Eder.

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Eder, K., Kalman, B. Molecular Heterogeneity of Glioblastoma and its Clinical Relevance. Pathol. Oncol. Res. 20, 777–787 (2014). https://doi.org/10.1007/s12253-014-9833-3

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  • DOI: https://doi.org/10.1007/s12253-014-9833-3

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