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Candidate genes for the progression of malignant gliomas identified by microarray analysis

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An Erratum to this article was published on 27 February 2008

Abstract

Malignant astrocytomas of World Health Organization (WHO) grade III or IV have a reduced median survival time, and possible pathways have been described for the progression of anaplastic astrocytomas and glioblastomas, but the molecular basis of malignant astrocytoma progression is still poorly understood. Microarray analysis provides the chance to accelerate studies by comparison of the expression of thousands of genes in these tumours and consequently identify targeting genes. We compared the transcriptional profile of 4,608 genes in tumours of 15 patients including 6 anaplastic astrocytomas (WHO grade III) and 9 glioblastomas (WHO grade IV) using microarray analysis. The microarray data were corroborated by real-time reverse transcription-polymerase chain reaction analysis of two selected genes. We identified 166 gene alterations with a fold change of 2 and higher whose mRNA levels differed (absolute value of the t statistic of 1.96) between the two malignant glioma groups. Further analyses confirmed same transcription directions for Olig2 and IL-13Rα2 in anaplastic astrocytomas as compared to glioblastomas. Microarray analyses with a close binary question reveal numerous interesting candidate genes, which need further histochemical testing after selection for confirmation. IL-13Rα2 and Olig2 have been identified and confirmed to be interesting candidate genes whose differential expression likely plays a role in malignant progression of astrocytomas.

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References

  1. Bouvier C, Bartoli C, Guirre-Cruz L, Virard I, Colin C, Fernandez C et al (2003) Shared oligodendrocyte lineage gene expression in gliomas and oligodendrocyte progenitor cells. J Neurosurg 99(2):344–350

    Article  PubMed  CAS  Google Scholar 

  2. Chakravarti A, Zhai G, Suzuki Y, Sarkesh S, Black PM, Muzikansky A et al (2004) The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas. J Clin Oncol 22(10):1926–1933

    Article  PubMed  CAS  Google Scholar 

  3. Debinski W, Gibo DM (2000) Molecular expression analysis of restrictive receptor for interleukin 13, a brain tumour-associated cancer/testis antigen. Mol Med 6(5):440–449

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  5. Fukuda S, Kondo T, Takebayashi H, Taga T (2004) Negative regulatory effect of an oligodendrocytic bHLH factor OLIG2 on the astrocytic differentiation pathway. Cell Death Differ 11(2):196–202

    Article  PubMed  CAS  Google Scholar 

  6. Fuller GN, Hess KR, Rhee CH, Yung WK, Sawaya RA, Bruner JM et al (2002) Molecular classification of human diffuse gliomas by multidimensional scaling analysis of gene expression profiles parallels morphology-based classification, correlates with survival, and reveals clinically-relevant novel glioma subsets. Brain Pathol 12(1):108–116

    Article  PubMed  CAS  Google Scholar 

  7. Giulietti A, Overbergh L, Valckx D, Decallonne B, Bouillon R, Mathieu C (2001) An overview of real-time quantitative PCR: applications to quantify cytokine gene expression. Methods 25(4):386–401

    Article  PubMed  CAS  Google Scholar 

  8. Hoelzinger DB, Mariani L, Weis J, Woyke T, Berens TJ, McDonough WS et al (2005) Gene expression profile of glioblastoma multiforme invasive phenotype points to new therapeutic targets. Neoplasia 7(1):7–16

    Article  PubMed  CAS  Google Scholar 

  9. Ichimura K, Ichimura K, Ohgaki H, Kleihues P, Collins VP (2004) Molecular pathogenesis of astrocytic tumours. J Neurooncol 70(2):137–160

    Article  PubMed  Google Scholar 

  10. Joshi BH, Plautz GE, Puri RK (2000) Interleukin-13 receptor alpha chain: a novel tumour-associated transmembrane protein in primary explants of human malignant gliomas. Cancer Res 60(5):1168–1172

    PubMed  CAS  Google Scholar 

  11. Kawakami K, Kawakami M, Snoy PJ, Husain SR, Puri RK (2001) In vivo overexpression of IL-13 receptor alpha2 chain inhibits tumourigenicity of human breast and pancreatic tumours in immunodeficient mice. J Exp Med 194(12):1743–1754

    Article  PubMed  CAS  Google Scholar 

  12. Kawakami K, Kawakami K, Taguchi J, Murata T, Puri RK (2005) Evidence that IL-13R alpha2 chain in human glioma cells is responsible for the antitumour activity mediated by receptor-directed cytotoxin therapy. J Immunother 28(3):193–202

    Article  PubMed  CAS  Google Scholar 

  13. Kawakami K, Kawakami K, Kioi M, Liu Q, Kawakami M, Puri RK (2001) The interleukin-13 receptor alpha2 chain: an essential component for binding and internalization but not for interleukin-13-induced signal transduction through the STAT6 pathway. Blood 97(9):2673–2679

    Article  PubMed  CAS  Google Scholar 

  14. Kawakami M, Kawakami M, Kawakami K, Takahashi S, Abe M, Puri RK (2004) Analysis of interleukin-13 receptor alpha2 expression in human pediatric brain tumours. Cancer 101(5):1036–1042

    Article  PubMed  CAS  Google Scholar 

  15. Lang FF, Bruner JM, Fuller GN, Aldape K, Prados MD, Chang S et al (2003) Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results. J Clin Oncol 21(13):2508–2518

    Article  PubMed  CAS  Google Scholar 

  16. Ligon KL, Alberta JA, Kho AT, Weiss J, Kwaan MR, Nutt CL et al (2004) The oligodendroglial lineage marker OLIG2 is universally expressed in diffuse gliomas. J Neuropathol Exp Neurol 63(5):499–509

    PubMed  CAS  Google Scholar 

  17. Liu TF, Tatter SB, Willingham MC, Yang M, Hu JJ, Frankel AE (2003) Growth factor receptor expression varies among high-grade gliomas and normal brain: epidermal growth factor receptor has excellent properties for interstitial fusion protein therapy. Mol Cancer Ther 2(8):783–787

    PubMed  CAS  Google Scholar 

  18. Lu QR, Park JK, Noll E, Chan JA, Alberta J, Yuk D et al (2001) Oligodendrocyte lineage genes (OLIG) as molecular markers for human glial brain tumours. Proc Natl Acad Sci U S A 98(19):10851–10856

    Article  PubMed  CAS  Google Scholar 

  19. Mariani L, Beaudry C, McDonough WS, Hoelzinger DB, Demuth T, Ross KR et al (2001) Glioma cell motility is associated with reduced transcription of proapoptotic and proliferation genes: a cDNA microarray analysis. J Neurooncol 53(2):161–176

    Article  PubMed  CAS  Google Scholar 

  20. Mischel PS, Shai R, Shi T, Horvath S, Lu KV, Choe G et al (2003) Identification of molecular subtypes of glioblastoma by gene expression profiling. Oncogene 22(15):2361–2373

    Article  PubMed  CAS  Google Scholar 

  21. Mokhtari K, Paris S, guirre-Cruz L, Privat N, Criniere E, Marie Y et al (2005) Olig2 expression, GFAP, p53 and 1p loss analysis contribute to glioma subclassification. Neuropathol Appl Neurobiol 31(1):62–69

    Article  PubMed  CAS  Google Scholar 

  22. Ohgaki H (2005) Genetic pathways to glioblastomas. Neuropathology 25(1):1–7

    Article  PubMed  Google Scholar 

  23. Pomeroy SL, Tamayo P, Gaasenbeek M, Sturla LM, Angelo M, McLaughlin ME et al (2002) Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415(6870):436–442

    Article  PubMed  CAS  Google Scholar 

  24. Reifenberger G, Collins VP (2004) Pathology and molecular genetics of astrocytic gliomas. J Mol Med 82(10):656–670

    Article  PubMed  CAS  Google Scholar 

  25. Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL et al (2004) Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22(1):133–142

    Article  PubMed  CAS  Google Scholar 

  26. Rickman DS, Bobek MP, Misek DE, Kuick R, Blaivas M, Kurnit DM et al (2001) Distinctive molecular profiles of high-grade and low-grade gliomas based on oligonucleotide microarray analysis. Cancer Res 61(18):6885–6891

    PubMed  CAS  Google Scholar 

  27. Riemenschneider MJ, Koy TH, Reifenberger G (2004) Expression of oligodendrocyte lineage genes in oligodendroglial and astrocytic gliomas. Acta Neuropathol (Berl) 107(3):277–282

    Article  CAS  Google Scholar 

  28. Sanson M, Thillet J, Hoang-Xuan K (2004) Molecular changes in gliomas. Curr Opin Oncol 16(6):607–613

    Article  PubMed  CAS  Google Scholar 

  29. Schramm A, Schulte JH, Klein-Hitpass L, Havers W, Sieverts H, Berwanger B et al (2005) Prediction of clinical outcome and biological characterization of neuroblastoma by expression profiling. Oncogene 24(53):7902–7912

    Article  PubMed  CAS  Google Scholar 

  30. Setoguchi T, Kondo T (2004) Nuclear export of OLIG2 in neural stem cells is essential for ciliary neurotrophic factor-induced astrocyte differentiation. J Cell Biol 166(7):963–968

    Article  PubMed  CAS  Google Scholar 

  31. Shai R, Shi T, Kremen TJ, Horvath S, Liau LM, Cloughesy TF et al (2003) Gene expression profiling identifies molecular subtypes of gliomas. Oncogene 22(31):4918–4923

    Article  PubMed  CAS  Google Scholar 

  32. Thome J, Gsell W, Rosler M, Kornhuber J, Frolich L, Hashimoto E et al (1997) Oxidative-stress associated parameters (lactoferrin, superoxide dismutases) in serum of patients with Alzheimer's disease. Life Sci 60(1):13–19

    Article  PubMed  CAS  Google Scholar 

  33. van den, Boom J, Wolter M, Kuick R, Misek DE, Youkilis AS, Wechsler DS et al (2003) Characterization of gene expression profiles associated with glioma progression using oligonucleotide-based microarray analysis and real-time reverse transcription-polymerase chain reaction. Am J Pathol 163(3):1033–1043

    Google Scholar 

  34. Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A et al (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3(7):RESEARCH0034.

    Google Scholar 

  35. Wang J, Jani-Sait SN, Escalon EA, Carroll AJ, de Jong PJ, Kirsch IR et al (2000) The t(14;21)(q11.2;q22) chromosomal translocation associated with T-cell acute lymphoblastic leukemia activates the BHLHB1 gene. Proc Natl Acad Sci U S A 97(7):3497–3502

    Article  PubMed  CAS  Google Scholar 

  36. Wennerberg K, Rossman KL, Der CJ (2005) The Ras superfamily at a glance. J Cell Sci 118(Pt 5):843–846

    Article  PubMed  CAS  Google Scholar 

  37. Yang YH, Dudoit S, Luu P, Lin DM, Peng V, Ngai J et al (2002) Normalization for cDNA nicroarray data: a robust composite method addressing single and multiple slide systematic variation. Nucleic Acids Res 30(4):e15

    Article  PubMed  Google Scholar 

  38. Zhou Q, Anderson DJ (2002) The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification. Cell 109(1):61–73

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

For these studies, the first author (OB) has been financed by the Kempkes Foundation Marburg, Germany. We like to thank Prof. Eilers and Prof. Neubauer and their co-workers very much for their intensive assistance, help and collaboration to finish these studies. Special thanks to Dr. Krause and his microarray facility.

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Authors and Affiliations

  1. Department of Neurosurgery, Philipps-University Marburg, Baldingerstrasse, 35033, Marburg, Germany

    Oliver Bozinov, Sylvia Köhler, Ludwig Benes, Dorothea Miller, Ulrich Sure & Helmut Bertalanffy

  2. Institute of Molecular Biology and Tumor Research, Bioinformatics, Philipps-University Marburg, Marburg, Germany

    Birgit Samans

  3. Department of Hematology and Oncology, Philipps-University Marburg, Marburg, Germany

    Markus Ritter

Authors
  1. Oliver Bozinov
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  2. Sylvia Köhler
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  3. Birgit Samans
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  4. Ludwig Benes
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  7. Ulrich Sure
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Correspondence to Oliver Bozinov.

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Comments

Dietmar Krex, Dresden, Germany

In the present study by Bozinov et al., microarray analysis was performed in six anaplastic astrocytomas and nine GBMs (WHO grade III and IV, respectively) to identify molecular markers associated with progression and further dedifferentiation in malignant gliomas. Although there are numerous published data about the molecular differences between low- and high-grade gliomas, only little is known about molecular markers that are involved in late-stage malignization of glial tumours. Microarray-based approaches are reasonable to screen for candidate genes, although specificity of these analyses is low while costs are high. The latter is also a reason why in most studies only small numbers of patients are studied. To validate the results, and to identify promising candidate genes, data can be pooled from various analyses. Therefore, there is a clear need for more array-based approaches. Of course, like in the present study, results additionally need to be confirmed by another experimental approach. Bozinov et al. have picked two interesting genes Olig2 and IL-13Rα2 that were confirmed to be up- and downregulated, respectively, in glioblastomas as compared to anaplastic astrocytomas. Particularly the downregulation of the IL-13Rα2 gene is challenging and needs confirmation in larger series, as it is in contrast to several preclinical and clinical studies and indicates that the IL-13 receptor might not be a perfect target for a molecular therapy in a pure glioblastoma population.

Comments

Kaoru Kurisu, Hiroshima, Japan

The authors emphasized the usefulness of microarray analysis in the determination of affected genes. In addition, they pointed out new transcriptional networks which concern the up and downregulation of signaling pathways. This approach is very beneficial to pick up the affected genes, but after obtaining the results, we have to check the function of them as mentioned by the authors in the conclusion. On the point of treatment application of these results, Olig2 and IL-13Rα2 are very fascinating to develop new molecular targeting to control tumor growth, invasion and dissemination on so on. Of course, after initial treatment, neoplasm can get another function as tolerance against the first treatment drugs and molecules. Therefore, we have to identify the advanced stage function of these candidates. In our department, survival was identified as a good prognostic factor in astrocytic tumors (Cancer. 2003; 97(4):1077–83) and its intracellular expression pattern can indicate the prognosis of high-grade astrocytomas (J Neurooncol. 2007 Apr; 82(2):193–8). Therefore, expression pattern or intracellular localization of the candidate factors is very important to understand the biological behavior of them. I hope the authors will develop their integrated works on these affected genes and related factors to overcome the worst neoplasm of central nervous system, glioblastoma.

An erratum to this article can be found at http://dx.doi.org/10.1007/s10143-008-0125-9

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Bozinov, O., Köhler, S., Samans, B. et al. Candidate genes for the progression of malignant gliomas identified by microarray analysis. Neurosurg Rev 31, 83–90 (2008). https://doi.org/10.1007/s10143-007-0107-3

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  • DOI: https://doi.org/10.1007/s10143-007-0107-3

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