DETERMINATION OF MOLECULAR GENETIC MARKERS IN PROGNOSIS OF THE EFFECTIVENESS OF TREATMENT OF MALIGNANT INTRACEREBRAL BRAIN TUMORS
Abstract
Intracerebral malignant brain tumors remain one of the most complex problems of neuro-oncology. Today, promising results of the use of targeted drugs have been received, which determine the important diagnostic and predictive value of molecular genetic markers of glial and metastatic brain tumors.
Aim: The study of the prevalence of MGMT (O6-methylguanine-DNA methyltransferase) and PTEN (phosphatase and tensin homologue deleted on chromosome 10) gene expression by real time polymerase chain reaction in tumor tissue of gliomas and brain metastases.
Materials and methods: From thirty patients were received tumor material (29 cases of glioma III-IV degree of anaplasia and one case of metastatic brain lesion of adenocarcinoma). The normalized expression of MGMT and PTEN genes was determined by real-time polymerase chain reaction.
Results: In all 30 (100 %) patients with tumor fragments, we determined normalized expression of MGMT and PTEN genes. In most cases, 53 % of the observations (16 out of 30 patients) showed a low normalized expression of MGMT gene (<40 c. u.) and a low normalized PTEN expression rate of 73 % (22 out of 30 patients) (<40 c. u.). The average expression level of the MGMT gene in the range from 40 to 100 c. u. (6/20 % of patients) was considered prognostic favourable for the response to temozolomide chemotherapy.
Conclusions: The study of MGMT gene expression, a chemotherapy marker for temozolomide, indicates a trend toward correlation between expression levels and therapeutic efficacy. The study of the expression of the PTEN gene, the blocker of the PI3K / AKT signal pathway, indicates a different degree of expression of this enzyme in the tumour samples studied. The predictive value of the indicator for target therapy is appropriate in comparison with the EGFR mutation. Further profound analysis of the results is required with increasing number of sampling and observation period.
Downloads
References
Nørøxe, D. S., Poulsen, H. S., Lassen, U. (2016). Hallmarks of glioblastoma: a systematic review. ESMO Open, 1 (6), e000144. doi: http://doi.org/10.1136/esmoopen-2016-000144
Wick, W., Osswald, M., Wick, A., Winkler, F. (2018). Treatment of glioblastoma in adults. Therapeutic Advances in Neurological Disorders, 11. doi: http://doi.org/10.1177/1756286418790452
Walker, M. D., Alexander, E., Hunt, W. E., MacCarty, C. S., Mahaley, M. S., Mealey, J. et. al. (1978). Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. Journal of Neurosurgery, 49 (3), 333–343. doi: http://doi.org/10.3171/jns.1978.49.3.0333
Walker, M. D., Green, S. B., Byar, D. P., Alexander, E., Batzdorf, U., Brooks, W. H. et. al. (1980). Randomized Comparisons of Radiotherapy and Nitrosoureas for the Treatment of Malignant Glioma after Surgery. New England Journal of Medicine, 303 (23), 1323–1329. doi: http://doi.org/10.1056/nejm198012043032303
Stupp, R., Mason, W. P., van den Bent, M. J., Weller, M., Fisher, B., Taphoorn, M. J. B. et. al. (2005). Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. New England Journal of Medicine, 352 (10), 987–996. doi: http://doi.org/10.1056/nejmoa043330
Holland, E., Ene, C. (2015). Personalized Medicine for Gliomas. Surgical Neurology International, 6 (2), 89–95. doi: http://doi.org/10.4103/2152-7806.151351
Jiapaer, S., Furuta, T., Tanaka, S., Kitabayashi, T., Nakada, M. (2018). Potential Strategies Overcoming the Temozolomide Resistance for Glioblastoma. Neurologia Medico-Chirurgica, 58 (10), 405–421. doi: http://doi.org/10.2176/nmc.ra.2018-0141
Lee, S. Y. (2016). Temozolomide resistance in glioblastoma multiforme. Genes & Diseases, 3 (3), 198–210. doi: http://doi.org/10.1016/j.gendis.2016.04.007
Wang, J., Hu, G., Quan, X. (2019). Analysis of the factors affecting the prognosis of glioma patients. Open Medicine, 14 (1), 331–335. doi: http://doi.org/10.1515/med-2019-0031
Hartmann, C., Hentschel, B., Simon, M., Westphal, M., Schackert, G. et. al. (2013). Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations. Clinical Cancer Research, 19 (18), 5146–5157. doi: http://doi.org/10.1158/1078-0432.ccr-13-0017
Reifenberger, G., Weber, R. G., Riehmer, V., Kaulich, K., Willscher, E. et. al. (2014). Molecular characterization of long-term survivors of glioblastoma using genome- and transcriptome-wide profiling. International Journal of Cancer, 135 (8), 1822–1831. doi: http://doi.org/10.1002/ijc.28836
Louis, D. N., Perry, A., Reifenberger, G., von Deimling, A., Figarella-Branger, D., Cavenee, W. K. et. al. (2016). The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathologica, 131 (6), 803–820. doi: http://doi.org/10.1007/s00401-016-1545-1
Medina, T. M., Lewis, K. D. (2016). The evolution of combined molecular targeted therapies to advance the therapeutic efficacy in melanoma: a highlight of vemurafenib and cobimetinib. OncoTargets and Therapy, 9, 3739–3752. doi: http://doi.org/10.2147/ott.s86774
Xiao, W.-Z., Han, D.-H., Wang, F., Wang, Y.-Q., Zhu, Y.-H., Wu, Y.-F. et. al. (2014). Relationships between PTEN gene mutations and prognosis in glioma: a meta-analysis. Tumor Biology, 35 (7), 6687–6693. doi: http://doi.org/10.1007/s13277-014-1885-1
Brandes, A. A., Franceschi, E., Paccapelo, A., Tallini, G., De Biase, D., Ghimenton, C. et. al. (2017). Role of MGMT Methylation Status at Time of Diagnosis and Recurrence for Patients with Glioblastoma: Clinical Implications. The Oncologist, 22 (4), 432–437. doi: http://doi.org/10.1634/theoncologist.2016-0254
Nguyen, H., Shabani, S., Awad, A., Kaushal, M., Doan, N. (2018). Molecular Markers of Therapy-Resistant Glioblastoma and Potential Strategy to Combat Resistance. International Journal of Molecular Sciences, 19 (6), 1765. doi: http://doi.org/10.3390/ijms19061765
Kwatra, M. (2017). A Rational Approach to Target the Epidermal Growth Factor Receptor in Glioblastoma. Current Cancer Drug Targets, 17 (3), 290–296. doi: http://doi.org/10.2174/1568009616666161227091522
Liu, F., Mischel, P. S. (2017). Targeting epidermal growth factor receptor co-dependent signaling pathways in glioblastoma. Wiley Interdisciplinary Reviews: Systems Biology and Medicine, 10 (1), e1398. doi: http://doi.org/10.1002/wsbm.1398
Eskilsson, E., Røsland, G. V., Solecki, G., Wang, Q., Harter, P. N., Graziani, G. et. al. (2017). EGFR heterogeneity and implications for therapeutic intervention in glioblastoma. Neuro-Oncology, 20 (6), 743–752. doi: http://doi.org/10.1093/neuonc/nox191
Elsamadicy, A. A., Chongsathidkiet, P., Desai, R., Woroniecka, K., Farber, S. H., Fecci, P. E., Sampson, J. H. (2017). Prospect of rindopepimut in the treatment of glioblastoma. Expert Opinion on Biological Therapy, 17 (4), 507–513. doi: http://doi.org/10.1080/14712598.2017.1299705
Benitez, J. A., Ma, J., D’Antonio, M., Boyer, A., Camargo, M. F., Zanca, C. et. al. (2017). PTEN regulates glioblastoma oncogenesis through chromatin-associated complexes of DAXX and histone H3.3. Nature Communications, 8 (1). doi: http://doi.org/10.1038/ncomms15223
Kang, Y.-J., Balter, B., Csizmadia, E., Haas, B., Sharma, H., Bronson, R., Yan, C. T. (2017). Erratum: Corrigendum: Contribution of classical end-joining to PTEN inactivation in p53-mediated glioblastoma formation and drug-resistant survival. Nature Communications, 8 (1). doi: http://doi.org/10.1038/ncomms15795
Copyright (c) 2019 Oleksandr Glavatskyi, Irina Vasileva, Olena Galanta, Hennadii Khmelnytskyi, Irina Shuba, Konstantin Kardash, Oksana Zemskova
This work is licensed under a Creative Commons Attribution 4.0 International License.
Our journal abides by the Creative Commons CC BY copyright rights and permissions for open access journals.
Authors, who are published in this journal, agree to the following conditions:
1. The authors reserve the right to authorship of the work and pass the first publication right of this work to the journal under the terms of a Creative Commons CC BY, which allows others to freely distribute the published research with the obligatory reference to the authors of the original work and the first publication of the work in this journal.
2. The authors have the right to conclude separate supplement agreements that relate to non-exclusive work distribution in the form in which it has been published by the journal (for example, to upload the work to the online storage of the journal or publish it as part of a monograph), provided that the reference to the first publication of the work in this journal is included.