MOLECULAR MARKERS IN PREDICTING THE OUTCOME OF DIFFUSE GLIOMA GRADE 4 TREATMENT

Authors

  • O. Glavatskyi Romodanov Neurosurgery Institute, National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
  • I. Vasylieva Romodanov Neurosurgery Institute, National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
  • T. Malysheva Romodanov Neurosurgery Institute, National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
  • N. Chopik Romodanov Neurosurgery Institute, National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
  • O. Tsiubko Romodanov Neurosurgery Institute, National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
  • I. Shuba Romodanov Neurosurgery Institute, National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
  • A. Shmelova Romodanov Neurosurgery Institute, National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
  • O. Zemskova Romodanov Neurosurgery Institute, National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
  • L. Yakovenko Romodanov Neurosurgery Institute, National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
  • E. Pedachenko Romodanov Neurosurgery Institute, National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine

DOI:

https://doi.org/10.15407/exp-oncology.2025.02.216

Keywords:

glioblastoma, MGMT, IDH1/2, temozolomide

Abstract

Aim. To assess the expression of MGMT (O6-methylguanine-DNA methyltransferase) gene by MGMT RNA abundance and the presence of IDH1/2 (isocitrate dehydrogenase) variants in glioblastoma (GBM) samples for predicting the efficacy of temozolomide (TMZ) treatment, recurrence risk, and patients’ survival. Materials and Methods. The expression of the MGMT gene and the presence of IDH1/2 variants were assessed by RT-PCR in tumor samples from 39 patients with histologically verified GBM or diffuse astrocytoma, grade 4. The number of MGMT RNA copies was determined by the calibration curves based on the pMA-RQ plasmid with the inserted MGMT gene. Results. The number of MGMT RNA copies in GMB samples varied broadly from 1.7 to 88,270.2 copies per 1000 cells. The patients with a low level of MGMT expression (<1000 copies) in tumors had a more favorable prognosis for the TMZ treatment compared to the patients with a high level of MGMT RNA abundance (>10,000 copies). Among the patients included in the study, a wild type of IDH1/2 was detected in 36 cases, while 3 cases were IDH1 heterozygous. Conclusion. The level of MGMT expression is considered a significant factor for prognosing GMB patients’ survival. Patients with a low level of MGMT expression are considered candidates for efficient therapy with alkylating agents

References

Unless otherwise noted, all statistical figures have been sourced from the Central Brain Tumor Registry of the United States (CBTRUS) in CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2015–2019, www.cbtrus.org. Oct. 2022.

Lee SY. Temozolomide resistance in glioblastoma multiforme. Genes Dis. 2016;3(3):198-210. https://doi.org/10.1016/ j.gendis.2016.04.007

White K, Connor K, Clerkin J, et al. New hints towards a precision medicine strategy for IDH wild-type glioblas- toma. Ann Oncol. 2020;31(12):1679-1692. https://doi.org/10.1016/j.annonc.2020.08.2336

Louis DN, Perry A, Reifenberger G. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803-820. https://doi.org/10.1007/s00401-016-1545-1

Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231-1251. https://doi.org/10.1093/neuonc/noab106

Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma.

N Engl J Med. 2005;352(10):997-1003. https://doi.org/10.1056/NEJMoa043331

Katsigiannis S, Grau S, Krischek B, et al. MGMT-positive vs MGMT-negative patients with glioblastoma: identifica- tion of prognostic factors and resection threshold. Neurosurgery. 2021;88(4):E323-E329. https://doi.org/10.1093/ neuros/nyaa562

Lazarević M, Jovanović N, Cvetković VJ, et al. A comparison of MGMT testing by MSP and qMSP in paired snap- frozen and formalin-fixed paraffin-embedded gliomas. Diagnostics (Basel). 2023;13(3):360. https://doi.org/10.3390/ diagnostics13030360

Tierling S, Jürgens-Wemheuer WM, Leismann A, et al. Bisulfite profiling of the MGMT promoter and comparison with routine testing in glioblastoma diagnostics. Clin Epigenetics. 2022;14(1):26. https://doi.org/10.1186/s13148-022-01244-4

Gibson D, Ravi A, Rodriguez E, et al. Quantitative analysis of MGMT promoter methylation in glioblastoma sug- gests nonlinear prognostic effect. Neurooncol Adv. 2023;5(1):vdad115. https://doi.org/10.1093/noajnl/vdad115

Leske H, Camenisch Gross U, Hofer S, et al. MGMT methylation pattern of long-term and short-term survivors of glioblastoma reveals CpGs of the enhancer region to be of high prognostic value. Acta Neuropathol Commun. 2023;11(1):139. https://doi.org/10.1186/s40478-023-01622-w

Gibson D, Vo AH, Lambing H, et al. A systematic review of high impact CpG sites and regions for MGMT methyla- tion in glioblastoma [A systematic review of MGMT methylation in GBM]. BMC Neurol. 2024;24(1):103. https:// doi.org/10.1186/s12883-024-03605-3

Liang BB, Wang YH, Huang JJ, et al. Genome-wide DNA methylation analysis identifies potent CpG signature for temzolomide response in non-G-CIMP glioblastomas with unmethylated MGMT promoter: MGMT-dependent roles of GPR81. CNS Neurosci Ther. 2024;30(4):e14465. https://doi.org/10.1111/cns.14465

McCornack C, Woodiwiss T, Hardi A, et al. The function of histone methylation and acetylation regulators in GBM pathophysiology. Front Oncol. 2023;13:1144184. https://doi.org/10.3389/fonc.2023.1144184

Mladek AC, Yan H, Tian S, et al. RBBP4-p300 axis modulates expression of genes essential for cell survival and is a po- tential target for therapy in glioblastoma. Neuro Oncol. 2022;24(8):1261-1272. https://doi.org/10.1093/neuonc/noac051

Gonzalez-Aponte MF, Damato AR, Trebucq LL, et al. Circadian regulation of MGMT expression and promot- er methylation underlies daily rhythms in TMZ sensitivity in glioblastoma. J Neurooncol. 2024;166(3):419-430. https://doi.org/10.1007/s11060-023-04535-9

Garrett M, Fujii Y, Osaka N, et al. Emerging roles of wild-type and mutant IDH1 in growth, metabolism and thera- peutics of glioma. In: Debinski W, editor. Gliomas [Internet]. Brisbane (AU): Exon Publications; 2021, Chapter 4. Available from: https://www.ncbi.nlm.nih.gov/books/NBK570701/

Li H, Li J, Cheng G, et al. IDH mutation and MGMT promoter methylation are associated with the pseudopro- gression and improved prognosis of glioblastoma multiforme patients who have undergone concurrent and adju- vant temozolomide-based chemoradiotherapy. Clin Neurol Neurosurg. 2016;151:31-36. https://doi.org/10.1016/j. clineuro.2016.10.004

Kurdi M, Shafique Butt N, Baeesa S, et al. The impact of IDH1 mutation and MGMT promoter methylation on recurrence-free interval in glioblastoma patients treated with radiotherapy and chemotherapeutic agents. Pathol Oncol Res. 2021;27:1609778. https://doi.org/10.3389/pore.2021.1609778

Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Trans- plant. 2013;48(3):452-458. https://doi.org/10.1038/bmt.2012.244

Perazzoli G, Prados J, Ortiz R, et al. Temozolomide resistance in glioblastoma cell lines: implication of MGMT, MMR, P-glycoprotein and CD133 expression. PLoS One. 2015;10(10):e0140131. https://doi.org/10.1371/journal.pone.0140131

Kitange GJ, Carlson BL, Schroeder MA, et al. Induction of MGMT expression is associated with temozolomide re- sistance in glioblastoma xenografts. Neuro Oncol. 2009;11(3):281-291. https://doi.org/10.1215/15228517-2008-090

Li Q, Ren B, Gui Q, et al. Blocking MAPK/ERK pathway sensitizes hepatocellular carcinoma cells to temozolomide via downregulating MGMT expression. Ann Transl Med. 2020;8(20):1305. https://doi.org/10.21037/atm-20-5478

Millward CP, Brodbelt AR, Haylock B, et al. The impact of MGMT methylation and IDH-1 mutation on long- term outcome for glioblastoma treated with chemoradiotherapy. Acta Neurochir (Wien). 2016;158(10):1943-1953. https://doi.org/10.1007/s00701-016-2928-8

Pandith AA, Qasim I, Baba SM, et al. Favorable role of IDH1/2 mutations aided with MGMT promoter gene methyl- ation in the outcome of patients with malignant glioma. Future Sci OA. 2020;7(3):FSO663. https://doi.org/10.2144/ fsoa-2020-0057

Alzial G, Renoult O, Paris F, et al. Wild-type isocitrate dehydrogenase under the spotlight in glioblastoma. Onco- gene. 2022;41:613-621. https://doi.org/10.1038/s41388-021-02056-1

Hartmann C, Meyer J, Balss J, et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol. 2009;118(4):469-474. https://doi.org/10.1007/s00401-009-0561-9

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. https://doi.org/10.1158/1078-0432.CCR-09-0715

Yang P, Zhang W, Wang Y, et al. IDH mutation and MGMT promoter methylation in glioblastoma: results of a pro- spective registry. Oncotarget. 2015;6(38):40896-40906. https://doi.org/10.18632/oncotarget.5683.

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Published

07.10.2025

How to Cite

Glavatskyi, O., Vasylieva, I., Malysheva, T., Chopik, N., Tsiubko, O., Shuba, I., … Pedachenko, E. (2025). MOLECULAR MARKERS IN PREDICTING THE OUTCOME OF DIFFUSE GLIOMA GRADE 4 TREATMENT. Experimental Oncology, 47(2), 216–222. https://doi.org/10.15407/exp-oncology.2025.02.216

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