How to Cite
Abstract
The article is devoted to the issue of molecular genetic diagnosis of cerebral glioblastomas. Despite significant advances in neurooncology, little progress has been made in prolonging the life of patients with cerebral glioblastoma, and a significant part of the effectiveness of treatment depends on the recognition of two prognostic biomarkers: mutations of the isocitrate dehydrogenase (IDH) promoter and the methylation of the O6-methylguanine methyl transferase (MGMT) promoter. The article summarizes the data of world and domestic clinical studies, allowing to supplement the histological characteristics of primary glioblastomas with genetic markers: the presence of the TERT mutation, EFGR amplification, loss of PTEN function, LOH 10q, and the presence of the BRAF mutation.
It should be noted that the amplification of EGFR, causing resistance to apoptotic stimuli and alkylating chemotherapy with Temozolomide, attracts much attention as a therapeutic target. The frequency of occurrence of the TERT mutation is 90% of all tumors of various genesis, most often the TERT mutation is found in oligodendroglioma or primary glioblastoma. Loss of heterozygosity in the region of localization of the PTEN gene is observed in many types of sporadic tumors, including more than 40% of glioblastomas. Mutations in this gene are found in tumors of the brain, endometrium, prostate, kidney, and mammary gland. The presence of a PTEN mutation is a poor prognostic factor.
LOH 22q is much more common in secondary glioblastomas (82%) than in primary glioblastomas (41%).
Among brain tumors, the BRAF mutation is most common with pleomorphic xanastrocytoma (60-70%).The BRAF V600E mutation was found in epithelioid glioblastoma, which is a rare and aggressive type of glioblastoma, characterized by an unfavorable prognosis (about 6 months) and frequent leptomeningeal spread.
Thus, knowledge of the molecular mechanisms of carcinogenesis will enable a personalized approach to treatment with glioblastomas of the brain.
References
Ostrom Q.T., Gittleman H., Truitt G. et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011–2015. Neuro-Oncology. 2018; 20(4):1–86. https://doi.org/10.1093/neuonc/noy131.
Каприн А.Д. Злокачественные новообразования в России в 2017 году (заболеваемость и смертность) / А.Д. Каприн, В.В. Старинский, Г.В. Петрова. – М.: МНИОИ им. П.А. Герцена - филиал ФГБУ «ФМИЦ им. П.А. Герцена» Минздрава России, 2018 [Kaprin A.D. Malignant neoplasms in Russia in 2017 (morbidity and mortality) / A.D. Kaprin, V.V. Starinskiy, G.V. Petrova. - M.: Moscow National Research Oncology Institute named after P.A. Herzen – branch FGBU "NMITS radiology" of the Ministry of Health of Russia, 2018 (In Russ.)].
Смолин А.В., Бекяшев А.Х., Кобяков Г.Л. и др. Первые результаты Российского многоцентрового исследования по эпидемиологии злокачественных глиом. Современная онкология. 2014;2:50-55 [Smolin A.V., Bekiashev A.K., Kobyakov G.L. et al. First results of the Russian multicenter epidemiology project on the malignant gliomas. Modern oncology. 2014;2:50-55 (In Russ.)].
Лобанова Н.В., Шишкина Л.В., Рыжова М.В. и др. Клинические, иммуногистохимические и молекулярно-генетические факторы прогноза у больных с глиобластомой. Архив патологии. 2016;4:10-19. https://doi.org/10.17116/patol201678410-19 [Lobanova N.V., Shishkina L.V., Ryzhova M.V. et al. Clinical, immunohistochemical, and molecular genetic prognostic factors in adult patients with glioblastoma. Archive of Pathology. 2016;4:10-19. https://doi.org/10.17116/patol201678410-19 (In Russ.)].
Карташев А.В., Якубович Е.И. Генетические маркеры злокачественных глиом. Вестник Северо-Западного государственного медицинского университета им И.И. Мечникова. 2016;8(3):107-114 [Kartashev A.V., Yakubovich E.I. Genetic markers of malignant gliomas. Herald of North-Western state Medical University named after I.I. Mechnikov. 2016;8(3);107-114 (In Russ.)].
Verena Staedtke, Omar Dildar a Dzaye, Matthias Holdhoff. Actionable molecular biomarkers in primary brain tumors. Trends Cancer. 2016; 2(7): 338–349. https://doi.org/10.1016/j.trecan.2016.06.003.
Chunzhi Zhang, Lynette M. Moore, Xia Li et al. IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma.Neuro-Oncology.2013;15(9):1114-1126. https://doi.org/10.1093/neuonc/not087.
Sasha L.V., Erik Teugels, Jan Sadones et al. Correlation between IDH1 Gene Mutation Status and Survival of Patients Treated for Recurrent Glioma. Anticancer Research. 2011;31:4457-4464.
Табаков Д.В., Катаргин А.Н., Строганова А.М. и др. Мутации изоцитратдегидрогеназ 1 и 2 и метилирование гена MGMT в глиомах. Успехи молекулярной онкологии. 2017;4: 53-59. https://doi.org/10.17650/2313-805X-2017-4-1-53-59 [Tabakov D.V., Katargin A.N., Stroganova A.M. et al. Isocitrate dehydrogenase 1 and 2 genes mutations and MGMT methylation in gliomas. Advances in molecular oncology. 2017;4(1):53-59. https://doi.org/10.17650/2313-805X-2017-4-1-53-59 (In Russ.)].
Ricky Chen, Matthew Smith-Cohn, Adam L. Cohen et al. Glioma Subclassifications and Their Clinical Significance. Neurotherapeutics. 2017;14:284–297. https://doi.org/10.1007/s13311-017-0519-x.
Dr Roger Stupp, Monika E Hegi, Warren P Mason et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. The Lancet. 2009;10(5):459-466. https://doi.org/10.1016/S1470-2045(09)70025-7.
Когония Л.М., Маркарова Е.В., Сташук Г.А. и др. Клинический опыт эффективного использования паллиативной таргетной терапии у пациентки с EGFR-отрицательной аденокарциномой легкого. Медицинсий совет. 2019;10:142-145. https://doi.org/10.21518/2079-701X-2019-10-142-145 [Kogonia L.M., Markarova E.V., Stashuk G.A. et al. Clinical experience of effective use of palliative targeted therapy in a patient with EGFR-negative lung adenocarcinoma. Medical Council. 2019;10:142-145. https://doi.org/10.21518/2079-701X-2019-10-142-145 (In Russ.)].
Gomez G.G., Wykosky J, Furnari F.B., Cavenee W.K. Therapeutic resistance in cancer: microRNA regulation of EGFR signaling networks. Cancer Biol Med. 2013;10(4):192-205. https://doi.org/10.7497%2Fj.issn.2095-3941.2013.04.003.
Chen J.R., Xu H.Z., Yao Y., Qin Z.Y. Prognostic value of epidermal growth factor receptor amplification and EGFRvIII in glioblastoma: meta-analysis. Acta Neurol Scand. 2015;132(5):310-22. https://doi.org/10.1111/ane.12401.
Тюляндин С.А., Носов Д.А. Ингибиторы тирозинкиназы рецептора эпидермального фактора роста у больных немелкоклеточным раком легкого: 10 лет спустя. Злокачественные опухоли. 2012;1(2):5-13. https://doi.org/10.18027/2224-5057-2012-2-5-13 [Tjulandin S., Nosov D. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Non-Small Cell Lung Cancer: Ten years later. Malignant Tumours. 2011;1:41-48. https://doi.org/10.18027/2224-5057-2012-2-5-13 (In Russ.)].
Manfred Westphal, Cecile L. Maire, Katrin Lamszus. EGFR as a Target for Glioblastoma Treatment: An Unfulfilled Promise. CNS Drugs. 2017;31(9):723-735. https://doi.org/10.1007/s40263-017-0456-6.
Зверева М., Рубцова М. Нобелевская премия по физиологии и медицине 2009 года. Счётчик клеточного времени. Наука и жизнь. 2010;1:2-5 [Zvereva M., Rubtsova M. Nobel Prize in Physiology or Medicine in 2009. Cell Time Counter. Science and life. 2010; 1:2-5 (In Russ.)].
Yang Yuana, Chen Qib, Gou Malingd et al. TERT mutation in glioma: Frequency, prognosis and risk. Journal of Clinical neuroscience. 2016;26:57-62.https://doi.org/10.1016/j.jocn.2015.05.066.
Jeanette E. Eckel-Passow, Daniel H. Lachance, Annette M. Molinaro et al. Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. N Engl J Med. 2015;372(26):2499-2508. https://dx.doi.org/10.1056%2FNEJMoa1407279.
A. Juratli, Rachel Thowe, Silke Hennig et al. TERT Promoter Mutation Detection in Cell-Free Tumor-Derived DNA in Patients with IDH Wild-Type Glioblastomas: A Pilot Prospective Study. Clin Cancer Res. 2018 1;24(21):5282-5291. https://doi.org/10.1158/1078-0432.CCR-17-3717.
Mirinae Seo, Nariya Cho, Hye Shin Ahn, Hyeong-Gon Moon. Cowden Syndrome Presenting as Breast Cancer: Imaging and Clinical Features. Korean Journal of Radiology. 2014;15(5):586. http://dx.doi.org/10.3348/kjr.2014.15.5.586.
Berrin Tunca, Ahmet Bekar, Gulsah Cecener et al. Impact of novel PTEN mutations in Turkish patients with glioblastoma multiforme.J Neurooncol. 2007;82:263–269. https://doi.org/10.1007/s11060-006-9293-z.
Yang J.M., Schiapparelli P., Nguyen H.N. et al. Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization. Oncogene. 2017;36(26):3673-3685. https://doi.org/10.1038/onc.2016.493.
Han F., Hu R., Yang H. et al. PTEN gene mutations correlate to poor prognosis in glioma patients: a meta-analysis. Onco Targets Ther. 2016;9:3485-92. https://doi.org/10.2147/OTT.
Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2(1):a001008. https://doi.org/10.1101/cshperspect.a001008.
Любченко Л.Н., Семьянихина А.В., Фу Р.Г. и др. Синдром Ли—Фраумени: тр53-ассоциированные первично-множественные злокачественные опухоли. Вестник РОНЦ им. Н. Н. Блохина РАМН. 2012;23(2):52-58 [Lyubchenko L.N., Semyanykhina A.V., Fu R.G. et al. Lee — Fraumeni Syndrome: TP53-associated primary multiple malignant tumors. Blokhin Russian Cancer Reseach. 2012;23(2):52-58 (In Russ.)].
Kakkar A, Suri V, Jha P et al. Loss of heterozygosity on chromosome 10q in glioblastomas, and its association with their genetic alterations and survival in Indian patients. Neurology India. 2011;59(2):254-61. https://doi.org/10.4103/0028-3886.79139.
Sebastian Brandner, Zane Jaunmuktane. Neurological update: gliomas and other primary brain tumours in adults. Journal of Neurology. 2018;265(3):717–727. https://doi.org/10.1007/s00415-017-8652-3.
Насхлеташвили Д.Р. BRAF как мишень для таргетной терапии первичных опухолей ЦНС. Материалы IV Петербургского международного онкологического форума «Белые ночи 2018». 2018:291 [Naskhletashvili D.R. BRAF as a target for targeted therapy of primary CNS tumors. Materials of the IV St. Petersburg International Cancer Forum «White Nights 2018». 2018:291 (In Russ.)].
Kazutaka Sugimoto, Makoto Ideguchi, Tokuhiro Kimura et al. Epithelioid/rhabdoid glioblastoma: a highly aggressive subtype of glioblastoma. Brain Tumor Pathology.2016; 33(2):137–146. https://doi.org/10.1007/s10014-015-0243-3.
Yu Kanemaru, Manabu Natsumeda, Masayasu Okada et al. Dramatic response of BRA F V600E-mutant epithelioid glioblastoma to combination therapy with BRAF and MEK inhibitor: establishment and xenograft of a cell line to predict clinical efficacy. Kanemaru et al. Acta Neuropathologica Communications.2019;7:119. https://doi.org/10.1186/s40478-019-0774-7.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
© АННМО «Вопросы онкологии», Copyright (c) 2021