oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2019-18-3-34-44oncotomsk-1094Research ArticleЛАБОРАТОРНЫЕ И ЭКСПЕРИМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯLABORATORY AND EXPERIMENTAL STUDIESМОРФОЛОГИЧЕСКИЕ И МОЛЕКУЛЯРНО-ГЕНЕТИЧЕСКИЕ ОСОБЕННОСТИ ПЕРВИЧНЫХ ГЛИОБЛАСТОМ У ПАЦИЕНТОВ С НЕОБЫЧНО ВЫСОКОЙ ПРОДОЛЖИТЕЛЬНОСТЬЮ ЖИЗНИMORPHOLOGIC AND MOLECULAR FEATURES OF PRIMARY GLIOBLASTOMA IN PATIENTS SURVIVING MORE THAN 3 YEARShttps://orcid.org/0000-0003-1564-0943МацкоМ. В.MatskoM. V.

Мацко Марина Витальевна, кандидат медицинский наук, старший научный сотрудник сектора клинической морфологии, врачонколог, «РНХИ им. проф. А.Л. Поленова» – филиал ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России

г. Санкт-Петербург, 191014, ул. Маяковского, 12, 

г. Санкт-Петербург, 197758, пос. Песочный, ул. Ленинградская, 68а, 

г. Санкт-Петербург, 199034, Университетская набережная, 7/9, 

г. Санкт-Петербург, 195271, просп. Кондратьевский, 72а

SPIN-код: 2014-2268.

AuthorID (РИНЦ): 918790

ResearcherID (WOS): W-9626-2018

Marina V. Matsko, MD, PhD, Senior Researcher, physician-oncologist, Polenov Russian Neurosurgical Institute – the branch of Almazov NMRC

12, Mayakovsky Street, 191014-St. Petersburg, 

68a, Leningradskaya Street, 197758-St. Petersburg, 

7/9, Universitetskaya Naberezhnaya, 199034-St. Petersburg, 

72a, Kondratyevsky Ave, 195271-St. Petersburg

Researcher ID (WOS): W-9626-2018

marinamatsko@mail.ruМацкоД. Е.MatskoD. E.

Мацко Дмитрий Евгеньевич, доктор медицинских наук, профессор, «РНХИ им. проф. А.Л. Поленова» – филиал ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России

г. Санкт-Петербург, 191014, ул. Маяковского, 12, 

г. Санкт-Петербург, 197758, пос. Песочный, ул. Ленинградская, 68а, 

г. Санкт-Петербург, 199034, Университетская набережная, 7/9, 

г. Санкт-Петербург, 195271, просп. Кондратьевский, 72а

Dmitry E. Matsko, MD, Professor, Polenov Russian Neurosurgical Institute – the branch of Almazov NMRC

12, Mayakovsky Street, 191014-St. Petersburg, 

68a, Leningradskaya Street, 197758-St. Petersburg, 

7/9, Universitetskaya Naberezhnaya, 199034-St. Petersburg, 

72a, Kondratyevsky Ave, 195271-St. Petersburg

ВолковН. М.VolkovN. M.

Волков Никита Михайлович, кандидат медицинских наук, начальник отдела организации клинических исследований, ГБУЗ «Санкт-Петербургский клинический научно-практический центр специализированных видов медицинской помощи (онкологический)»

г. Санкт-Петербург, 197758, пос. Песочный, ул. Ленинградская, 68а, 

г. Санкт-Петербург, 195271, просп. Кондратьевский, 72а

SPIN-код: 1605-0256.

AuthorID (РИНЦ): 883973

Nikita M. Volkov, MD, PhD, Head of the Department of Clinical Trials, Clinical Scientific-Practical Center of Oncology

68a, Leningradskaya Street, 197758-St. Petersburg, 

72a, Kondratyevsky Ave, 195271-St. Petersburg

https://orcid.org/0000-0002-8343-4917УлитинА. Ю.UlitinA. Yu.

Улитин Алексей Юрьевич, доктор медицинских наук, врач-нейрохирург, «РНХИ им. проф. А.Л. Поленова» – филиал ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России

г. Санкт-Петербург, 191014, ул. Маяковского, 12, 

г. Санкт-Петербург, 195067, пр. Пискарёвский, 47

Alexey Yu. Ulitin, MD, Professor, physician-neurosurgeon, Polenov Russian Neurosurgical Institute – the branch of Almazov NMRC

12, Mayakovsky Street, 191014-St. Petersburg, 

47, Piskarevsky Ave., 195067-St. Petersburg

https://orcid.org/0000-0003-4807-7915МоисеенкоВ. М.MoiseenkoV. M.

Моисеенко Владимир Михайлович, доктор медицинских наук, профессор, ГБУЗ «Санкт-Петербургский клинический научнопрактический центр специализированных видов медицинской помощи (онкологический)»

г. Санкт-Петербург, 197758, пос. Песочный, ул. Ленинградская, 68а, 

г. Санкт-Петербург, 195271, просп. Кондратьевский, 72а

SPIN-код: 8184-2980.

Author ID: 602994

Vladimir M. Moiseenko, MD, Professor, Clinical Scientific-Practical Center of Oncology

68a, Leningradskaya Street, 197758-St. Petersburg, 

72a, Kondratyevsky Ave, 195271-St. Petersburg

https://orcid.org/0000-0003-4529-7891ИмянитовЕ. Н.ImyanitovE. N.

Имянитов Евгений Наумович, доктор медицинских наук, профессор, член-корр. РАН, руководитель научного отдела биологии опухолевого роста, Санкт-Петербургский государственный университет

г. Санкт-Петербург, 199034, Университетская набережная, 7/9, 

г. Санкт-Петербург, 197758, пос. Песочный, ул. Ленинградская, 68, 

г. Санкт-Петербург, 195067, пр. Пискарёвский, 47, 

г. Санкт-Петербург, 194100, ул. Александра Матросова, 22

SPIN-код: 1909-7323.

AuthorID (Scopus): 7003644486

Evgeny N. Imyanitov, MD, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Department of Tumor Growth Biology, Saint-Petersburg State University

7/9, Universitetskaya Naberezhnaya, 199034-St. Petersburg, 

68a, Leningradskaya Street, 197758-St. Petersburg, 

47, Piskarevsky Ave., 195067-St. Petersburg, 

22, Alexandra Matrosova Street, 194100-St. Petersburg

Author ID (Scopus): 7003644486

https://orcid.org/0000-0001-5454-5186ИевлеваА. Г.IyevlevaA. G.

Иевлева Аглая Геннадиевна, кандидат медицинский наук, старший научный сотрудник отдела биологии опухолевого роста, ФГБУ «НМИЦ онкологии им. Н.Н. Петрова» Минздрава России

г. Санкт-Петербург, 197758, пос. Песочный, ул. Ленинградская, 68, 

г. Санкт-Петербург, 194100, ул. Александра Матросова, 22

Researcher ID (WOS): P-83052016.

Author ID (Scopus): 6506417697

Aglaya G. Ievleva, MD, PhD, Senior Researcher of the Department of Tumor Growth Biology, N.N. Petrov NMRC of Oncology

68a, Leningradskaya Street, 197758-St. Petersburg, 

22, Alexandra Matrosova Street, 194100-St. Petersburg

Researcher ID (WOS): P-8305-2016.

Author ID (Scopus): 6506417697

«РНХИ им. проф. А.Л. Поленова» – филиал ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России; ГБУЗ «Санкт-Петербургский клинический научно-практический центр специализированных видов медицинской помощи (онкологический)»; Санкт-Петербургский государственный университет; ЧОУ ВПО «Санкт-Петербургский медико-социальный институт»РоссияPolenov Russian Neurosurgical Institute – the branch of Almazov NMRC; Clinical Scientific-Practical Center of Oncology; Saint-Petersburg State University; Saint-Petersburg Medico-Social InstituteRussian FederationГБУЗ «Санкт-Петербургский клинический научно-практический центр специализированных видов медицинской помощи (онкологический)»; ЧОУ ВПО «Санкт-Петербургский медико-социальный институт»РоссияClinical Scientific-Practical Center of Oncology; Saint-Petersburg Medico-Social InstituteRussian Federation«РНХИ им. проф. А.Л. Поленова» – филиал ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России; ГБОУ ВПО «Северо-Западный государственный медицинский университет им. И.И. Мечникова» Минздрава РоссииРоссияPolenov Russian Neurosurgical Institute – the branch of Almazov NMRC; I.I. Mechnikov North-Western Medical UniversityRussian FederationСанкт-Петербургский государственный университет; ФГБУ «НМИЦ онкологии им. Н.Н. Петрова» Минздрава России; ГБОУ ВПО «Северо-Западный государственный медицинский университет им. И.И. Мечникова» Минздрава России; ФГБОУ ВО «Санкт-Петербургский государственный педиатрический медицинский университет» Минздрава РоссииРоссияSaint-Petersburg State University; N.N. Petrov NMRC of Oncology; I.I. Mechnikov North-Western Medical University; Saint-Petersburg State Pediatric Medical UniversityRussian FederationФГБУ «НМИЦ онкологии им. Н.Н. Петрова» Минздрава России; ФГБОУ ВО «Санкт-Петербургский государственный педиатрический медицинский университет» Минздрава РоссииРоссияN.N. Petrov NMRC of Oncology; Saint-Petersburg State Pediatric Medical UniversityRussian Federation2019300620191833444Copyright © Мацко М.В., Мацко Д.Е., Волков Н.М., Улитин А.Ю., Моисеенко В.М., Имянитов Е.Н., Иевлева А.Г., 20192019Мацко М.В., Мацко Д.Е., Волков Н.М., Улитин А.Ю., Моисеенко В.М., Имянитов Е.Н., Иевлева А.Г.Matsko M.V., Matsko D.E., Volkov N.M., Ulitin A.Y., Moiseenko V.M., Imyanitov E.N., Iyevleva A.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/1094

Первичная глиобластома (ГБ) – опухоль ЦНС, которая характеризуется быстрым течением и агрессивным поведением. Длительная продолжительность жизни пациентов с первичной ГБ является редким феноменом. По данным большинства исследователей, под «долгоживущими» пациентами с ГБ подразумеваются больные с продолжительностью жизни 3 года и более. В литературе указываются различные факторы, которые могут способствовать такой выживаемости. Цель исследования – проведение сравнительной оценки демографических, клинических, морфологических, иммуногистохимических и молекулярных особенностей первичной ГБ у пациентов с различной выживаемостью.

Материал и методы

Материал и методы. Авторами выполнено проспективное исследование 69 пациентов с первичной ГБ, наблюдавшихся в РНХИ им. проф. А.Л. Поленова с 2009 г. В рамках данной работы оценивались клинические характеристики больных, а также был выполнен анализ ряда морфологических (Ki67, P53, INA , EGFR) и молекулярногенетических параметров (экспрессия РНК генов MGMT, VEGF, PDGFRA; мутации в генах ID H1/2; ко-делеция 1p/19q).

Результаты

Результаты. Продолжительность жизни более трёх лет наблюдалась у 11 (15,9 %) пациентов. В качестве позитивных прогностических факторов выступали молодой возраст больного (p=0,002), использование интенсивной терапии темозоломидом (6 и более курсов) в первой линии (p=0,016), проведение второй линии терапии (р=0,017), а также низкий уровень экспрессии гена MGMT в опухолевой ткани (p=0,038). Другие изучаемые показатели, такие как пол больных, уровень экспрессии генов VEGF и PDGFRA, наличие мутации в гене ID H1, сочетанная делеция 1p/19q, а также иммуногистохимические маркеры Ki67, p53, INA , EGFR не были ассоциированы с выживаемостью свыше 3 лет (p>0,05).

Заключение

Заключение. Таким образом, относительно благоприятное течение первичной ГБ ассоциировано с определёнными клиническими и биологическими особенностями данного заболевания. Высокий уровень 3-летнейвыживаемости больных с первичной ГБ в нашем исследовании объясняется в первую очередь индивидуальным подходом к лечению и интенсивной химиотерапевтической тактикой (от 6 до 15 циклов ХТ темозоломидом в первой линии и проведение второй линии терапии) в отличие от стандартных, ограниченных по длительности терапии, протоколов лечения.

Primary glioblastoma (GB) is a rapidly progressing central nervous system tumor with aggressive biological behavior. Long-term glioblastoma survival, defined as survival beyond 3 years, is a rare phenomenon. Various factors contributing to such prolonged lifespan have been proposed.

Aim

Aim. This study aimed to compare demographic, clinical, morphologic, immunohistochemical and molecular features of primary GB in patients with different survival.

Material andMethods

Material andMethods. This prospective study included 69 patients, who were treated at A.L. Polenov Neurosurgery institute. The analysis considered clinical, morphologic, immunohistochemical (Ki67, P53, INA , EGFR) and genetic (MGMT, VEGF and PDGFRA gene expression; ID H1/2 mutational status, 1p/19q co-deletion) characteristics of the disease.

Results

Results. 11 (15.9 %) patients survived beyond 3 years. Prolonged survival was associated with younger patient age (p=0.002), use of more than 6 cycles of temozolomide in the 1st line therapy (p=0.016), use of the 2nd line therapy (p=0.017) and low level of MGMT expression in the tumor tissue (p=0.038). Other factors including patients’ gender, VEGF and PDGFRA mRNA expression levels, ID H1 mutation, 1p/19q deletion, and the immunohistochemical markers Ki67, p53, INA , EGFR, were not associated with prolonged survival (p>0.05).

Conclusion

Conclusion. Prolonged survival in GB patients is a non-random event and can be explained by several clinical and biological factors. A high percentage of 3-year survival of GB patients in our study may be explained by an individual approach to treatment and intensive chemotherapeutic tactics (from 6 to 15 cycles of temozolomide in the 1st line therapy and use of the 2nd line therapy), as opposed to standard short treatment protocols.

глиобластомапродолжительность жизни при глиобластомепрогностические факторы при глиобластомеIDH1/2MGMTVEGFPDGFRAglioblastomasurvivalprognostic factorsIDH1/2MGMTVEGFPDGFRAReferencesBurton E.C., Lamborn K.R., Forsyth P., Scott J., O’Campo J., Uyehara-Lock J., Prados M., Berger M., Passe S., Uhm J., O’Neill B.P., Jenkins R.B., Aldape K.D. Aberrant p53, mdm2, and proliferation differ in glioblastomas from long-term compared with typical survivors. Clin Cancer Res. 2002 Jan; 8(1): 180–7.Burton E.C., Lamborn K.R., Forsyth P., Scott J., O’Campo J., Uyehara-Lock J., Prados M., Berger M., Passe S., Uhm J., O’Neill B.P., Jenkins R.B., Aldape K.D. Aberrant p53, mdm2, and proliferation differ in glioblastomas from long-term compared with typical survivors. Clin Cancer Res. 2002 Jan; 8(1): 180–7.Scoccianti S., Magrini S.M., Ricardi U., Detti B., Buglione M., Sotti G., Krengli M., Maluta S., Parisi S., Bertoni F., Mantovani C., Tombolini V., De Renzis C., Lioce M., Fatigante L., Fusco V., Muto P., Berti F., Rubino G., Cipressi S., Fariselli L., Lupattelli M., Santoni R., Pirtoli L., Biti G. Patterns of care and survival in a retrospective analysis of 1059 patients with glioblastoma multiforme treated between 2002 and 2007: a multicenter study by the Central Nervous System Study Group of Airo (Italian Association of Radiation Oncology). Neurosurgery. 2010 Aug; 67(2): 446–58. doi: 10.1227/01.NEU.0000371990.86656.E8.Scoccianti S., Magrini S.M., Ricardi U., Detti B., Buglione M., Sotti G., Krengli M., Maluta S., Parisi S., Bertoni F., Mantovani C., Tombolini V., De Renzis C., Lioce M., Fatigante L., Fusco V., Muto P., Berti F., Rubino G., Cipressi S., Fariselli L., Lupattelli M., Santoni R., Pirtoli L., Biti G. Patterns of care and survival in a retrospective analysis of 1059 patients with glioblastoma multiforme treated between 2002 and 2007: a multicenter study by the Central Nervous System Study Group of Airo (Italian Association of Radiation Oncology). Neurosurgery. 2010 Aug; 67(2): 446–58. doi: 10.1227/01.NEU.0000371990.86656.E8.Johnson D.R., Leeper H.E., Uhm J.H. Glioblastoma survival in the United States improved after Food and Drug Administration approval of bevacizumab: a population-based analysis. Cancer. 2013 Oct 1; 119(19): 3489–95. doi: 10.1002/cncr.28259.Johnson D.R., Leeper H.E., Uhm J.H. Glioblastoma survival in the United States improved after Food and Drug Administration approval of bevacizumab: a population-based analysis. Cancer. 2013 Oct 1; 119(19): 3489–95. doi: 10.1002/cncr.28259.Gilbert M.R., Dignam J.J., Armstrong T.S., Wefel J.S., Blumenthal D.T., Vogelbaum M.A., Colman H., Chakravarti A., Pugh S., Won M., Jeraj R., Brown P.D., Jaeckle K.A., Schiff D., Stieber V.W., Brachman D.G., WernerWasik M., Tremont-Lukats I.W., Sulman E.P., Aldape K.D., Curran W.J., Mehta M.P. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20; 370(8): 699–708. doi:10.1056/NEJMoa1308573.Gilbert M.R., Dignam J.J., Armstrong T.S., Wefel J.S., Blumenthal D.T., Vogelbaum M.A., Colman H., Chakravarti A., Pugh S., Won M., Jeraj R., Brown P.D., Jaeckle K.A., Schiff D., Stieber V.W., Brachman D.G., WernerWasik M., Tremont-Lukats I.W., Sulman E.P., Aldape K.D., Curran W.J., Mehta M.P. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20; 370(8): 699–708. doi:10.1056/NEJMoa1308573.Gerber N.K., Goenka A., Turcan S., Reyngold M., Makarov V., Kannan K., Beal K., Omuro A., Yamada Y., Gutin P., Brennan C.W., Huse J.T., Chan T.A. Transcriptional diversity of long-term glioblastoma survivors. Neuro Oncol. 2014 Sep; 16(9): 1186–95. doi:10.1093/neuonc/nou043.Gerber N.K., Goenka A., Turcan S., Reyngold M., Makarov V., Kannan K., Beal K., Omuro A., Yamada Y., Gutin P., Brennan C.W., Huse J.T., Chan T.A. Transcriptional diversity of long-term glioblastoma survivors. Neuro Oncol. 2014 Sep; 16(9): 1186–95. doi:10.1093/neuonc/nou043.Johnson D.R., Ma D.J., Buckner J.C., Hammack J.E. Conditional probability of long-term survival in glioblastoma: a population-based analysis. Cancer. 2012 Nov 15; 118(22): 5608–13. doi:10.1002/cncr.27590.Johnson D.R., Ma D.J., Buckner J.C., Hammack J.E. Conditional probability of long-term survival in glioblastoma: a population-based analysis. Cancer. 2012 Nov 15; 118(22): 5608–13. doi:10.1002/cncr.27590.Feng Y., Wang Z., Bao Z., Yan W., You G., Wang Y., Hu H., Zhang W., Zhang Q., Jiang T. SOCS3 Promoter Hypermethylation Is a Favorable Prognosticator and a Novel Indicator for G-CIMPPositive GBM Patients. PLoS One. 2014 Mar 14; 9(3): e91829. doi:10.1371/journal.pone.0091829.Feng Y., Wang Z., Bao Z., Yan W., You G., Wang Y., Hu H., Zhang W., Zhang Q., Jiang T. SOCS3 Promoter Hypermethylation Is a Favorable Prognosticator and a Novel Indicator for G-CIMPPositive GBM Patients. PLoS One. 2014 Mar 14; 9(3): e91829. doi:10.1371/journal.pone.0091829.Mazaris P., Hong X., Altshuler D., Schultz L., Poisson L.M., Jain R., Mikkelsen T., Rosenblum M., Kalkanis S. Key determinants of short-term and long-term glioblastoma survival: a 14-year retrospective study of patients from the Hermelin Brain Tumor Center at Henry Ford Hospital. Clin Neurol Neurosurg. 2014 May; 120: 103–12. doi: 10.1016/j.clineuro.2014.03.001.Mazaris P., Hong X., Altshuler D., Schultz L., Poisson L.M., Jain R., Mikkelsen T., Rosenblum M., Kalkanis S. Key determinants of short-term and long-term glioblastoma survival: a 14-year retrospective study of patients from the Hermelin Brain Tumor Center at Henry Ford Hospital. Clin Neurol Neurosurg. 2014 May; 120: 103–12. doi: 10.1016/j.clineuro.2014.03.001.Geisenberger C., Mock A., Warta R., Rapp C., Schwager C., Korshunov A., Nied A.K., Capper D., Brors B., Jungk C., Jones D., Collins V.P., Ichimura K., Bäcklund L.M., Schnabel E., Mittelbron M., Lahrmann B., Zheng S., Verhaak R.G., Grabe N., Pfister S.M., Hartmann C., von Deimling A., Debus J., Unterberg A., Abdollahi A., Herold-Mende C. Molecular profiling of long-term survivors identifies a subgroup of glioblastoma characterized by chromosome 19/20 co-gain. Acta Neuropathol. 2015 Sep; 130(3): 419–34. doi: 10.1007/s00401-015-1427-y.Geisenberger C., Mock A., Warta R., Rapp C., Schwager C., Korshunov A., Nied A.K., Capper D., Brors B., Jungk C., Jones D., Collins V.P., Ichimura K., Bäcklund L.M., Schnabel E., Mittelbron M., Lahrmann B., Zheng S., Verhaak R.G., Grabe N., Pfister S.M., Hartmann C., von Deimling A., Debus J., Unterberg A., Abdollahi A., Herold-Mende C. Molecular profiling of long-term survivors identifies a subgroup of glioblastoma characterized by chromosome 19/20 co-gain. Acta Neuropathol. 2015 Sep; 130(3): 419–34. doi: 10.1007/s00401-015-1427-y.Shannon S., Vaca C., Jia D., Entersz I., Schaer A., Carcione J., Weaver M., Avidar Y., Pettit R., Nair M., Khan A., Foty R.A. DexamethasoneMediated Activation of Fibronectin Matrix Assembly Reduces Dispersal of Primary HumanGlioblastoma Cells. PLoS One. 2015 Aug 18; 10(8): e0135951. doi: 10.1371/journal.pone.0135951.Shannon S., Vaca C., Jia D., Entersz I., Schaer A., Carcione J., Weaver M., Avidar Y., Pettit R., Nair M., Khan A., Foty R.A. DexamethasoneMediated Activation of Fibronectin Matrix Assembly Reduces Dispersal of Primary HumanGlioblastoma Cells. PLoS One. 2015 Aug 18; 10(8): e0135951. doi: 10.1371/journal.pone.0135951.Bähr O., Herrlinger U., Weller M., Steinbach J.P. Very late relapses in glioblastoma long-term survivors. J Neurol. 2009 Oct; 256(10): 1756–8. doi: 10.1007/s00415-009-5167-6.Bähr O., Herrlinger U., Weller M., Steinbach J.P. Very late relapses in glioblastoma long-term survivors. J Neurol. 2009 Oct; 256(10): 1756–8. doi: 10.1007/s00415-009-5167-6.Sawaya R., Suki D. Long-Term Survival in Patients With Glioblastoma Multiforme: Frequency and Prognostic Factors. Oncology (Williston Park). 2016 Apr; 30 Suppl. pii: 216594.Sawaya R., Suki D. Long-Term Survival in Patients With Glioblastoma Multiforme: Frequency and Prognostic Factors. Oncology (Williston Park). 2016 Apr; 30 Suppl. pii: 216594.Fiore D., Donnarumma E., Roscigno G., Iaboni M., Russo V., Affinito A., Adamo A., De Martino F., Quintavalle C., Romano G., Greco A., Soini Y., Brunetti A., Croce C.M., Condorelli G. miR-340 predicts glioblastoma survival and modulates key cancer hallmarks through downregulation of NRAS. Oncotarget. 2016 Apr 12; 7(15): 19531–47. doi: 10.18632/oncotarget.6968.Fiore D., Donnarumma E., Roscigno G., Iaboni M., Russo V., Affinito A., Adamo A., De Martino F., Quintavalle C., Romano G., Greco A., Soini Y., Brunetti A., Croce C.M., Condorelli G. miR-340 predicts glioblastoma survival and modulates key cancer hallmarks through downregulation of NRAS. Oncotarget. 2016 Apr 12; 7(15): 19531–47. doi: 10.18632/oncotarget.6968.Millward C.P., Brodbelt A.R., Haylock B., Zakaria R., Baborie A., Crooks D., Husband D., Shenoy A., Wong H., Jenkinson M.D. The impact of MGMT methylation and IDH-1 mutation on long-term outcome for glioblastoma treated with chemoradiotherapy. Acta Neurochir (Wien). 2016 Oct; 158(10): 1943–53. doi: 10.1007/s00701-016-2928-8.Millward C.P., Brodbelt A.R., Haylock B., Zakaria R., Baborie A., Crooks D., Husband D., Shenoy A., Wong H., Jenkinson M.D. The impact of MGMT methylation and IDH-1 mutation on long-term outcome for glioblastoma treated with chemoradiotherapy. Acta Neurochir (Wien). 2016 Oct; 158(10): 1943–53. doi: 10.1007/s00701-016-2928-8.Shinawi T., Hill V.K., Krex D., Schackert G., Gentle D., Morris M.R., Wei W., Cruickshank G., Maher E.R., Latif F. DNA methylation profiles of longand short-term glioblastoma survivors. Epigenetics. 2013 Feb; 8(2): 149–56. doi: 10.4161/epi.23398.Shinawi T., Hill V.K., Krex D., Schackert G., Gentle D., Morris M.R., Wei W., Cruickshank G., Maher E.R., Latif F. DNA methylation profiles of longand short-term glioblastoma survivors. Epigenetics. 2013 Feb; 8(2): 149–56. doi: 10.4161/epi.23398.Reifenberger G., Weber R.G., Riehmer V., Kaulich K., Willscher E., Wirth H., Gietzelt J., Hentschel B., Westphal M., Simon M., Schackert G., Schramm J., Matschke J., Sabel M.C., Gramatzki D., Felsberg J., Hartmann C., Steinbach J.P., Schlegel U., Wick W., Radlwimmer B., Pietsch T., Tonn J.C., von Deimling A., Binder H., Weller M., Loeffler M. Molecular characterization of long-term survivors of glioblastoma using genomeand transcriptome-wide profiling. Int J Cancer. 2014 Oct 15; 135(8): 1822–31. doi: 10.1002/ijc.28836.Reifenberger G., Weber R.G., Riehmer V., Kaulich K., Willscher E., Wirth H., Gietzelt J., Hentschel B., Westphal M., Simon M., Schackert G., Schramm J., Matschke J., Sabel M.C., Gramatzki D., Felsberg J., Hartmann C., Steinbach J.P., Schlegel U., Wick W., Radlwimmer B., Pietsch T., Tonn J.C., von Deimling A., Binder H., Weller M., Loeffler M. Molecular characterization of long-term survivors of glioblastoma using genomeand transcriptome-wide profiling. Int J Cancer. 2014 Oct 15; 135(8): 1822–31. doi: 10.1002/ijc.28836.Adeberg S., Bostel T., König L., Welzel T., Debus J., Combs S.E. A comparison of long-term survivors and short-term survivors with glioblastoma, subventricular zone involvement: a predictive factor for survival? Radiat Oncol. 2014 Apr 23; 9: 95. doi: 10.1186/1748-717X-9-95.Adeberg S., Bostel T., König L., Welzel T., Debus J., Combs S.E. A comparison of long-term survivors and short-term survivors with glioblastoma, subventricular zone involvement: a predictive factor for survival? Radiat Oncol. 2014 Apr 23; 9: 95. doi: 10.1186/1748-717X-9-95.Amelot A., De Cremoux P., Quillien V., Polivka M., Adle-Biassette H., Lehmann-Che J., Françoise L., Carpentier A.F., George B., Mandonnet E., Froelich S. IDH-Mutation Is a Weak Predictor of Long-Term Survival in Glioblastoma Patients. PLoS One. 2015 Jul 9; 10(7): e0130596. doi: 10.1371/journal.pone.0130596.Amelot A., De Cremoux P., Quillien V., Polivka M., Adle-Biassette H., Lehmann-Che J., Françoise L., Carpentier A.F., George B., Mandonnet E., Froelich S. IDH-Mutation Is a Weak Predictor of Long-Term Survival in Glioblastoma Patients. PLoS One. 2015 Jul 9; 10(7): e0130596. doi: 10.1371/journal.pone.0130596.Scott J.N., Rewcastle N.B., Brasher P.M., Fulton D., MacKinnon J.A., Hamilton M., Cairncross J.G., Forsyth P. Which glioblastoma multiforme patient will become a long-term survivor? A population-based study. Ann Neurol. 1999 Aug; 46(2): 183–8.Scott J.N., Rewcastle N.B., Brasher P.M., Fulton D., MacKinnon J.A., Hamilton M., Cairncross J.G., Forsyth P. Which glioblastoma multiforme patient will become a long-term survivor? A population-based study. Ann Neurol. 1999 Aug; 46(2): 183–8.Baur M., Preusser M., Piribauer M., Elandt K., Hassler M., Hudec M., Dittrich C., Marosi C. Frequent MGMT (0(6)-methylguanineDNA methyltransferase) hypermethylation in long-term survivors of glioblastoma: a single institution experience. Radiol Oncol. 2010 Jun; 44(2): 113–20. doi: 10.2478/v10019-010-0023-y.Baur M., Preusser M., Piribauer M., Elandt K., Hassler M., Hudec M., Dittrich C., Marosi C. Frequent MGMT (0(6)-methylguanineDNA methyltransferase) hypermethylation in long-term survivors of glioblastoma: a single institution experience. Radiol Oncol. 2010 Jun; 44(2): 113–20. doi: 10.2478/v10019-010-0023-y.Sanai N., Polley M.Y., McDermott M.W., Parsa A.T., Berger M.S. An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg. 2011 Jul; 115(1): 3–8. doi: 10.3171/2011.2.JNS10998.Sanai N., Polley M.Y., McDermott M.W., Parsa A.T., Berger M.S. An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg. 2011 Jul; 115(1): 3–8. doi: 10.3171/2011.2.JNS10998.Chaichana K.L., Pendleton C., Chambless L., Camara-Quintana J., Nathan J.K., Hassam-Malani L., Li G., Harsh G.R. 4th, Thompson R.C., Lim M., Quinones-Hinojosa A. Multi-institutional validation of a preoperative scoring system which predicts survival for patients with glioblastoma. J Clin Neurosci. 2013 Oct; 20(10): 1422–6. doi: 10.1016/j.jocn.2013.02.007.Chaichana K.L., Pendleton C., Chambless L., Camara-Quintana J., Nathan J.K., Hassam-Malani L., Li G., Harsh G.R. 4th, Thompson R.C., Lim M., Quinones-Hinojosa A. Multi-institutional validation of a preoperative scoring system which predicts survival for patients with glioblastoma. J Clin Neurosci. 2013 Oct; 20(10): 1422–6. doi: 10.1016/j.jocn.2013.02.007.Glas M., Happold C., Rieger J., Wiewrodt D., Bähr O., Steinbach J.P., Wick W., Kortmann R.D., Reifenberger G., Weller M., Herrlinger U. Longterm survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide. J Clin Oncol. 2009 Mar 10; 27(8): 1257–61. doi: 10.1200/JCO.2008.19.2195.Glas M., Happold C., Rieger J., Wiewrodt D., Bähr O., Steinbach J.P., Wick W., Kortmann R.D., Reifenberger G., Weller M., Herrlinger U. Longterm survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide. J Clin Oncol. 2009 Mar 10; 27(8): 1257–61. doi: 10.1200/JCO.2008.19.2195.Chandler K.L., Prados M.D., Malec M., Wilson C.B. Long-term survival in patients with glioblastoma multiforme. Neurosurgery 1993 May; 32(5): 716–20.Chandler K.L., Prados M.D., Malec M., Wilson C.B. Long-term survival in patients with glioblastoma multiforme. Neurosurgery 1993 May; 32(5): 716–20.McLendon R.E., Halperin E.C. Is the long-term survival of patients with intracranial glioblastoma multiforme overstated? Cancer. 2003 Oct 15; 98(8): 1745–8. doi: 10.1002/cncr.11666.McLendon R.E., Halperin E.C. Is the long-term survival of patients with intracranial glioblastoma multiforme overstated? Cancer. 2003 Oct 15; 98(8): 1745–8. doi: 10.1002/cncr.11666.Zhang C., Yao Y., Wang Y., Chen Z., Wu J., Mao Y., Zhou L. Temozolomide for adult brain stem glioblastoma: case report of a long-term survivor. Int J Neurosci. 2010 Dec; 120(12): 787–91. doi: 10.3109/00207454.2010.520377.Zhang C., Yao Y., Wang Y., Chen Z., Wu J., Mao Y., Zhou L. Temozolomide for adult brain stem glioblastoma: case report of a long-term survivor. Int J Neurosci. 2010 Dec; 120(12): 787–91. doi: 10.3109/00207454.2010.520377.Hartmann C., Hentschel B., Simon M., Westphal M., Schackert G., Tonn J.C., Loeffler M., Reifenberger G., Pietsch T., von Deimling A., Weller M., German Glioma Network. Long-term survival in primary glioblastoma with versus without isocitrate dehydrogenase mutations. Clin Cancer Res. 2013 Sep 15; 19(18): 5146–57. doi: 10.1158/1078-0432.CCR-13-0017.Hartmann C., Hentschel B., Simon M., Westphal M., Schackert G., Tonn J.C., Loeffler M., Reifenberger G., Pietsch T., von Deimling A., Weller M., German Glioma Network. Long-term survival in primary glioblastoma with versus without isocitrate dehydrogenase mutations. Clin Cancer Res. 2013 Sep 15; 19(18): 5146–57. doi: 10.1158/1078-0432.CCR-13-0017.Мацко М.В., Лучин Е.И., Иевлева А.Г., Бахолдин Д.В., Абышева С.Н., Завгородняя Е.В., Потапова О.Н., Имянитов Е.Н., Мацко Д.Е. Значимый регресс глиобластомы с низкой экспрессией гена MGMT при химиолучевой терапии. Вопросы онкологии. 2011; 57(2): 245–249.Matsko M.V., Luchin E.I., Iyevleva A.G., Bakholdin D.V., Abysheva S.N., Zavgorodnyaya E.V., Potapova O.N., Imyanitov E.N., Ulitin A.Yu., Matsko D.E. Significant regression of glioblastoma with low level of mgmt gene expression following radiotherapy. Problems in oncology. 2011; 57(2): 245–249. (in Russian).Hegi M.E., Diserens A.C., Gorlia T., Hamou M.F., de Tribolet N., Weller M., Kros J.M., Hainfellner J.A., Mason W., Mariani L., Bromberg J.E., Hau P., Mirimanoff R.O., Cairncross J.G., Janzer R.C., Stupp R. Mgmt gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005; 352: 997–1003. doi: 10.1056/NEJMoa043331.Hegi M.E., Diserens A.C., Gorlia T., Hamou M.F., de Tribolet N., Weller M., Kros J.M., Hainfellner J.A., Mason W., Mariani L., Bromberg J.E., Hau P., Mirimanoff R.O., Cairncross J.G., Janzer R.C., Stupp R. Mgmt gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005; 352: 997–1003. doi: 10.1056/NEJMoa043331.Weiler M., Hartmann C., Wiewrodt D., Herrlinger U., Gorlia T., Bähr O., Meyermann R., Bamberg M., Tatagiba M., von Deimling A., Weller M., Wick W. Chemoradiotherapy of newly diagnosed glioblastoma with intensified temozolomide. Int J Radiat Oncol Biol Phys. 2010 Jul 1; 77(3): 670–6. doi: 10.1016/j.ijrobp.2009.05.031.Weiler M., Hartmann C., Wiewrodt D., Herrlinger U., Gorlia T., Bähr O., Meyermann R., Bamberg M., Tatagiba M., von Deimling A., Weller M., Wick W. Chemoradiotherapy of newly diagnosed glioblastoma with intensified temozolomide. Int J Radiat Oncol Biol Phys. 2010 Jul 1; 77(3): 670–6. doi: 10.1016/j.ijrobp.2009.05.031.Quillien V., Lavenu A., Karayan-Tapon L., Carpentier C., Labussière M., Lesimple T., Chinot O., Wager M., Honnorat J., Saikali S., Fina F., Sanson M., Figarella-Branger D. Comparative Assessment of 5 Methods (Methylation-Specific Polymerase Chain Reaction, MethyLight, Pyrosequencing, Methylation-Sensitive High-Resolution Melting, and Immunohistochemistry) to Analyze O6-Methylguanine-DNAMethyltranferase in a Series of 100 Glioblastoma Patients. Cancer. 2012 Sep 1; 118(17): 4201–11. doi: 10.1002/cncr.27392.Quillien V., Lavenu A., Karayan-Tapon L., Carpentier C., Labussière M., Lesimple T., Chinot O., Wager M., Honnorat J., Saikali S., Fina F., Sanson M., Figarella-Branger D. Comparative Assessment of 5 Methods (Methylation-Specific Polymerase Chain Reaction, MethyLight, Pyrosequencing, Methylation-Sensitive High-Resolution Melting, and Immunohistochemistry) to Analyze O6-Methylguanine-DNAMethyltranferase in a Series of 100 Glioblastoma Patients. Cancer. 2012 Sep 1; 118(17): 4201–11. doi: 10.1002/cncr.27392.Lalezari S., Chou A.P., Tran A., Solis O.E., Khanlou N., Chen W., Li S., Carrillo J.A., Chowdhury R., Selfridge J., Sanchez D.E., Wilson R.W., Zurayk M., Lalezari J., Lou J.J., Ormiston L., Ancheta K., Hanna R., Miller P., Piccioni D., Ellingson B.M., Buchanan C., Mischel P.S., Nghiemphu P.L., Green R., Wang H.J., Pope W.B., Liau L.M., Elashoff R.M., Cloughesy T.F., Yong W.H., Lai A. Combined analysis of O6-methylguanine-DNA methyltransferase protein expression and promoter methylation provides optimized prognostication of glioblastoma outcome. Neuro Oncol. 2013 Mar; 15(3): 370–81. doi: 10.1093/neuonc/nos308.Lalezari S., Chou A.P., Tran A., Solis O.E., Khanlou N., Chen W., Li S., Carrillo J.A., Chowdhury R., Selfridge J., Sanchez D.E., Wilson R.W., Zurayk M., Lalezari J., Lou J.J., Ormiston L., Ancheta K., Hanna R., Miller P., Piccioni D., Ellingson B.M., Buchanan C., Mischel P.S., Nghiemphu P.L., Green R., Wang H.J., Pope W.B., Liau L.M., Elashoff R.M., Cloughesy T.F., Yong W.H., Lai A. Combined analysis of O6-methylguanine-DNA methyltransferase protein expression and promoter methylation provides optimized prognostication of glioblastoma outcome. Neuro Oncol. 2013 Mar; 15(3): 370–81. doi: 10.1093/neuonc/nos308.Rapp M., Goeppert M., Felsberg J., Steiger H.J., Sabel M. The impact of sequential vs. combined radiochemotherapy with temozolomide, resection and MGMT promoter hypermethylation on survival of patients with primary glioblastoma – a single centre retrospective study. Br J Neurosurg. 2013 Aug; 27(4): 430–5. doi: 10.3109/02688697.2013.767317.Rapp M., Goeppert M., Felsberg J., Steiger H.J., Sabel M. The impact of sequential vs. combined radiochemotherapy with temozolomide, resection and MGMT promoter hypermethylation on survival of patients with primary glioblastoma – a single centre retrospective study. Br J Neurosurg. 2013 Aug; 27(4): 430–5. doi: 10.3109/02688697.2013.767317.Parsons D.W., Jones S., Zhang X., Lin J.C., Leary R.J., Angenendt P., Mankoo P., Carter H, Siu I.M., Gallia G.L., Olivi A., McLendon R., Rasheed B.A., Keir S., Nikolskaya T., Nikolsky Y., Busam D.A., Tekleab H., Diaz L.A.Jr., Hartigan J., Smith D.R., Strausberg R.L., Marie S.K., Shinjo S.M., Yan H., Riggins G.J., Bigner D.D., Karchin R., Papadopoulos N., Parmigiani G., Vogelstein B., Velculescu V.E., Kinzler K.W. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008 Sep 26; 321(5897): 1807–12. doi: 10.1126/science.1164382.Parsons D.W., Jones S., Zhang X., Lin J.C., Leary R.J., Angenendt P., Mankoo P., Carter H, Siu I.M., Gallia G.L., Olivi A., McLendon R., Rasheed B.A., Keir S., Nikolskaya T., Nikolsky Y., Busam D.A., Tekleab H., Diaz L.A.Jr., Hartigan J., Smith D.R., Strausberg R.L., Marie S.K., Shinjo S.M., Yan H., Riggins G.J., Bigner D.D., Karchin R., Papadopoulos N., Parmigiani G., Vogelstein B., Velculescu V.E., Kinzler K.W. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008 Sep 26; 321(5897): 1807–12. doi: 10.1126/science.1164382.Sanson M., Marie Y., Paris S., Idbaih A., Laffaire J., Ducray F., El Hallani S., Boisselier B., Mokhtari K., Hoang-Xuan K., Delattre J.Y. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol. 2009 Sep 1; 27(25): 4150–4. doi: 10.1200/JCO.2009.21.9832.Sanson M., Marie Y., Paris S., Idbaih A., Laffaire J., Ducray F., El Hallani S., Boisselier B., Mokhtari K., Hoang-Xuan K., Delattre J.Y. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol. 2009 Sep 1; 27(25): 4150–4. doi: 10.1200/JCO.2009.21.9832.Yan H., Parsons D.W., Jin G., McLendon R., Rasheed B.A., Yuan W., Kos I., Batinic-Haberle I., Jones S., Riggins G.J., Friedman H., Friedman A., Reardon D., Herndon J., Kinzler K.W., Velculescu V.E., Vogelstein B., Bigner D.D. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009 Feb 19; 360(8): 765–73. doi: 10.1056/NEJMoa0808710.Yan H., Parsons D.W., Jin G., McLendon R., Rasheed B.A., Yuan W., Kos I., Batinic-Haberle I., Jones S., Riggins G.J., Friedman H., Friedman A., Reardon D., Herndon J., Kinzler K.W., Velculescu V.E., Vogelstein B., Bigner D.D. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009 Feb 19; 360(8): 765–73. doi: 10.1056/NEJMoa0808710.Turcan S., Rohle D., Goenka A., Walsh L.A., Fang F., Yilmaz E., Campos C., Fabius A.W., Lu C., Ward P.S., Thompson C.B., Kaufman A., Guryanova O., Levine R., Heguy A., Viale A., Morris L.G., Huse J.T., Mellinghoff I.K., Chan T.A. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012 Feb 15; 483(7390): 479–83. doi: 10.1038/nature10866.Turcan S., Rohle D., Goenka A., Walsh L.A., Fang F., Yilmaz E., Campos C., Fabius A.W., Lu C., Ward P.S., Thompson C.B., Kaufman A., Guryanova O., Levine R., Heguy A., Viale A., Morris L.G., Huse J.T., Mellinghoff I.K., Chan T.A. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012 Feb 15; 483(7390): 479–83. doi: 10.1038/nature10866.Christensen B.C., Smith A.A., Zheng S., Koestler D.C., Houseman E.A., Marsit C.J., Wiemels J.L., Nelson H.H., Karagas M.R., Wrensch M.R., Kelsey K.T., Wiencke J.K. DNA methylation, isocitrate dehydrogenase mutation, and survival in glioma. Natl Cancer Inst. 2011 Jan 19; 103(2): 143–53. doi: 10.1093/jnci/djq497.Christensen B.C., Smith A.A., Zheng S., Koestler D.C., Houseman E.A., Marsit C.J., Wiemels J.L., Nelson H.H., Karagas M.R., Wrensch M.R., Kelsey K.T., Wiencke J.K. DNA methylation, isocitrate dehydrogenase mutation, and survival in glioma. Natl Cancer Inst. 2011 Jan 19; 103(2): 143–53. doi: 10.1093/jnci/djq497.Zou P., Xu H., Chen P., Yan Q., Zhao L., Zhao P., Gu A. IDH1/ IDH2 mutations define the prognosis and molecular profiles of patients with gliomas: a meta-analysis. PLoS One. 2013 Jul 22; 8(7): e68782. doi: 10.1371/journal.pone.0068782.Zou P., Xu H., Chen P., Yan Q., Zhao L., Zhao P., Gu A. IDH1/ IDH2 mutations define the prognosis and molecular profiles of patients with gliomas: a meta-analysis. PLoS One. 2013 Jul 22; 8(7): e68782. doi: 10.1371/journal.pone.0068782.Molenaar R.J., Verbaan D., Lamba S., Zanon C., Jeuken J.W., BootsSprenger S.H., Wesseling P., Hulsebos T.J., Troost D., van Tilborg A.A., Leenstra S., Vandertop W.P., Bardelli A., van Noorden C.J., Bleeker F.E. The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone. Neuro Oncol. 2014 Sep; 16(9): 1263–73. doi: 10.1093/neuonc/nou005.Molenaar R.J., Verbaan D., Lamba S., Zanon C., Jeuken J.W., BootsSprenger S.H., Wesseling P., Hulsebos T.J., Troost D., van Tilborg A.A., Leenstra S., Vandertop W.P., Bardelli A., van Noorden C.J., Bleeker F.E. The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone. Neuro Oncol. 2014 Sep; 16(9): 1263–73. doi: 10.1093/neuonc/nou005.Balss J., Meyer J., Mueller W., Korshunov A., Hartmann C., von Deimling A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 2008 Dec; 116(6): 597–602. doi: 10.1007/s00401008-0455-2.Balss J., Meyer J., Mueller W., Korshunov A., Hartmann C., von Deimling A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 2008 Dec; 116(6): 597–602. doi: 10.1007/s00401008-0455-2.Ichimura K., Pearson D.M., Kocialkowski S., Bäcklund L.M., Chan R., Jones D.T., Collins V.P. IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro Oncol. 2009 Aug; 11(4): 341–7. doi: 10.1215/15228517-2009-025.Ichimura K., Pearson D.M., Kocialkowski S., Bäcklund L.M., Chan R., Jones D.T., Collins V.P. IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro Oncol. 2009 Aug; 11(4): 341–7. doi: 10.1215/15228517-2009-025.Hartmann C., Meyer J., Balss J., Capper D., Mueller W., Christians A., Felsberg J., Wolter M., Mawrin C., Wick W., Weller M., Herold-Mende C., Unterberg A., Jeuken J.W., Wesseling P., Reifenberger G., von Deimling A. 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 Oct; 118(4): 469–74. doi: 10.1007/s00401-009-0561-9.Hartmann C., Meyer J., Balss J., Capper D., Mueller W., Christians A., Felsberg J., Wolter M., Mawrin C., Wick W., Weller M., Herold-Mende C., Unterberg A., Jeuken J.W., Wesseling P., Reifenberger G., von Deimling A. 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 Oct; 118(4): 469–74. doi: 10.1007/s00401-009-0561-9.Weller M., Felsberg J., Hartmann C., Berger H., Steinbach J.P., Schramm J., Westphal M., Schackert G., Simon M., Tonn J.C., Heese O., Krex D., Nikkhah G., Pietsch T., Wiestler O., Reifenberger G., von Deimling A., Loeffler M. Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J Clin Oncol. 2009 Dec 1; 27(34): 5743–50. doi: 10.1200/JCO.2009.23.0805.Weller M., Felsberg J., Hartmann C., Berger H., Steinbach J.P., Schramm J., Westphal M., Schackert G., Simon M., Tonn J.C., Heese O., Krex D., Nikkhah G., Pietsch T., Wiestler O., Reifenberger G., von Deimling A., Loeffler M. Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J Clin Oncol. 2009 Dec 1; 27(34): 5743–50. doi: 10.1200/JCO.2009.23.0805.Hartmann C., Hentschel B., Wick W., Capper D., Felsberg J., Simon M., Westphal M., Schackert G., Meyermann R., Pietsch T., Reifenberger G., Weller M., Loeffler M., von Deimling A. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol. 2010 Dec; 120(6): 707–18. doi: 10.1007/s00401-010-0781-z.Hartmann C., Hentschel B., Wick W., Capper D., Felsberg J., Simon M., Westphal M., Schackert G., Meyermann R., Pietsch T., Reifenberger G., Weller M., Loeffler M., von Deimling A. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol. 2010 Dec; 120(6): 707–18. doi: 10.1007/s00401-010-0781-z.Combs S.E., Rieken S., Wick W., Abdollahi A., von Deimling A., Debus J., Hartmann C. Prognostic significance of IDH-1 and MGMT in patients with glioblastoma: one step forward, and one step back? Radiat Oncol. 2011 Sep 13; 6: 115. doi: 10.1186/1748-717X-6-115.Combs S.E., Rieken S., Wick W., Abdollahi A., von Deimling A., Debus J., Hartmann C. Prognostic significance of IDH-1 and MGMT in patients with glioblastoma: one step forward, and one step back? Radiat Oncol. 2011 Sep 13; 6: 115. doi: 10.1186/1748-717X-6-115.Myung J.K., Cho H.J., Park C.K., Kim S.K., Phi J.H., Park S.H. IDH1 mutation of gliomas with long-term survival analysis. Oncol Rep. 2012 Nov; 28(5): 1639–44. doi: 10.3892/or.2012.1994.Myung J.K., Cho H.J., Park C.K., Kim S.K., Phi J.H., Park S.H. IDH1 mutation of gliomas with long-term survival analysis. Oncol Rep. 2012 Nov; 28(5): 1639–44. doi: 10.3892/or.2012.1994.Sarmiento J.M., Mukherjee D., Black K.L., Fan X., Hu J.L., Nuno M.A., Patil C.G. Do Long-Term Survivor Primary Glioblastoma Patients Harbor IDH1 Mutations? J Neurol Surg A Cent Eur Neurosurg. 2016 May; 77(3): 195–200. doi: 10.1055/s-0035-1566121.Sarmiento J.M., Mukherjee D., Black K.L., Fan X., Hu J.L., Nuno M.A., Patil C.G. Do Long-Term Survivor Primary Glioblastoma Patients Harbor IDH1 Mutations? J Neurol Surg A Cent Eur Neurosurg. 2016 May; 77(3): 195–200. doi: 10.1055/s-0035-1566121.Yan W., Zhang W., You G., Bao Z., Wang Y., Liu Y., Kang C., You Y., Wang L., Jiang T. Correlation of IDH1 mutation with clinicopathologic factors and prognosis in primary glioblastoma: a report of 118 patients from China. PLoS One. 2012; 7(1): e30339. doi: 10.1371/journal.pone.0030339.Yan W., Zhang W., You G., Bao Z., Wang Y., Liu Y., Kang C., You Y., Wang L., Jiang T. Correlation of IDH1 mutation with clinicopathologic factors and prognosis in primary glioblastoma: a report of 118 patients from China. PLoS One. 2012; 7(1): e30339. doi: 10.1371/journal.pone.0030339.Мацко Д.Е., Мацко М.В., Имянитов Е.Н. Нейроонкология. Практическая онкология. 2017; 18(1): 103–114.Matsko D.E., Matsko M.V., Imyanitov E.N. Neurooncology. Practical Oncology. 2017; 18(1): 103–114. (in Russian).Krex D., Klink B., Hartmann C., von Deimling A., Pietsch T., Simon M., Sabel M., Steinbach J.P., Heese O., Reifenberger G., Weller M., Schackert G.; German Glioma Network. Long-term survival with glioblastoma multiforme. Brain. 2007 Oct; 130(Pt 10): 2596–606. doi: 10.1093/brain/awm204.Krex D., Klink B., Hartmann C., von Deimling A., Pietsch T., Simon M., Sabel M., Steinbach J.P., Heese O., Reifenberger G., Weller M., Schackert G.; German Glioma Network. Long-term survival with glioblastoma multiforme. Brain. 2007 Oct; 130(Pt 10): 2596–606. doi: 10.1093/brain/awm204.Zhang G.B., Cui X.L., Sui D.L., Ren X.H., Zhang Z., Wang Z.C., Lin S. Differential molecular genetic analysis in glioblastoma multiforme of longand short-term survivors: a clinical study in Chinese patients. J Neurooncol. 2013 Jun; 113(2): 251–8. doi:10.1007/s11060-013-1102-x.Zhang G.B., Cui X.L., Sui D.L., Ren X.H., Zhang Z., Wang Z.C., Lin S. Differential molecular genetic analysis in glioblastoma multiforme of longand short-term survivors: a clinical study in Chinese patients. J Neurooncol. 2013 Jun; 113(2): 251–8. doi:10.1007/s11060-013-1102-x.Burton E.C., Lamborn K.R., Forsyth P., Scott J., O’Campo J., Uyehara-Lock J., Prados M., Berger M., Passe S., Uhm J., O’Neill B.P., Jenkins R.B., Aldape K.D. Aberrant p53, mdm2, and proliferation differ in glioblastomas from long-term compared with typical survivors. Clin Cancer Res. 2002 Jan; 8(1): 180–7.Burton E.C., Lamborn K.R., Forsyth P., Scott J., O’Campo J., Uyehara-Lock J., Prados M., Berger M., Passe S., Uhm J., O’Neill B.P., Jenkins R.B., Aldape K.D. Aberrant p53, mdm2, and proliferation differ in glioblastomas from long-term compared with typical survivors. Clin Cancer Res. 2002 Jan; 8(1): 180–7.Wen P.Y., Macdonald D.R., Reardon D.A., Cloughesy T.F., Sorensen A.G., Galanis E., Degroot J., Wick W., Gilbert M.R., Lassman A.B., Tsien C., Mikkelsen T., Wong E.T., Chamberlain M.C., Stupp R., Lamborn K.R., Vogelbaum M.A., van den Bent M.J., Chang S.M. Updated response assessment criteria for high-grade gliomas: response assessment in neurooncology working group. J Clin Oncol. 2010 Apr 10; 28(11): 1963–72. doi: 10.1200/JCO.2009.26.3541.Wen P.Y., Macdonald D.R., Reardon D.A., Cloughesy T.F., Sorensen A.G., Galanis E., Degroot J., Wick W., Gilbert M.R., Lassman A.B., Tsien C., Mikkelsen T., Wong E.T., Chamberlain M.C., Stupp R., Lamborn K.R., Vogelbaum M.A., van den Bent M.J., Chang S.M. Updated response assessment criteria for high-grade gliomas: response assessment in neurooncology working group. J Clin Oncol. 2010 Apr 10; 28(11): 1963–72. doi: 10.1200/JCO.2009.26.3541.Martinez R., Schackert G., Yaya-Tur R., Rojas-Marcos I., Herman J.G., Esteller M. Frequent hypermethylation of the DNA repair gene MGMT in long-term survivors of glioblastoma multiforme. J Neurooncol. 2007 May; 83(1): 91–3. doi: 10.1007/s11060-006-9292-0.Martinez R., Schackert G., Yaya-Tur R., Rojas-Marcos I., Herman J.G., Esteller M. Frequent hypermethylation of the DNA repair gene MGMT in long-term survivors of glioblastoma multiforme. J Neurooncol. 2007 May; 83(1): 91–3. doi: 10.1007/s11060-006-9292-0.Korshunov A., Sycheva R., Golanov A. Genetically distinct and clinically relevant subtypes of glioblastoma defined by array-based comparative genomic hybridization (array-CGH). Acta Neuropathol. 2006 May; 111(5): 465–74. doi: 10.1007/s00401-006-0057-9.Korshunov A., Sycheva R., Golanov A. Genetically distinct and clinically relevant subtypes of glioblastoma defined by array-based comparative genomic hybridization (array-CGH). Acta Neuropathol. 2006 May; 111(5): 465–74. doi: 10.1007/s00401-006-0057-9.Sonoda Y., Kumabe T., Watanabe M., Nakazato Y., Inoue T., Kanamori M., Tominaga T. Long-term survivors of glioblastoma: clinical features and molecular analysis. Acta Neurochir (Wien). 2009 Nov; 151(11): 1349–58. doi: 10.1007/s00701-009-0387-1.Sonoda Y., Kumabe T., Watanabe M., Nakazato Y., Inoue T., Kanamori M., Tominaga T. Long-term survivors of glioblastoma: clinical features and molecular analysis. Acta Neurochir (Wien). 2009 Nov; 151(11): 1349–58. doi: 10.1007/s00701-009-0387-1.Lu J., Cowperthwaite M.C., Burnett M.G., Shpak M. Molecular Predictors of Long-Term Survival in Glioblastoma Multiforme Patients. PLoS One. 2016 Apr 28; 11(4): e0154313. doi: 10.1371/journal.pone.0154313.Lu J., Cowperthwaite M.C., Burnett M.G., Shpak M. Molecular Predictors of Long-Term Survival in Glioblastoma Multiforme Patients. PLoS One. 2016 Apr 28; 11(4): e0154313. doi: 10.1371/journal.pone.0154313.Matsko M.V., Imyanitov E.N. Predictive role of O6-methylguanine DNA methyltransferase status for the treatment of brain tumors. Epigenetics Territory and Cancer. Springer, 2015. 251–279.Matsko M.V., Imyanitov E.N. Predictive role of O6-methylguanine DNA methyltransferase status for the treatment of brain tumors. Epigenetics Territory and Cancer. Springer, 2015. 251–279.Sturm D., Witt H., Hovestadt V., Khuong-Quang D.A., Jones D.T., Konermann C., Pfaff E., Tönjes M., Sill M., Bender S., Kool M., Zapatka M., Becker N., Zucknick M., Hielscher T., Liu X.Y., Fontebasso A.M., Ryzhova M., Albrecht S., Jacob K., Wolter M., Ebinger M., Schuhmann M.U., van Meter T., Frühwald M.C., Hauch H., Pekrun A., Radlwimmer B., Niehues T., von Komorowski G., Dürken M., Kulozik A.E., Madden J., Donson A., Foreman N.K., Drissi R., Fouladi M., Scheurlen W., von Deimling A., Monoranu C., Roggendorf W., Herold-Mende C., Unterberg A., Kramm C.M., Felsberg J., Hartmann C., Wiestler B., Wick W., Milde T., Witt O., Lindroth A.M., Schwartzentruber J., Faury D., Fleming A., Zakrzewska M., Liberski P.P., Zakrzewski K., Hauser P., Garami M., Klekner A., Bognar L., Morrissy S., Cavalli F., Taylor M.D., van Sluis P., Koster J., Versteeg R., Volckmann R., Mikkelsen T., Aldape K., Reifenberger G., Collins V.P., Majewski J., Korshunov A., Lichter P., Plass C., Jabado N., Pfister S.M. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell. 2012 Oct 16; 22(4): 425–37. doi: 10.1016/j.ccr.2012.08.024.Sturm D., Witt H., Hovestadt V., Khuong-Quang D.A., Jones D.T., Konermann C., Pfaff E., Tönjes M., Sill M., Bender S., Kool M., Zapatka M., Becker N., Zucknick M., Hielscher T., Liu X.Y., Fontebasso A.M., Ryzhova M., Albrecht S., Jacob K., Wolter M., Ebinger M., Schuhmann M.U., van Meter T., Frühwald M.C., Hauch H., Pekrun A., Radlwimmer B., Niehues T., von Komorowski G., Dürken M., Kulozik A.E., Madden J., Donson A., Foreman N.K., Drissi R., Fouladi M., Scheurlen W., von Deimling A., Monoranu C., Roggendorf W., Herold-Mende C., Unterberg A., Kramm C.M., Felsberg J., Hartmann C., Wiestler B., Wick W., Milde T., Witt O., Lindroth A.M., Schwartzentruber J., Faury D., Fleming A., Zakrzewska M., Liberski P.P., Zakrzewski K., Hauser P., Garami M., Klekner A., Bognar L., Morrissy S., Cavalli F., Taylor M.D., van Sluis P., Koster J., Versteeg R., Volckmann R., Mikkelsen T., Aldape K., Reifenberger G., Collins V.P., Majewski J., Korshunov A., Lichter P., Plass C., Jabado N., Pfister S.M. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell. 2012 Oct 16; 22(4): 425–37. doi: 10.1016/j.ccr.2012.08.024.Toedt G., Barbus S., Wolter M., Felsberg J., Tews B., Blond F., Sabel M.C., Hofmann S., Becker N., Hartmann C., Ohgaki H., von Deimling A., Wiestler O.D., Hahn M., Lichter P., Reifenberger G., Radlwimmer B. Molecular signatures classify astrocytic gliomas by IDH1 mutation status. Int J Cancer. 2011 Mar 1; 128(5): 1095–103. doi: 10.1002/ijc.25448.Toedt G., Barbus S., Wolter M., Felsberg J., Tews B., Blond F., Sabel M.C., Hofmann S., Becker N., Hartmann C., Ohgaki H., von Deimling A., Wiestler O.D., Hahn M., Lichter P., Reifenberger G., Radlwimmer B. Molecular signatures classify astrocytic gliomas by IDH1 mutation status. Int J Cancer. 2011 Mar 1; 128(5): 1095–103. doi: 10.1002/ijc.25448.Noushmehr H., Weisenberger D.J., Diefes K., Phillips H.S., Pujara K., Berman B.P., Pan F., Pelloski C.E., Sulman E.P., Bhat K.P., Verhaak R.G., Hoadley K.A., Hayes D.N., Perou C.M., Schmidt H.K., Ding L., Wilson R.K., Van Den Berg D., Shen H., Bengtsson H., Neuvial P., Cope L.M., Buckley J., Herman J.G., Baylin S.B., Laird P.W., Aldape K.; Cancer Genome Atlas Research Network. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010 May 18; 17(5): 510–22. doi: 10.1016/j.ccr.2010.03.017.Noushmehr H., Weisenberger D.J., Diefes K., Phillips H.S., Pujara K., Berman B.P., Pan F., Pelloski C.E., Sulman E.P., Bhat K.P., Verhaak R.G., Hoadley K.A., Hayes D.N., Perou C.M., Schmidt H.K., Ding L., Wilson R.K., Van Den Berg D., Shen H., Bengtsson H., Neuvial P., Cope L.M., Buckley J., Herman J.G., Baylin S.B., Laird P.W., Aldape K.; Cancer Genome Atlas Research Network. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010 May 18; 17(5): 510–22. doi: 10.1016/j.ccr.2010.03.017.Suh J.H., Park C.K., Park S.H. Alpha internexin expression related with molecular characteristics in adult glioblastoma and oligodendroglioma. J Korean Med Sci. 2013 Apr; 28(4): 593–601. doi: 10.3346/jkms.2013.28.4.593.Suh J.H., Park C.K., Park S.H. Alpha internexin expression related with molecular characteristics in adult glioblastoma and oligodendroglioma. J Korean Med Sci. 2013 Apr; 28(4): 593–601. doi: 10.3346/jkms.2013.28.4.593.Durand K., Guillaudeau A., Pommepuy I., Mesturoux L., Chaunavel A., Gadeaud E., Porcheron M., Moreau J.J., Labrousse F. Alphainternexin expression in gliomas: relationship with histological type and 1p, 19q, 10p and 10q status. J Clin Pathol. 2011 Sep; 64(9): 793–801. doi: 10.1136/jcp.2010.087668.Durand K., Guillaudeau A., Pommepuy I., Mesturoux L., Chaunavel A., Gadeaud E., Porcheron M., Moreau J.J., Labrousse F. Alphainternexin expression in gliomas: relationship with histological type and 1p, 19q, 10p and 10q status. J Clin Pathol. 2011 Sep; 64(9): 793–801. doi: 10.1136/jcp.2010.087668.Ducray F., Crinière E., Idbaih A., Mokhtari K., Marie Y., Paris S., Navarro S., Laigle-Donadey F., Dehais C., Thillet J., Hoang-Xuan K., Delattre J.Y., Sanson M. alpha-Internexin expression identifies 1p19q codeleted gliomas. Neurology. 2009 Jan 13; 72(2): 156–61. doi: 10.1212/01.wnl.0000339055.64476.cb.Ducray F., Crinière E., Idbaih A., Mokhtari K., Marie Y., Paris S., Navarro S., Laigle-Donadey F., Dehais C., Thillet J., Hoang-Xuan K., Delattre J.Y., Sanson M. alpha-Internexin expression identifies 1p19q codeleted gliomas. Neurology. 2009 Jan 13; 72(2): 156–61. doi: 10.1212/01.wnl.0000339055.64476.cb.Мацко М.В., Мацко Д.Е., Моисеенко В.М., Улитин А.Ю., Волков Н.М., Иевлева А.Г., Имянитов Е.Н. Предиктивная роль гена MGMT при лечении Темозоломидом больных с глиобластомой. Материалы XI международного научного конгресса «Рациональная фармакотерапия». СПб., 2016. 97–98.Matsko M.V., Matsko D.E., Moiseenko V.M., Ulitin A.Yu., Iyevleva A.G., Imyanitov E.N. Predictive role of a gene MGMT at treatment of patients with glioblastoma by Temozolomid. Abstracts of the XI International Scientific Congress «Rational Pharmacotherapy». Saint-Peterburg, 2016. 97–98. (in Russian).

The authors declare that there are no conflicts of interest present.