Molekularna dijagnostika glioblastoma –klinički uticaji IDH mutacija i epigenetičkog utišavanja aktivnosti MGMT gena
Molecular diagnostics of glioblastoma – clinical impact of IDH mutations and epigenetic silencing of MGMT
Апстракт
Savremeni terapijski pristupi u lečenju pacijenata obolelih od glioblastoma (GBM) oslanjaju se
na primenu alkilirajućih agenasa poput Temozolomida (“Stupp”-ov protokol). Sveobuhvatnim studijama
izučavanja genomskih asocijacija (GWAS) i randomizovanim kliničkim ispitivanjima otkriven je
uticaj statusa nekoliko važnih molekularnih markera na terapijski odgovor i klinički ishod kod GBM
pacijenata. Najvažnijim takvim markerom smatra se status mutacije gena za izocitrat-dehidrogenazu
1 (IDH1-R132H), koji je uvršten u važeću Klasifikaciju tumora centralnog nervnog sistema Svetske
zdravstvene organizacije. Određivanjem njegovog statusa moguće je razlikovati primarne od sekundarnih
GBM koje odlikuju značajne razlike u toku i ishodu bolesti. Takođe, pokazano je da je IDH1-
R132H mutacija usko povezana sa mehanizmima epigenetičkog utišavanja aktivnosti gena za
reparacioni enzim O⁶-metilguanin-metiltransferazu (MGMT) putem metilacije njegovog promotornog
regiona. Zbog direktnog suprotst...avljanja MGMT enzima dejstvu alkilirajućih agenasa, navedena inaktivacija
njegove aktivnosti predstavlja povoljan prognostički i predikcioni faktor GBM. Predmet
ovog revijskog rada biće pregled aktuelnih saznanja o ulozi navedenih markera u etiologiji GBM,
značaja njihove udružene evaluacije i problema šire implementacije njihovog određivanja u kliničkoj
praksi.
Current therapy protocols for the management of glioblastoma (GBM) patients mostly rely on the use
of alkylating agents, such as Temozolomide (Stupp protocol). During the past several decades, comprehensive
genome-wide association studies (GWAS) and randomized clinical trials have revealed and confirmed
the impact of numerous molecular markers on the therapy response in GBM patients. Among them,
the mutation status of the isocitrate dehydrogenase 1 gene (IDH1-R132H) was presented as the most important
molecular marker of GBM. Due to its importance, in 2016 it was introduced to the World Health Organisation
(WHO) Classification of Tumours of the Central Nervous System (CNS), which is still valid.
Through IDH1-R132H mutation evaluation, it is possible to distinguish the primary from the secondary
GBM which significantly differ in the clinical course and outcome. Moreover, it was shown that IDH1-R132H
mutation is closely related to the molecular mechanisms which drive epigenetic ...silencing of the O6-Methylguanine-
DNA Methyltransferase gene (MGMT) through methylation of its promoter region. Due to
the direct opposition of the MGMT enzyme to the alkylating agents‘ activity, its inactivation represents a
favorable prognostic and predictive factor in GBM. This review article discusses the current insights on the
role of IDH1 mutation and MGMT epigenetic silencing in GBM etiology, the importance of their mutual evaluation,
and the challenges of their evaluation in clinical practice.
Кључне речи:
glioblastom / molekularni markeri / epigenetika / MGMT / IDH1 / glioblastoma / molecular markers / epigeneticsИзвор:
Trendovi u molekularnoj Biologiji, 2022, 2, 125-142Издавач:
- Beograd : Institut za molekularnu genetiku i genetičko inženjerstvo
Финансирање / пројекти:
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200124 (Универзитет у Нишу, Природно-математички факултет) (RS-MESTD-inst-2020-200124)
Институција/група
Institut za molekularnu genetiku i genetičko inženjerstvoTY - CHAP AU - Jovanović, Nikola AU - Mitrović, Tatjana PY - 2022 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1817 AB - Savremeni terapijski pristupi u lečenju pacijenata obolelih od glioblastoma (GBM) oslanjaju se na primenu alkilirajućih agenasa poput Temozolomida (“Stupp”-ov protokol). Sveobuhvatnim studijama izučavanja genomskih asocijacija (GWAS) i randomizovanim kliničkim ispitivanjima otkriven je uticaj statusa nekoliko važnih molekularnih markera na terapijski odgovor i klinički ishod kod GBM pacijenata. Najvažnijim takvim markerom smatra se status mutacije gena za izocitrat-dehidrogenazu 1 (IDH1-R132H), koji je uvršten u važeću Klasifikaciju tumora centralnog nervnog sistema Svetske zdravstvene organizacije. Određivanjem njegovog statusa moguće je razlikovati primarne od sekundarnih GBM koje odlikuju značajne razlike u toku i ishodu bolesti. Takođe, pokazano je da je IDH1- R132H mutacija usko povezana sa mehanizmima epigenetičkog utišavanja aktivnosti gena za reparacioni enzim O⁶-metilguanin-metiltransferazu (MGMT) putem metilacije njegovog promotornog regiona. Zbog direktnog suprotstavljanja MGMT enzima dejstvu alkilirajućih agenasa, navedena inaktivacija njegove aktivnosti predstavlja povoljan prognostički i predikcioni faktor GBM. Predmet ovog revijskog rada biće pregled aktuelnih saznanja o ulozi navedenih markera u etiologiji GBM, značaja njihove udružene evaluacije i problema šire implementacije njihovog određivanja u kliničkoj praksi. AB - Current therapy protocols for the management of glioblastoma (GBM) patients mostly rely on the use of alkylating agents, such as Temozolomide (Stupp protocol). During the past several decades, comprehensive genome-wide association studies (GWAS) and randomized clinical trials have revealed and confirmed the impact of numerous molecular markers on the therapy response in GBM patients. Among them, the mutation status of the isocitrate dehydrogenase 1 gene (IDH1-R132H) was presented as the most important molecular marker of GBM. Due to its importance, in 2016 it was introduced to the World Health Organisation (WHO) Classification of Tumours of the Central Nervous System (CNS), which is still valid. Through IDH1-R132H mutation evaluation, it is possible to distinguish the primary from the secondary GBM which significantly differ in the clinical course and outcome. Moreover, it was shown that IDH1-R132H mutation is closely related to the molecular mechanisms which drive epigenetic silencing of the O6-Methylguanine- DNA Methyltransferase gene (MGMT) through methylation of its promoter region. Due to the direct opposition of the MGMT enzyme to the alkylating agents‘ activity, its inactivation represents a favorable prognostic and predictive factor in GBM. This review article discusses the current insights on the role of IDH1 mutation and MGMT epigenetic silencing in GBM etiology, the importance of their mutual evaluation, and the challenges of their evaluation in clinical practice. PB - Beograd : Institut za molekularnu genetiku i genetičko inženjerstvo T2 - Trendovi u molekularnoj Biologiji T1 - Molekularna dijagnostika glioblastoma –klinički uticaji IDH mutacija i epigenetičkog utišavanja aktivnosti MGMT gena T1 - Molecular diagnostics of glioblastoma – clinical impact of IDH mutations and epigenetic silencing of MGMT EP - 142 IS - 2 SP - 125 UR - https://hdl.handle.net/21.15107/rcub_imagine_1817 ER -
@inbook{ author = "Jovanović, Nikola and Mitrović, Tatjana", year = "2022", abstract = "Savremeni terapijski pristupi u lečenju pacijenata obolelih od glioblastoma (GBM) oslanjaju se na primenu alkilirajućih agenasa poput Temozolomida (“Stupp”-ov protokol). Sveobuhvatnim studijama izučavanja genomskih asocijacija (GWAS) i randomizovanim kliničkim ispitivanjima otkriven je uticaj statusa nekoliko važnih molekularnih markera na terapijski odgovor i klinički ishod kod GBM pacijenata. Najvažnijim takvim markerom smatra se status mutacije gena za izocitrat-dehidrogenazu 1 (IDH1-R132H), koji je uvršten u važeću Klasifikaciju tumora centralnog nervnog sistema Svetske zdravstvene organizacije. Određivanjem njegovog statusa moguće je razlikovati primarne od sekundarnih GBM koje odlikuju značajne razlike u toku i ishodu bolesti. Takođe, pokazano je da je IDH1- R132H mutacija usko povezana sa mehanizmima epigenetičkog utišavanja aktivnosti gena za reparacioni enzim O⁶-metilguanin-metiltransferazu (MGMT) putem metilacije njegovog promotornog regiona. Zbog direktnog suprotstavljanja MGMT enzima dejstvu alkilirajućih agenasa, navedena inaktivacija njegove aktivnosti predstavlja povoljan prognostički i predikcioni faktor GBM. Predmet ovog revijskog rada biće pregled aktuelnih saznanja o ulozi navedenih markera u etiologiji GBM, značaja njihove udružene evaluacije i problema šire implementacije njihovog određivanja u kliničkoj praksi., Current therapy protocols for the management of glioblastoma (GBM) patients mostly rely on the use of alkylating agents, such as Temozolomide (Stupp protocol). During the past several decades, comprehensive genome-wide association studies (GWAS) and randomized clinical trials have revealed and confirmed the impact of numerous molecular markers on the therapy response in GBM patients. Among them, the mutation status of the isocitrate dehydrogenase 1 gene (IDH1-R132H) was presented as the most important molecular marker of GBM. Due to its importance, in 2016 it was introduced to the World Health Organisation (WHO) Classification of Tumours of the Central Nervous System (CNS), which is still valid. Through IDH1-R132H mutation evaluation, it is possible to distinguish the primary from the secondary GBM which significantly differ in the clinical course and outcome. Moreover, it was shown that IDH1-R132H mutation is closely related to the molecular mechanisms which drive epigenetic silencing of the O6-Methylguanine- DNA Methyltransferase gene (MGMT) through methylation of its promoter region. Due to the direct opposition of the MGMT enzyme to the alkylating agents‘ activity, its inactivation represents a favorable prognostic and predictive factor in GBM. This review article discusses the current insights on the role of IDH1 mutation and MGMT epigenetic silencing in GBM etiology, the importance of their mutual evaluation, and the challenges of their evaluation in clinical practice.", publisher = "Beograd : Institut za molekularnu genetiku i genetičko inženjerstvo", journal = "Trendovi u molekularnoj Biologiji", booktitle = "Molekularna dijagnostika glioblastoma –klinički uticaji IDH mutacija i epigenetičkog utišavanja aktivnosti MGMT gena, Molecular diagnostics of glioblastoma – clinical impact of IDH mutations and epigenetic silencing of MGMT", pages = "142-125", number = "2", url = "https://hdl.handle.net/21.15107/rcub_imagine_1817" }
Jovanović, N.,& Mitrović, T.. (2022). Molekularna dijagnostika glioblastoma –klinički uticaji IDH mutacija i epigenetičkog utišavanja aktivnosti MGMT gena. in Trendovi u molekularnoj Biologiji Beograd : Institut za molekularnu genetiku i genetičko inženjerstvo.(2), 125-142. https://hdl.handle.net/21.15107/rcub_imagine_1817
Jovanović N, Mitrović T. Molekularna dijagnostika glioblastoma –klinički uticaji IDH mutacija i epigenetičkog utišavanja aktivnosti MGMT gena. in Trendovi u molekularnoj Biologiji. 2022;(2):125-142. https://hdl.handle.net/21.15107/rcub_imagine_1817 .
Jovanović, Nikola, Mitrović, Tatjana, "Molekularna dijagnostika glioblastoma –klinički uticaji IDH mutacija i epigenetičkog utišavanja aktivnosti MGMT gena" in Trendovi u molekularnoj Biologiji, no. 2 (2022):125-142, https://hdl.handle.net/21.15107/rcub_imagine_1817 .