Molecular diagnostics of glioblastoma – clinical impact of IDH mutations and epigenetic silencing of MGMT

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