[Master regulators associated with poor prognosis in glioblastoma multiforme].

Glioblastoma multiforme (GBM) is a highly malignant brain tumor with average survival time of 15 months. Less than 2% of the patients survive beyond 36 months. To understand the molecular mechanism responsible for poor prognosis, we analyzed GBM samples of TCGA microarray (n=560) data. We have identified 720 genes that have a significant impact upon survival based on univariate cox regression. We applied the Genome Enhancer pipeline to analyze potential mechanisms of regulation of activity of these genes and to build gene regulatory networks. We identified 12 transcription factors enriched in the promoters of these genes including the key molecule of GBM - STAT3. We found that STAT3 had significant differential expression across extreme survivor groups (short-term survivors- survival 36 months) and also had a significant impact on survival. In the next step, we identified master regulators in the signal transduction network that regulate the activity of these transcription factors. Master regulators are filtered based on their differential expression across extreme survivors groups and impact on survival. This work validates our earlier report on master regulators IGFBP2, PDGFA, OSMR, and AEBP1 driving short survival. Additionally, we propose CD14, CD44, DUSP6, GRB10, IL1RAP, FGFR3, and POSTN as master regulators driving poor survival. These master regulators are proposed as promising therapeutic targets to counter poor prognosis in GBM. Finally, the algorithm has prioritized several drugs for the further study as potential remedies to conquer the aggressive forms of GBM and to extend survival of the patients. Glioblastoma (GBM, glioblastoma multiforme) iavliaetsia zlokachestvennoĭ opukhol'iu golovnogo mozga so srednim srokom vyzhivaniia 15 mesiatsev. Menee 2% patsientov vyzhivaiut posle 36 mesiatsev. Dlia ponimaniia molekuliarnogo mekhanizma, otvetstvennogo za plokhoĭ prognoz, my proanalizirovali 560 obraztsov GBM transkriptomnykh dannykh na osnove mikrochipov iz bazy dannykh TCGA (The Cancer Genome Atlas). Analiz s pomoshch'iu odnomernoĭ regressii Koksa pozvolil identifitsirovat' 720 genov, kotorye okazyvaiut znachitel'noe vliianie na prodolzhitel'nost' vyzhivaniia. Dlia ustanovleniia potentsial'nykh mekhanizmov reguliatsii aktivnosti étikh genov i postroeniia seteĭ gennoĭ reguliatsii my ispol'zovali programmnoe obespechenie Genome Enhancer (https://genexplain.com/genome-enhancer/). V rezul'tate my vyiavili 12 transkriptsionnykh faktorov, saĭty kotorykh obogashcheny v promotorakh étikh genov, vkliuchaia kliuchevoĭ faktor reguliatsii mnogikh patologicheskikh protsessov v GBM — STAT3. My ustanovili, chto gen STAT3 differentsial'no ékspressiruetsia v ékstremal'nykh gruppakh vyzhivaniia (kratkovremennoe vyzhivanie —vyzhivaemost' menee 12 mesiatsev i dolgovremennoe vyzhivanie — vyzhivaemost' bolee 36 mesiatsev), i ego ékspressiia korreliruet s prodolzhitel'nost'iu zhizni u patsientov pri glioblastome. Na sleduiushchem étape my opredelili master-reguliatory v seti peredachi signalov v kletkakh, kotorye reguliruiut aktivnost' étikh transkriptsionnykh faktorov. Pod master-reguliatorami my podrazumevaem takie upravliaiushchie belki v reguliatornoĭ signal'noĭ seti, kotorye igraiut kliuchevuiu rol' v upravlenii issleduemym molekuliarnym protsessom. Master-reguliatory byli otfil'trovany na osnove dannykh ob ikh differentsial'noĭ ékspressii v ékstremal'nykh gruppakh vyzhivaniia i korreliatsii s prodolzhitel'nost'iu zhizni u patsientov s GBM. Provedennoe issledovanie podtverzhdaet poluchennye nami ranee rezul'taty, soglasno kotorym master-reguliatory IGFBP2, PDGFA, OSMR i AEBP1 sviazany s umen'sheniem vremeni vyzhivaniia patsientov s GBM. Krome togo, my vyiavili geny CD14, CD44, DUSP6, GRB10, IL1RAP, FGFR3 i POSTN v kachestve master-reguliatorov vyzhivaniia pri glioblastome. Éti master-reguliatory predlozheny v kachestve perspektivnykh misheneĭ dlia terapevticheskogo vozdeĭstviia pri neblagopriiatnym prognoze pri GBM. Na osnove ikh analiza s ispol'zovaniem programm Genome Enhancer i PASS my otobrali neskol'ko perspektivnykh lekarstvennykh preparatov v kachestve potentsial'nykh sredstv dlia bor'by s agressivnymi formami GBM i povysheniia vyzhivaemosti patsientov.