Abstract
The BRAF gene and the TERT promoter are among the most frequently altered genomic loci in low-grade (LGG) and high-grade-glioma (HGG), respectively. The coexistence of BRAF and TERT promoter aberrations characterizes a subset of aggressive glioma. Therefore, we investigated interactions between those alterations in malignant glioma. We analyzed co-occurrence of BRAFV600E and TERT promoter mutations in our clinical data (n = 8) in addition to published datasets (n = 103) and established a BRAFV600E-positive glioma cell panel (n = 9) for in vitro analyses. We investigated altered gene expression, signaling events and TERT promoter activity upon BRAF- and E-twenty-six (ETS)-factor inhibition by qRT-PCR, chromatin immunoprecipitation (ChIP), Western blots and luciferase reporter assays. TERT promoter mutations were significantly enriched in BRAFV600E-mutated HGG as compared to BRAFV600E-mutated LGG. In vitro, BRAFV600E/TERT promoter double-mutant glioma cells showed exceptional sensitivity towards BRAF-targeting agents. Remarkably, BRAF-inhibition attenuated TERT expression and TERT promoter activity exclusively in double-mutant models, while TERT expression was undetectable in BRAFV600E-only cells. Various ETS-factors were broadly expressed, however, only ETS1 expression and phosphorylation were consistently downregulated following BRAF-inhibition. Knock-down experiments and ChIP corroborated the notion of a functional role for ETS1 and, accordingly, all double-mutant tumor cells were highly sensitive towards the ETS-factor inhibitor YK-4-279. In conclusion, our data suggest that concomitant BRAFV600E and TERT promoter mutations synergistically support cancer cell proliferation and immortalization. ETS1 links these two driver alterations functionally and may represent a promising therapeutic target in this aggressive glioma subgroup.
Highlights
Glioma represents the most common tumor type in the central nervous system (CNS) across all age groups [37]
telomerase reverse transcriptase (TERT) promoter mutations are associated with TERT expression and enhanced aggressiveness in BRAFV600Emutated glioma We analyzed the TERT promoter mutation status in a small cohort of pediatric cases with BRAFV600E-mutated glioma (n = 8, Additional file 1: Table S3) treated at the General Hospital of Vienna
TERT promoter mutation status of these BRAFV600E-positive glioma patients was correlated to clinical parameters including gender, age, WHO grade and overall survival
Summary
Glioma represents the most common tumor type in the central nervous system (CNS) across all age groups [37]. The biology and clinical behavior of glioma are highly heterogeneous as reflected by WHO grades ranging from I to IV [27]. BRAF is a serine/threonine kinase and central mediator in the well-described oncogenic mitogen-activated protein kinase (MAPK) signaling pathway [14]. Various alterations such as activating mutations of BRAF are commonly found in cancerous tissues [14]. In the pediatric patient population, more than half of LGG are characterized by genetic alterations of the BRAF. First analyses show promising results in both the pediatric [3, 7, 21, 42] and the adult patient population [17]
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