A new GTF2I-BRAF fusion mediating MAPK pathway activation in pilocytic astrocytoma

2017-04-27 12:11:35

Plos One  April 27 2017

DiTajana Tešan Tomic, Josefin Olausson, Annica Wilzén, Magnus Sabel, Katarina Truvé, Helene Sjögren, Sándor Dósa, Magnus Tisell, Birgitta Lannering, Fredrik Enlund, Tommy Martinsson, Pierre Åman, Frida Abel


Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. A recurrent feature of PA is deregulation of the mitogen activated protein kinase (MAPK) pathway most often through KIAA1549-BRAF fusion, but also by other BRAF- or RAF1-gene fusions and point mutations (e.g. BRAFV600E). These features may serve as diagnostic and prognostic markers, and also facilitate development of targeted therapy. The aims of this study were to characterize the genetic alterations underlying the development of PA in six tumor cases, and evaluate methods for fusion oncogene detection. Using a combined analysis of RNA sequencing and copy number variation data we identified a new BRAF fusion involving the 5’ gene fusion partner GTF2I (7q11.23), not previously described in PA. The new GTF2I-BRAF 19–10 fusion was found in one case, while the other five cases harbored the frequent KIAA1549-BRAF 16–9 fusion gene. Similar to other BRAF fusions, the GTF2I-BRAF fusion retains an intact BRAF kinase domain while the inhibitory N-terminal domain is lost. Functional studies on GTF2I-BRAF showed elevated MAPK pathway activation compared to BRAFWT. Comparing fusion detection methods, we found Fluorescence in situ hybridization with BRAF break apart probe as the most sensitive method for detection of different BRAF rearrangements (GTF2I-BRAF and KIAA1549-BRAF). Our finding of a new BRAF fusion in PA further emphasis the important role of B-Raf in tumorigenesis of these tumor types. Moreover, the consistency and growing list of BRAF/RAF gene fusions suggests these rearrangements to be informative tumor markers in molecular diagnostics, which could guide future treatment strategies.


Central nervous system (CNS) tumors are the second most common pediatric malignancies after acute lymphoblastic leukemia. Among all brain tumors, low-grade gliomas (LGG, World Health Organization (WHO) grade I and grade II) account for around 30–40% of cases. The most common LGGs are the Pilocytic astrocytomas (PA, grade I) accounting for at least 17% of CNS neoplasms in children (0–14 years). The majority of pediatric PA occurs in the cerebellum (>40%), but can also be found in the supratentorial compartment, the optic pathway, hypothalamus, brainstem and spinal cord. PA are histologically characterized by bipolar tumor cells, biphasic pattern, Rosenthal fibers and eosinophilic granular bodies but can exhibit varying histology and can show similarities to other high-grade astrocytomas, making the diagnosis somewhat challenging. PA has a favorable prognosis indicated by 20 years survival rate of 90% for low-grade astrocytomas. Dissemination is uncommon, but may occur in newly diagnosed PAs. Surgical resection is a first line therapy, and radiation and chemotherapy are applicable in case of inoperable or partly resected tumors. Despite good prognosis, recurrence of the tumor occurs in 10–20% of cases and the effects of tumor and current treatment strategies can cause severe psychosocial and physical dysfunction. This emphasizes considerable need for reliable tumor markers to improve histological diagnosis of PA and ensure appropriate therapy, but also to guide and facilitate the development of personalized targeted therapy.

Empire Genomic's BRAF Break Apart FISH Probe was used in this publication.

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