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      Oncogenic BRAF Alterations and Their Role in Brain Tumors

      review-article
      1 , 2 , *
      Cancers
      MDPI
      BRAF V600E, KIAA1549-BRAF, MAPK, astrocytoma, glioblastoma

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          Abstract

          Alterations of the v-raf murine sarcoma viral oncogene homolog B (BRAF) have been extensively studied in several tumor entities and are known to drive cell growth in several tumor entities. Effective targeted therapies with mutation-specific small molecule inhibitors have been developed and established for metastasized malignant melanoma. The BRAF V600E mutation and KIAA1549-BRAF fusion are alterations found in several brain tumors and show a distinct prognostic impact in some entities. Besides the diagnostic significance for the classification of central nervous system tumors, these alterations present possible therapy targets that may be exploitable for oncological treatments, as it has been established for malignant melanomas. In this review the different central nervous system tumors harboring BRAF alterations are presented and the diagnostic significance, prognostic role, and therapeutic potential are discussed.

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          Most cited references87

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          Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience

          Recently, we described a machine learning approach for classification of central nervous system tumors based on the analysis of genome-wide DNA methylation patterns [6]. Here, we report on DNA methylation-based central nervous system (CNS) tumor diagnostics conducted in our institution between the years 2015 and 2018. In this period, more than 1000 tumors from the neurosurgical departments in Heidelberg and Mannheim and more than 1000 tumors referred from external institutions were subjected to DNA methylation analysis for diagnostic purposes. We describe our current approach to the integrated diagnosis of CNS tumors with a focus on constellations with conflicts between morphological and molecular genetic findings. We further describe the benefit of integrating DNA copy-number alterations into diagnostic considerations and provide a catalog of copy-number changes for individual DNA methylation classes. We also point to several pitfalls accompanying the diagnostic implementation of DNA methylation profiling and give practical suggestions for recurring diagnostic scenarios. Electronic supplementary material The online version of this article (10.1007/s00401-018-1879-y) contains supplementary material, which is available to authorized users.
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            BRAF Inhibition in BRAF V600 -Mutant Gliomas: Results From the VE-BASKET Study

            Purpose BRAF V600 mutations are frequently found in several glioma subtypes, including pleomorphic xanthoastrocytoma (PXA) and ganglioglioma and much less commonly in glioblastoma. We sought to determine the activity of vemurafenib, a selective inhibitor of BRAF V600, in patients with gliomas that harbor this mutation. Patients and Methods The VE-BASKET study was an open-label, nonrandomized, multicohort study for BRAF V600-mutant nonmelanoma cancers. Patients with BRAF V600-mutant glioma received vemurafenib 960 mg twice per day continuously until disease progression, withdrawal, or intolerable adverse effects. Key end points included confirmed objective response rate by RECIST version 1.1, progression-free survival, overall survival, and safety. Results Twenty-four patients (median age, 32 years; 18 female and six male patients) with glioma, including malignant diffuse glioma (n = 11; six glioblastoma and five anaplastic astrocytoma), PXA (n = 7), anaplastic ganglioglioma (n = 3), pilocytic astrocytoma (n = 2), and high-grade glioma, not otherwise specified (n = 1), were treated. Confirmed objective response rate was 25% (95% CI, 10% to 47%) and median progression-free survival was 5.5 months (95% CI, 3.7 to 9.6 months). In malignant diffuse glioma, best response included one partial response and five patients with stable disease, two of whom had disease stabilization that lasted more than 1 year. In PXA, best response included one complete response, two partial responses, and three patients with stable disease. Additional partial responses were observed in patients with pilocytic astrocytoma and anaplastic ganglioglioma (one each). The safety profile of vemurafenib was generally consistent with that of previously published studies. Conclusion Vemurafenib demonstrated evidence of durable antitumor activity in some patients with BRAF V600-mutant gliomas, although efficacy seemed to vary qualitatively by histologic subtype. Additional study is needed to determine the optimal use of vemurafenib in patients with primary brain tumors and to identify the mechanisms driving differential responses across histologic subsets.
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              Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody.

              Activating mutations of the serine threonine kinase v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) are frequent in benign and malignant human tumors and are emerging as an important biomarker. Over 95% of BRAF mutations are of the V600E type and specific small molecular inhibitors are currently under pre-clinical or clinical investigation. BRAF mutation status is determined by DNA-based methods, most commonly by sequencing. Here we describe the development of a monoclonal BRAF V600E mutation-specific antibody that can differentiate BRAF V600E and wild type protein in routinely processed formalin-fixed and paraffin-embedded tissue. A total of 47 intracerebral melanoma metastases and 21 primary papillary thyroid carcinomas were evaluated by direct sequencing of BRAF and by immunohistochemistry using the BRAF V600E mutation-specific antibody clone VE1. Correlation of VE1 immunohistochemistry and BRAF sequencing revealed a perfect match for both papillary thyroid carcinomas and melanoma metastases. The staining intensity in BRAF V600E mutated tumor samples ranged from weak to strong. The generally homogenous VE1 staining patterns argue against a clonal heterogeneity of the tumors investigated. Caution is essential when only poorly preserved tissue is available for VE1 immunohistochemical analysis or when tissues with only little total BRAF protein are analyzed. Immunohistochemistry using antibody VE1 may substantially facilitate molecular analysis of BRAF V600E status for diagnostic, prognostic, and predictive purposes.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                08 June 2019
                June 2019
                : 11
                : 6
                : 794
                Affiliations
                [1 ]Department of Neurosurgery, Eberhard Karls University Tübingen, 72074 Tübingen, Germany; felix.behling@ 123456med.uni-tuebingen.de
                [2 ]Department of Neuropathology, Comprehensive Cancer Center Tübingen-Stuttgart and Eberhard Karls University Tübingen, Abt. für Neuropathologie, Calwer Str.3, 72074 Tübingen, Germany
                Author notes
                [* ]Correspondence: jens.schittenhelm@ 123456med.uni-tuebingen.de ; Tel.: +49-7071-29-82283
                Author information
                https://orcid.org/0000-0002-1083-1276
                https://orcid.org/0000-0002-9168-6209
                Article
                cancers-11-00794
                10.3390/cancers11060794
                6627484
                31181803
                6a57e3ee-aa41-4251-9a93-4c3839260299
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 17 May 2019
                : 06 June 2019
                Categories
                Review

                braf v600e,kiaa1549-braf,mapk,astrocytoma,glioblastoma
                braf v600e, kiaa1549-braf, mapk, astrocytoma, glioblastoma

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