185 Vol. 74, No. 1, January 2024 Open Access Abstract With advances in molecular genetics, exploring targetable mutations for treating glioblastoma (GBM) patients, has become a centre of interest in modern day neuropathology. BRAF mutation has been extensively reported in several brain tumours. Recent studies report identification of BRAF mutation in GBM patients, especially isocitrate dehydrogenase wildtype glioblastomas (IDH-WT GBM), and its potential role in patient outcomes. Here we discuss the existing literature on the prognostic value of BRAF mutation in GBM. Keywords: Glioblastoma, BRAF mutation, prognosis DOI: https://doi.org/10.47391/JPMA.24-05 Introduction In modern neuropathology, the analysis of molecular genetics has become an essential component, as it is important for diagnosis, treatment and prognosis of brain tumours. 1 Substantial research efforts focused on genomics coupled with expanding clinical molecular diagnostics have sparked interest in exploring targetable mutations in the management of GBM, the most common and aggressive variant of adult glioma. 2,3 One such targetable mutation is the BRAF V600E mutation, which has important therapeutic implications. These mutations affect a specific region prone to mutation at amino acid position 600 and is characterised by the substitution of valine with glutamate (referred as BRAFV600E). 3 The BRAFV600E mutation is believed to imitate phosphorylation of the activating amino acids T599 and S602, resulting in constitutive activation of the protein that affects cell proliferation, differentiation, and survival. Although this mutation is often linked with poor prognosis in certain gliomas, it is shown to correlate with better prognosis in cases of isocitrate dehydrogenase wildtype glioblastomas (GBM IDH-WT). 4 BRAF belongs to RAS/RAF/MEK/ERK kinase pathway. Clinical trials are underway to evaluate the effectiveness of RAF-targeted therapy alone or in combination with radiation for the treatment of low and high-grade BRAF-mutant gliomas. Therefore, identifying BRAF mutations in patients with GBM is of clinical significance as GBM patients may potentially benefit from BRAFV600E targetted therapy. Herein, we have reviewed prognosis of BRAF mutant GBM. Review of Evidence Chan et al., examined 578 cases of infiltrative gliomas over a period of 24 years. 4 The overall BRAF-V600E mutation rate observed was 5.9% (34 out of 578) in this cohort which included 21 cases of IDH-WT GBM. 4 BRAF mutation was seen to be associated with younger age and female gender. Univariate analysis showed that BRAF mutation in IDH-WT GBM was associated with significantly longer median overall survival of around 3.6 years compared to BRAF wild type in GBM with a median overall survival of 0.9 years. 4 Dono et al., analyzed 372 patients with gliomas and reviewed outcomes of different cancer-associated genes in these patients. 3 Among 372 gliomas, 249 were classified as GBM IDH-WT.4 Within the subset of 249 patients, only 8 (3.2%) cases exhibited BRAF mutations in GBM IDH-WT. In addition to this, all (2/2) patients with epithelioid-GBM (E- GBM) had BRAF mutant genes. Majority of patients with GBM IDH-WT underwent resection followed by temozolomide (TMZ) and radiotherapy according to the Stupp protocol. The median overall survival of patients with GBM IDH-WT with a BRAF mutation was 12.8 months which was lower than the median overall survival of 19.1 months for the remaining 241 GBM, IDH-WT (BRAF wild-type) cases in this database which led to the conclusion that that BRAF mutation in IDH-WT GBM may have a worse prognosis. This result contrasts with the previously mentioned study by Chan et al. 4 This may be because this study was limited by a small sample size due to the rarity of BRAF-mutant infiltrating gliomas. 3 In contrast to this, all E-GBM patients were alive at the time of submission of this study with a median overall survival of 12.1 months. Korshunov et al., analyzed 64 (33 paediatric and 31 adult) patients who were initially diagnosed as E-GBM. 5 All patients underwent gross total or subtotal resection followed by radiotherapy and chemotherapy with TMZ. 5 During the follow‐up period, 28 (60%) patients died with median overall survival of 23 months. 5 Molecular analysis revealed that E-GBM can be distinguished into three tumour subtypes: pleomorphic xanthoastrocytomas (PXA) EVIDENCE BASED NEURO-ONCOLOGY Prognostic Value of BRAF Mutation in Glioblastoma Ayesha Sohail1, Qurat-Ul-Ain Virani, Hafiza Fatima Aziz, Muhammad Shahzad Shamim Section of Neurosurgery, Department of Surgery, Aga Khan University, Karachi, Pakistan. Correspondence: Muhammad Shahzad Shamim. e-mail: shahzad.shamim@aku.edu ORCID ID: 0000-0001-8305-8854