BRAF AMP Frequently Co-occurs With IDH1/2, TP53, and ATRX Mutations in Adult Patients With Gliomas and Is Associated With Poorer Survival Than That of Patients Harboring BRAF V600E.

Abnormal RAS/RAF signaling plays a critical role in glioma. Although it is known that the V600E mutation of v-raf murine viral oncogene homolog B1 (BRAF V600E) and BRAF amplification (BRAF AMP) both result in constitutive activation of the RAS/RAF pathway, whether BRAF V600E and BRAF AMP have different effects on the survival of glioma patients needs to be clarified. Using cBioPortal, we retrieved studies of both mutations and copy number variations of the BRAF gene in CNS/brain tumors and investigated data from 69 nonredundant glioma patients. The BRAF mutation group had significantly more male patients (64.00% vs. 36.84%; P = 0.046) and a higher occurrence of glioblastoma multiforme (66.00% vs. 31.58%; P = 0.013) compared to those in the other group. The BRAF AMP group had significantly more patients with the mutant isocitrate dehydrogenase 1 and 2 (IDH1/2) (73.68% vs. 18.00%; P = 0.000), tumor protein p53 (TP53) (73.68% vs. 30.00%; P = 0.002), and alpha thalassemia/mental retardation syndrome X linked (ATRX) (63.16% vs. 18.00%; P = 0.001) than the mutation group. The BRAF AMP and IDH1/2 WT cohort had lower overall survival compared with the BRAF AMP and IDH1/2 MT groups (P = 0.001) and the BRAF mutation cohort (P = 0.019), including the BRAF V600E (P = 0.033) and BRAF non-V600E (P = 0.029) groups, using Kaplan-Meier survival curves and the log rank (Mantel-Cox) test. The BRAF AMP and IDH1/2 WT genotype was found to be an independent predictive factor for glioma with BRAF mutation and BRAF AMP using Cox proportional hazard regression analysis (HR = 0.138, P = 0.018). Our findings indicate that BRAF AMP frequently occurs with IDH1/2, TP53, and ATRX mutations. Adult patients with glioma with BRAF AMP and IDH1/2 WT had worse prognoses compared with those with BRAF mutation and BRAF AMP and IDH1/2 MT. This suggests that the assessment of the status of BRAF AMP and IDH1/2 in adult glioma/glioblastoma patients has prognostic value as these patients have relatively short survival times and may benefit from personalized targeted therapy using BRAF and/or MEK inhibitors.