AUTHOR=Da Rong , Wang Maode , Jiang Haitao , Wang Tuo , Wang Wei 

TITLE=BRAFAMP 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 BRAFV600E

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.531968

DOI=10.3389/fonc.2020.531968

ISSN=2234-943X

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