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.

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

doi:10.3389/fonc.2020.531968

Rong Da, Wei Wang + Show 3 more

Open Access

https://doi.org/10.3389/fonc.2020.531968

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Abstract

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.

Highlights

Gliomas are the most frequent primary brain neoplasms occurring in both the pediatric and adult populations (1)
BRAFV600E is rarely found in adult gliomas, it occurs predominately in pediatric gliomas, accounting for 68%–80% of pleomorphic xanthoastrocytoma (PXA), 20%–70% of ganglioglioma, 9%–10% of pilocytic astrocytoma (PA), 5%–15%
Because genetic alterations are important in tumor development and progression (33, 34) and both BRAFV600E and BRAF amplification (BRAFAMP) can activate the mitogenactivated protein kinase (MAPK) pathway, we investigated the different effects of these two BRAF alterations and the mutations associated on the survival of glioma patients

Summary

Introduction

Gliomas are the most frequent primary brain neoplasms occurring in both the pediatric and adult populations (1). Mutation site genotypes of genes such as isocitrate dehydrogenase (IDH), tumor protein p53(TP53), and alpha thalassemia/mental retardation syndrome X linked (ATRX) and 1p/19q codeletion should be evaluated. Determining the status of IDH mutation and 1p/19q is essential for the 2016 classification of diffused gliomas, including astrocytoma, oligoastrocytoma, oligodendroglioma, and glioblastoma (2). The RAS/RAF/MEK/extracellular signal-regulated kinase (ERK) mitogenactivated protein kinase (MAPK) pathway, which transduces mitogenic stimuli via the activation of growth factor receptors, is critical for cell proliferation, survival, and differentiation. Abnormal activation of RAS/RAF signaling plays a role in various tumors, and studies have revealed that the MAPK pathway is of great clinical significance in gliomas (3). Oncogenic mutations as well as the copy number amplification of RAS/RAF and/or abnormal activation of upstream growth factor receptors can cause hyperactivation of the RAS/RAF pathway (4), resulting in various neoplasms

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