On sequencing of the 2 components separately after microdissection, both showed identical IDH1 R132H and TP53R273C point mutations, whereas the BRAF V600E mutation was limited to the PXA-like component.
We suggest that the incidence of TP53 mutations in pleomorphic xanthoastrocytoma may be underestimated and that molecular approaches should be used for greater diagnostic precision.
In the present study, we performed immunostaining for p53 protein and examined the mutation status of exons 5-8 of the p53 gene in 55 PXAs, 8 of which had undergone one or multiple recurrences.
Single-strand conformation polymorphism analysis of p53 exons 5-8 revealed migration shifts in two cases, one primary PXA without recurrence and one recurrent grade II PXA in which the primary tumor did not show a shift.
Because mutations of FANCA and BRAF and copy number variations of CDKN2A/B are more frequent in PXA than in glioblastoma, they might be used to distinguish the 2 tumors.
A BRAFV600E mutation and homozygous deletion of CDKN2A/B were observed, which is similar to the genetic features of PXA or epithelioid glioblastoma, but the additional loss of ATRX nuclear immunoreactivity and absence of TERT promoter mutation were unusual findings, indicating a novel genetic profile.
The authors treated 4 BRAFV600E patients, each with a different type of primary brain tumor (pilocytic astrocytoma, papillary craniopharyngioma, ganglioglioma, and pleomorphic xanthoastrocytoma) with the combination of dabrafenib and trametinib.
The efficacy of bevacizumab, temozolomide, lomustine (CCNU), irinotecan (CPT 11), a tyrosine kinase inhibitor (sorafenib), a selective MEK1/2 inhibitor (cobimetinib), and a BRAF inhibitor (vemurafenib) were assessed in two subcutaneous xenografts: D645 PXA (V600E-mutant) and D2363 PXA (V600E-non-mutant) (n = 5-10 mice).
The ability of the polio: rhinovirus recombinant, PVSRIPO, to infect PXA (645 [BRAFV600E mutation], 2363) and medulloblastoma (D283, D341) cells were determined by viral propagation measurement and cell proliferation.
In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8<sup>+</sup> tumor-infiltrating lymphocytes, and longer survival with the addition of BEV.
Some glial-neuronal tumors (GNT) (pleomorphic xantho-astrocytoma [PXA], ganglioglioma [GG]) display BRAF-V600E mutation, which represents a diagnostic clue to these entities.
In summary, we showed that PLGG tumorigenicity was low despite the presence of putative CSCs, and our data supported GFAP<sup>-</sup>/Vimentin<sup>+</sup> cells, <i>CDKN2A</i> homozygous deletion in trisomy chromosome 9 cells, and <i>BRAF V600E</i> mutation as candidate drivers of tumor progression in the PXA xenografts.
BRAF mutations are most frequently detected in certain subtypes of low-grade glioma, such as pilocytic astrocytoma (PA), pleomorphic xanthoastrocytoma (PXA), ganglioglioma (GG) and dysembryoplastic neuroepithelial tumor (DNT).
Specifically, both the initial and recurrent tumors of the patient showed the same BRAFV600E mutation, which refutes previous suggestions that BRAF mutations may be limited to intracranial PXAs and also shows that BRAF mutations may occur earlier in PXA tumorigenesis.
Both components were positive for the mutant IDH1 R132H and showed loss of ATRX expression, whereas BRAFV600E was restricted to the PXA-like component.
Our data indicate, that in addition to the histological and immunohistochemical evaluation, investigation of MGMT promoter methylation and in particular BRAFV600E mutations represent reliable additional tools to sustain differentiation of gcGBM from PXA on a molecular basis.
BRAFV600E mutations are found frequently in circumscribed low-grade gliomas such as pleomorphic xanthoastrocytoma (PXA) and extra-cerebellar pilocytic astrocytoma, or epithelioid glioblastomas (E-GBM), a rare variant of GBM.