Genetic mechanisms such as activation of MAPK, BRAF gene deregulation and neurofibromatosis type 1 (NF1) syndrome have been associated with PA development.
Our results further emphasize the importance of BRAF alterations in PA and the need to characterize them in a given tumor as this can affect therapeutic strategies and their potential use as tumor marker in molecular diagnostics.
More recently, cases of PA with gangliocytic differentiation (PA-GD) have been described, and these cases are thus far restricted to those with the KIAA1549-BRAF fusion.
KIAA1549-BRAF is the most frequently identified genetic mutation in sporadic pilocytic astrocytoma (PA), creating a fusion BRAF (f-BRAF) protein with increased BRAF activity.
The review of imaging features indicated that cyst formation is associated with the existence of KIAA1549-BRAF fusion in PA and GG and the lack of BRAF mutation in GG.
BRAF-V600E mutations are most commonly found in pleomorphic xanthoastrocytoma, ganglioglioma, epithelioid glioblastoma, and gliomas diagnosed at a younger age; BRAF-KIAA1549 fusion is the most common BRAF alteration in pilocytic astrocytoma.
BRAF fusion involving the KIAA1549 gene is a hallmark of pilocytic astrocytoma, but it has also been recorded in rare cases of gangliogliomas, 1p/19q co-deleted oligodendroglial tumors, and it is also a common feature of disseminated oligodendroglial-like leptomeningeal neoplasm.
Using a combined analysis of RNA sequencing and copy number variation data we identified a new BRAF fusion involving the 5' gene fusion partner GTF2I (7q11.23), not previously described in PA.
Given that the BRAF sequence deleted is identical to that seen in other fusion events in PA, it most likely acts as tumor driver by activation of the MAPK pathway.
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).
In case 3, deletions involving BRAF and FAM131B were observed in both a primary and a recurrent PA. RNA-based sequence analysis of cases 2 and 3 confirmed a fusion between FAM131B exon 2 and BRAF exon 9.
The molecular data on PA support a key role for the BRAF oncogene in the pathogenesis of these tumors, with the KIAA1549-BRAF fusion being the most common alteration identified in sporadic cases, particularly those occurring in the posterior fossa.
Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAFV600E mutations and not with KIAA1549-BRAF fusions or FGFR1 mutations.
Chromosome band 7q34 deletions, which resulted in a FAM131B-BRAF fusion, were identified in one pilocytic astrocytoma (PA) and one dysembryoplastic neuroepithelial tumor (DNT).