Chromosome Band 7q34 Deletions Resulting in KIAA1549‐BRAF and FAM131B‐BRAF Fusions in Pediatric Low‐Grade Gliomas

Abstract

The majority of pediatric low grade gliomas (LGGs) are characterized by constitutive activation of the mitogen activated protein kinase (MAPK) pathway through various mechanisms including BRAF mutations, inactivation of NF1, and KIAA1549-BRAF and FAM131B-BRAF fusions. The KIAA1549-BRAF fusion typically results from a 2.0 Mb tandem duplication in chromosome band 7q34. In the present study, single nucleotide polymorphism (SNP)-based array analysis of three LGGs demonstrated deletions in 7q34 that resulted in a BRAF fusion. Case 1 was likely a pilocytic astrocytoma (PA) with three deletions in 7q33q34 and an exon15-9 KIAA1549-BRAF fusion. SNP array analysis of case 2, a possible dysembryoplastic neuroepithelial tumor (DNT), revealed a 2.6 Mb deletion which included the 5′ end of BRAF and extended to the 3′ end of FAM131B. In case 3, deletions involving BRAF and FAM131B were observed in both a primary and recurrent PA. RNA-based sequence analysis of cases 2 and 3 confirmed a fusion between FAM131B exon 2 and BRAF exon 9. The presence of fusion transcripts in these three LGGs highlights the utility of SNP array analysis to identify deletions that are suggestive of fusion proteins. BRAF fusions can result from multiple non-overlapping deletions suggesting various complex mechanisms of formation.

BRAF‐V600E immunohistochemistry in a large series of glial and glial–neuronal tumors

“…It is interesting to note that the four mutant PA in our cohort were all of supratentorial location (basal ganglia, third ventricle, and optic pathways). However, extra‐cerebellar BRAF‐V600E mutant PA remains rare (Roth et al., 2015) leading to wonder whether it is a distinct entity or actually GG whose neuronal component was not sampled.…”

Heterogeneity of histopathological presentation of pilocytic astrocytoma – diagnostic pitfalls. A review

“…This tandem duplication is found in 60-94% of PAs and leads to downstream activation of the MEK/MAPK/ERK/p16 pathway [12,23,85]. The KIAA1549-BRAF fusion is more commonly encountered in PAs originating in the cerebellum [40].…”

The Evolving Molecular Genetics of Low-grade Glioma

“…Pilocytic astrocytomas (grade I) show tandem duplications at chromosome 7q34 resulting in the formation of a fusion gene between the kinase domain of BRAF and KIAA1549 (BRAF - KIAA1549 fusion gene) (4–9). Rare BRAF fusions such as BRAF - FAM131B, BRAF-RNF130, BRAF-CLCN6, BRAF-MKRN1 and BRAF-GNAI1 have also been reported but at a much lower frequency (9, 10) (11). Interestingly, pilocytic astrocytomas show variable rates of BRAF fusion depending on their location in the central nervous system (CNS).…”