P05.02 * KIAA1549:BRAF FUSION GENE IN PEDIATRIC BRAIN TUMORS OF VARIOUS HISTOGENESIS

Abstract

INTRODUCTION: Pediatric GBMs (pGBM) are histologically indistinguishable from adult GBM (aGBM) however they are molecularly distinct. Few molecular data exists on the mechanism underlying development and progression of pGBM, whereas a number of gene expression profiling analyses performed in aGBM helped to identify molecular events leading to oncogenesis and provided more accurate means for classification of subtypes, outcomes and even response to treatments. The KIAA1549:BRAF fusion (K-B) gene has been considered a driver of genetic events and a useful diagnostic marker in adult pilocytic astrocytoma (PA). The K-B fusion, on the other hand, is an unusual finding in pediatric diffuse astrocytomas and oligoastocytoma and not reported in pHGG On the other hand, it has been reported a low frequency of B_F fusion gene in adult diffuse gliomas in association with IDH1 mutations. METHODS: To further elucidate the possible occurrence of the K-B fusion gene in non-PA tumors, we investigated its presence in a series of 69 pediatric brain neoplasms of different histogenesis and grade (34 non PA and 35 PA). Fusion has been investigated through the analysis of messenger RNA by reverse-transcription polymerase chain reaction (RT-PCR) followed by sequencing. Selected cases were screened for mutational analysis for IDH1, BRAFv600 and H3F3A. Positive cases have undergone to confirmation by the interphase Fluorescence in situ Hybridization (FISH) analysis and quantitative PCR (Taqman). RESULTS: We detected the KIAA1549:BRAF fusion (K-B) gene in 5 out of 34 (14.7%) non-PA primary tumors, i.e. 1 glioblastoma, 1 anaplastic astrocytoma, 1 anaplastic PXA, 1 ependymoma and 1 AT/RT. The fusion gene was also found in 21 out of 35 PAs (63.6%) and in 1/3 (33%) WHO grade I gangliogliomas. Quantitative PCR and FISH analysis confirmed the presence of the K-B fusion gene. The frequency of fusion harboring nuclei in non-PA neoplasms was lower than in PAs. Screening for IDH1, BRAFv600, and H3F3A mutations disclosed one case with the IDH1 and one with the K27M-H3.3 mutation, both unassociated with the K-B gene. CONCLUSION: Our study indicates that: 1) the K-B fusion gene can occasionally be detected in non-PA tumors of various histogenesis; 2) its occurrence in these neoplasms is probably due rather to a random alteration related to genomic instability than to a driving molecular event, as in PAs; and 3) the K-B fusion gene's role as a diagnostic marker outside the histological spectrum of pediatric low-grade gliomas should be carefully considered.