Novel RAF Fusions in Pediatric Low-Grade Gliomas Demonstrate MAPK Pathway Activation

Abstract

Brain tumors are the most common solid tumor in children, and low-grade gliomas (LGGs) are the most common childhood brain tumor. Here, we report on 3 patients with LGG harboring previously unreported or rarely reported RAF fusions: FYCO1-RAF1, CTTNBP2-BRAF, and SLC44A1-BRAF. We hypothesized that these tumors would show molecular similarity to the canonical KIAA1549-BRAF fusion that is the most widely seen alteration in pilocytic astrocytoma (PA), the most common pediatric LGG variant, and that this similarity would include mitogen-activated protein kinase (MAPK) pathway activation. To test our hypothesis, we utilized immunofluorescent imaging and RNA-sequencing in normal brain, KIAA1549-BRAF-harboring tumors, and our 3 tumors with novel fusions. We performed immunofluorescent staining of ERK and phosphorylated ERK (p-ERK), identifying increased p-ERK expression in KIAA1549-BRAF fused PA and the novel fusion samples, indicative of MAPK pathway activation. Geneset enrichment analysis further confirmed upregulated downstream MAPK activation. These results suggest that MAPK activation is the oncogenic mechanism in noncanonical RAF fusion-driven LGG. Similarity in the oncogenic mechanism suggests that LGGs with noncanonical RAF fusions are likely to respond to MEK inhibitors.

Effective Treatment of Lung Adenocarcinoma With a Novel SLC44A1-BRAF Fusion Using Pembrolizumab Followed by Trametinib: A Case Report

“…In the largest screening of BRAF fusion genes, all NSCLC with BRAF fusions were adenocarcinoma or NSCLC with adenocarcinoma features not in squamous or small cell lung cancers as ours [ 6 ]. Lind KT et al reported detecting this rare fusion in a 7-year-old male with low-grade glioma and molecular pathology of this brain tumor noted this fusion juxtaposed the serine-threonine kinase domain of BRAF and SLC44A1 and replaced the 5’ regulatory domain of BRAF while preserving the kinase domain of BRAF [ 10 ]. These molecular insights suggest that MEK inhibitor trametinib monotherapy could be a promising approach for NSCLC cases harboring BRAF fusions with intact kinase domains.…”

“…In a phase 2 study, first-generation BRAF inhibitors, such as sorafenib, proved ineffective in treating BRAF fusion malignancies [ 7 ], a finding potentially attributable to the distinct oncogenic properties of the BRAF fusion protein compared to the V600E mutation [ 8 ]. Only a minority of cases have responded positively to treatments involving trametinib and/or sorafenib [ 6 , 9 , 10 ]. Consequently, there is an urgent need to expand our understanding and treatment modalities for BRAF fusion tumors.…”

Neurosurgery for Optic Pathway Glioma: Optimizing Multidisciplinary Management

“…The two most common alterations in pLGG (including OPG) are in the BRAF gene with either KIAA1549:BRAF fusion or point mutation of BRAFV600E. Unique fusions that activate MAPK have also been reported ( 24 ). Mutations or fusions involving the FGFR1 or NTRK families in pLGG are more recent findings.…”

Multi-pronged analysis of pediatric low-grade glioma reveals a unique tumor microenvironment associated with BRAF alterations

“…These studies identified additional mutations in FGFR1 , PTPN11 , and NTRK2 fusion genes (14). In addition, the combination of RNA-seq and copy number variation data has identified novel fusion partners with the BRAF gene (15). These data have brought a greater understanding of pLGG biology and advances to therapy including the use of MAPK pathway inhibitors.…”