LGG-25. NOVEL FGFR2 FUSIONS DRIVE ONCOGENESIS VIA MAPK AND PI3K/mTOR PATHWAY ACTIVATION IN DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS
Year: 2018
Type: article
Abstract: Dysembryoplastic neuroepithelial tumor (DNT) is a benign glioneuronal neoplasm classified by the 2016 WHO under the mixed neuronal-glial tumors. Compared to other low-grade neuroepithelial tumors (LGNTs) in this category, the genetic profile of DNTs is poorly understood. DNTs have been shown to exhibit mutational variability, ranging from stable genomes to occurrence of BRAF V600E (30% of cases), whole chromosome gains and FGFR1 mutations. To further expand our understanding of genetic drivers of DNTs, we performed clinical integrated genomic profiling and identified two novel FGFR2-associated gene fusions, FGFR2-INA and FGFR2-CTNNA3, in three patients with the histologic diagnosis of DNT. All three DNT cases harbored novel in-frame fusions between the kinase domain of FGFR2 and INA or CTNNA3. To functionally characterize the novel FGFR2 fusions, we cloned FGFR2-INA and stably expressed it in heterologous cell models. Soft agar proliferation assays showed significant increase in colony count in FGFR2-INA expressing cells over control (p<0.0005). In western blot assays, increased protein phosphorylation of both the MAPK and PI3K/mTOR pathways was observed in FGFR2-INA cells. Mechanistically, we found that FGFR2-INA dimerizes in co-immunoprecipitation assays suggesting dimerization induced activation of FGFR2 fusion proteins. We thereby identify and describe two novel FGFR2 fusions associated with DNT that aberrantly activate the MAPK and PI3K/mTOR signaling pathways. This oncogenic mechanism is similar to that of BRAF V600E mutations and may explain tumorigenesis in at least a subset of DNTs. In FGFR2 fusion positive DNTs, this genetic event is the likely driver of tumorigenesis and suggests a potential therapeutic target.
Source: Neuro-Oncology
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2809101918