Novel FGFR2-INA fusion identified in two low-grade mixed neuronal-glial tumors drives oncogenesis via MAPK and PI3K/mTOR pathway activation

As a group, mixed neuronal-glial tumors (MNGTs) exhibit genetic variability, including stable genomes, whole chromosome gains, BRAF-V600E, and FGFR1 mutations [8, 9, 11, 12]. While histologic criteria are described to distinguish MNGT types ganglioglioma (GG) and dysembryoplastic neuroepithelial tumor (DNT), non-specific features preclude confident classification in a high proportion of cases [2, 8, 10, 12]. Herein, we report the characterization of a novel FGFR2-INA fusion gene identified during clinical genomic profiling in two cases of MNGTs that could not be specifically classified as GG or DNT. Clinical, imaging, histology, and fusion gene characteristics of each case are summarized in suppl. Table 1 (Online Resource 1). Both patients presented with seizures, cortical-based tumors, and one patient’s tumor was recurrent. By histology and immunohistochemistry, both cases consisted of oligodendrocyte-like cells and admixed neurons within microcytic spaces (Fig. 1a). GFAP-positive astrocytes, CD34 expression (MNGT-1), and calcification were observed. Both cases lacked pools of mucin, floating neurons, specific glioneuronal elements, eosinophilic granular bodies, and perivascular inflammation. Features were most similar to DNT; however, both lacked key criteria for this diagnosis. Targeted RNA-sequencing revealed a novel in-frame fusion between FGFR2 exon 17 and INA exon 2 (Fig. 1b) in both cases. Additional DNA sequence and copy number variants of clinical significance were also identified by targeted next-generation sequence panel [suppl. Tables 2, 3, 4 (Online Resource 1)] [7]. FGFR2, a receptor kinase, regulates several growth-related signaling pathways implicated in cancer progression, including RAS-RAF-MAPK and PI3K/AKT/mTOR [3]. INA encodes the alpha-internexin protein involved in cytoskeletal organization and neuronal morphogenesis [6]. The novel fusion retains the extracellular immunoglobin-like and tyrosine kinase domains of FGFR2, suggesting oncogenic activation of downstream signaling, and the truncated coil 2 and tail region of INA, suggesting dimerization (Fig. 1c). Payal Jain and Lea F. Surrey are co-first authors and contributed equally.

As a group, mixed neuronal-glial tumors (MNGTs) exhibit genetic variability, including stable genomes, whole chromosome gains, BRAF-V600E, and FGFR1 mutations [8,9,11,12]. While histologic criteria are described to distinguish MNGT types ganglioglioma (GG) and dysembryoplastic neuroepithelial tumor (DNT), non-specific features preclude confident classification in a high proportion of cases [2,8,10,12]. Herein, we report the characterization of a novel FGFR2-INA fusion gene identified during clinical genomic profiling in two cases of MNGTs that could not be specifically classified as GG or DNT.
Clinical, imaging, histology, and fusion gene characteristics of each case are summarized in suppl. Table 1 (Online Resource 1). Both patients presented with seizures, cortical-based tumors, and one patient's tumor was recurrent. By histology and immunohistochemistry, both cases consisted of oligodendrocyte-like cells and admixed neurons within microcytic spaces (Fig. 1a). GFAP-positive astrocytes, CD34 expression (MNGT-1), and calcification were observed. Both cases lacked pools of mucin, floating neurons, specific glioneuronal elements, eosinophilic granular bodies, and perivascular inflammation. Features were most similar to DNT; however, both lacked key criteria for this diagnosis.
Targeted RNA-sequencing revealed a novel in-frame fusion between FGFR2 exon 17 and INA exon 2 ( Fig. 1b) in both cases. Additional DNA sequence and copy number variants of clinical significance were also identified by targeted next-generation sequence panel [suppl. Tables 2, 3, 4 (Online Resource 1)] [7]. FGFR2, a receptor kinase, regulates several growth-related signaling pathways implicated in cancer progression, including RAS-RAF-MAPK and PI3K/AKT/mTOR [3]. INA encodes the alpha-internexin protein involved in cytoskeletal organization and neuronal morphogenesis [6]. The novel fusion retains the extracellular immunoglobin-like and tyrosine kinase domains of FGFR2, suggesting oncogenic activation of downstream signaling, and the truncated coil 2 and tail region of INA, suggesting dimerization (Fig. 1c). Payal Jain and Lea F. Surrey are co-first authors and contributed equally.
Marilyn M. Li and Angela J. Waanders are co-last authors and contributed equally.
We identify and characterize a novel FGFR2-INA fusion associated with unclassified MNGT in two patients lacking other reported driver alterations (BRAF-V600E and FGFR1). Other FGFR2 fusions have been identified in epileptogenic tumors of the young with some overlapping histologic features to the current two cases [4]. It is possible that these  tumors represent an emerging category of low-grade epileptogenic tumor. Our functional studies show that the FGFR2-INA fusion drives oncogenesis potentially via activation of the MAPK and PI3 K/mTOR pathways. Therefore, FGFR2-INA is the likely driver of tumorigenesis in at least a subset of MNGTs and is a potential target for small-molecule inhibitors.