VOPP1::EGFR fusion is associated with NFκB pathway activation in a glioneural tumor with histological features of ganglioglioma

Abstract

Glioneural tumors are primary brain tumors that consist of both neural and glial neoplastic cells, often presenting with seizures and primarily affecting children and young adults. Specifically, gangliogliomas are composed of neoplastic ganglion and glial cells, accompanied by other characteristic histological features such as lymphoid cuffing, eosinophilic granular bodies, and Rosenthal fibers. Oncogenic driver mutations and gene fusions have been shown to be of prognostic significance in gangliogliomas and can offer potential therapeutic targets. Typical molecular alterations are mitogen-activated protein kinase (MAPK) pathway activations with BRAF p.V600E being the most frequent one. Here, we report for the first time a gene fusion between epidermal growth factor receptor (EGFR) and vesicular, overexpressed in cancer, prosurvival protein 1 (VOPP1) as a potential oncogenic driver in a glioneuronal tumor morphologically resembling ganglioglioma. VOPP1::EGFR fusion associated with the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling. Furthermore, we provide histological and epigenetic findings and clinical outcome. The case expands the known molecular spectrum of oncogenic drivers in glioneuronal tumors and provides a link to potentially prognostic and therapeutically relevant alterations.

Keywords: EGFR; Ganglioglioma; Gene fusion; NFκB; VOPP1.

Fig. 1

T2 weighted MRI shows a well-defined partially cystic lesion in the right middle temporal gyrus (arrow) with small peritumoral edema (arrowhead) (A). Native (B) and contrast enhanced (C) T1 weighted MRI show a circular contrast enhancement of the lesion

Fig. 2

Representative microphotographs of H&E staining show brain parenchyma and a glioneural tumor exhibiting microcystic changes and perivascular lymphoid cuffing. Inset: higher magnification image showing interspersed ganglion cells (asterisks) (A). A neoplastic neuronal component was identified by positivity for NeuN immunohistochemistry (B) and chromogranin A immunohistochemistry (C), whereas the glial tumor component was Olig2 positive (D). Proliferation (Ki-67) was low, approximately 1–2% (E). Multiple CD34-positive stellate cells (asterisks) were identified (F). Scale bar = 100 μm for A and E; for B, D, F, scale bar = 50 μm; for C, F, inset A, and inset F, scale bar = 20 μm

Fig. 3

Schematic representation of RNA sequencing results reveals a gene fusion between Exon 1 of VOPP1 (blue) and Exon 18 of EGFR (orange). (A) A fragment of Exon 1 of VOPP1 is inverted from the antisense (3’ to 5’) to the sense direction (5’ to 3’) and then fused to Exon 18 of EGFR. Additionally, PCR products spanning the breakpoints were sequenced using Sanger sequencing, confirming the VOPP1::EGFR fusion between Exon 1 of VOPP1 and Exon 18 of EGFR (B). The copy number profile, calculated from the 850k methylation array, reveals a slight gain of chromosome 7 (C). The copy number calculation was obtained from the publicly available database of the German Cancer Research Center (DKFZ) [12] at www.molecularneuropathology.org. The inset of the chromosomal region chr7:54,346,472 − 56,019,558 shows only a slight increase in copy numbers for EGFR (log2 value 0.135) and VOPP1 (log2 value 0.041) compared to the neighboring genes, as shown using IGV files

Fig. 4

Representative microphotograph of ganglioglioma with the VOPP1::EGFR fusion show nuclear staining for NFκB (p65), indicating activation of the NFκB pathway(A). This was compared to three control cases of ganglioglioma: two with BRAF p.V600E mutation (control 1, 2) and one with a NF1 association (control 3), which showed no staining or only moderate staining for NFκB (p65) (C, E, G). Cyclin D1 is strongly expressed in the control cases (D, F, H), whereas there is no nuclear staining in the ganglioglioma with the VOPP1::EGFR fusion (B). Scale bars = 20 μm for A-H