Single-nucleus RNA sequencing: immature excitatory neurons and transformed glia build human BRAFV600E-negative gangliogliomas

Gangliogliomas are glioneuronal neoplasms, generally with a benign evolution, accounting for the most common tumors in patients with long-term pharmacoresistant epilepsy. BRAFV600E has been detected in a high percentage of World Health Organization grade 1 gangliogliomas. However, biopsy collections from epilepsy patients include tumors that meet neuropathological ganglioglioma criteria but lack the BRAFV600E mutation. The molecular pathology of such BRAFV600E-negative gangliogliomas remains largely unexplored. We here focused on decoding the molecular and cellular profiles of these BRAFV600E-negative gangliogliomas at the single-cell resolution. Our results identify an exclusive profile in excitatory, but not inhibitory, neurons, astrocytes and oligodendrocytes in BRAFV600E-negative gangliogliomas. Moreover, we confirm the presence of immature excitatory neurons with higher expression of genes related to glutamatergic transmission as well as metabolically active astro- and oligodendrocytes which may contribute to epileptogenicity. Our study provides important resources to understand the molecular profile of BRAFV600E-negative gangliogliomas aiming to drive forward future research directions to novel and tailored treatment options for epilepsy.