Transcriptomic profiling of nonneoplastic cortical tissues reveals epileptogenic mechanisms in dysembryoplastic neuroepithelial tumors.

Low-grade dysembryoplastic neuroepithelial tumors (DNTs) are a frequent cause of drug-refractory epilepsy. Molecular mechanisms underlying seizure generation in these tumors are poorly understood. This study was conducted to identify altered genes in nonneoplastic epileptogenic cortical tissues (ECTs) resected from DNT patients during electrocorticography (ECoG)-guided surgery. RNA sequencing (RNAseq) was used to determine the differentially expressed genes (DEGs) in these high-spiking ECTs compared to non-epileptic controls. A total of 477 DEGs (180 upregulated; 297 downregulated) were observed in the ECTs compared to non-epileptic controls. Gene ontology analysis revealed enrichment of genes belonging to the following Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways: (i) glutamatergic synapse; (ii) nitrogen metabolism; (iii) transcriptional misregulation in cancer; and (iv) protein digestion and absorption. The glutamatergic synapse pathway was enriched by DEGs such as GRM4, SLC1A6, GRIN2C, GRM2, GRM5, GRIN3A, and GRIN2B. Enhanced glutamatergic activity was observed in the pyramidal neurons of ECTs, which could be attributed to altered synaptic transmission in these tissues compared to non-epileptic controls. Besides glutamatergic synapse, altered expression of other genes such as GABRB1 (synapse formation), SLIT2 (axonal growth), and PROKR2 (neuron migration) could be linked to epileptogenesis in ECTs. Also, upregulation of GABRA6 gene in ECTs could underlie benzodiazepine resistance in these patients. Neural cell-type-specific gene set enrichment analysis (GSEA) revealed transcriptome of ECTs to be predominantly contributed by microglia and neurons. This study provides first comprehensive gene expression profiling of nonneoplastic ECTs of DNT patients and identifies genes/pathways potentially linked to epileptogenesis.