Abstract
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.
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Data availability
The RNA sequencing data is available in the NCBI’s Sequence Read Archive repository (BioProject: PRJNA612403). Reviewer’s link: https://dataview.ncbi.nlm.nih.gov/object/PRJNA612403?reviewer=1vj1su65ui3g88llq6106s8jjv.
Abbreviations
- LEATs:
-
Low-grade epilepsy-associated tumors
- DNTs:
-
Dysembryoplastic neuroepithelial tumors
- ECTs:
-
Epileptogenic cortical tissues
- RNAseq:
-
RNA sequencing
- DEGs:
-
Differentially expressed genes
- GSEA:
-
Gene set enrichment analysis
- GO:
-
Gene ontology
- ECoG:
-
Electrocorticography
- MRI:
-
Magnetic resonance imaging
- EEG:
-
Electroencephalography
- PET:
-
Positron emission tomography
- MEG:
-
Magnetoencephalography
- EPSCs:
-
Excitatory postsynaptic currents
- TLE:
-
Temporal lobe epilepsy
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Funding
The work in this study was generously supported by grants from the Office of the Principal Scientific Adviser to the Government of India wide sanction number: Prn.SA/Epilep/2017(G). The funder had no role in study design, data analysis, manuscript preparation, or decision to publish.
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KK designed the research, performed the experiments, analyzed the data, and wrote the paper; ABD designed the research and wrote the paper; MT designed the research and wrote the paper; VD performed the experiments; FS and MCS analyzed histopathological data; SL provided the autopsy samples; PSC provided DNT/glioma samples and wrote the paper; JB designed the research, performed experiments, analyzed the data, and wrote the paper. All authors read and approved the final manuscript.
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The study was pre-approved by the institutional human ethics committee (IHEC) of the All India Institute of Medical Sciences, New Delhi, and all the methods were performed in accordance with the relevant guidelines and regulations. A prior Informed written consent was obtained from all subjects, their parents, or legal guardians if the subjects were minor. We declare that we have followed the tenets of the Declaration of Helsinki in our study.
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Kumar, K., Banerjee Dixit, A., Tripathi, M. et al. Transcriptomic profiling of nonneoplastic cortical tissues reveals epileptogenic mechanisms in dysembryoplastic neuroepithelial tumors. Funct Integr Genomics 22, 905–917 (2022). https://doi.org/10.1007/s10142-022-00869-1
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DOI: https://doi.org/10.1007/s10142-022-00869-1