Hippocampal and neocortical BRAF mutant non-expansive lesions in focal epilepsies.

Autor: Lerond J; Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, Sorbonne Université, Paris, France., Mathon B; AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Department of Neurosurgery, Sorbonne Université, Paris, France., Scopin M; Institut du Fer à Moulin, Inserm, Sorbonne Université, Paris, France., Nichelli L; AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Department of Neuroradiology, Sorbonne Université, Paris, France., Guégan J; Institut du Cerveau-Paris Brain Institute-ICM-Data Analysis Core platform, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Sorbonne Université, Paris, France., Bertholle C; CNRS, INSERM, Institut Cochin, Université Paris Cité, Paris, France., Izac B; CNRS, INSERM, Institut Cochin, Université Paris Cité, Paris, France., Andrieu M; CNRS, INSERM, Institut Cochin, Université Paris Cité, Paris, France., Gareau T; Institut du Cerveau-Paris Brain Institute-ICM-Data Analysis Core platform, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Sorbonne Université, Paris, France., Donneger F; Institut du Fer à Moulin, Inserm, Sorbonne Université, Paris, France., Mohand Oumoussa B; Inserm, UMS Production et Analyse des données en Sciences de la vie et en Santé, PASS, Plateforme Post-génomique de la Pitié-Salpêtrière, Sorbonne Université, Paris, France., Letourneur F; CNRS, INSERM, Institut Cochin, Université Paris Cité, Paris, France., Tran S; AP-HP, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Department of Neuropathology, Sorbonne Université, Paris, France., Bertrand M; Institut du Cerveau-Paris Brain Institute-ICM-Data Analysis Core platform, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Sorbonne Université, Paris, France., Le Roux I; Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, Sorbonne Université, Paris, France., Touat M; AP-HP, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Department of Neurology 2-Mazarin, Sorbonne Université, Paris, France., Dupont S; IAP-HP, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière, Rehabilitation Unit, Sorbonne Université, Paris, France., Poncer JC; Institut du Fer à Moulin, Inserm, Sorbonne Université, Paris, France., Navarro V; AP-HP, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Epilepsy Unit, Department of Neurology and EEG Unit, Department of Clinical Neurophysiology, Reference Center for Rare Epilepsies, Sorbonne Université, Paris, France., Bielle F; AP-HP, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Department of Neuropathology, Sorbonne Université, Paris, France.; AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Onconeurotek, Paris, France.
Jazyk: angličtina
Zdroj: Neuropathology and applied neurobiology [Neuropathol Appl Neurobiol] 2023 Oct; Vol. 49 (5), pp. e12937.
DOI: 10.1111/nan.12937
Abstrakt: Objective: Mesial Temporal Lobe Epilepsy-associated Hippocampal Sclerosis (MTLE-HS) is a syndrome associated with various aetiologies. We previously identified CD34-positive extravascular stellate cells (CD34+ cells) possibly related to BRAF V600E oncogenic variant in a subset of MTLE-HS. We aimed to identify the BRAF V600E oncogenic variants and characterise the CD34+ cells.
Methods: We analysed BRAF V600E oncogenic variant by digital droplet Polymerase Chain Reaction in 53 MTLE-HS samples (25 with CD34+ cells) and nine non-expansive neocortical lesions resected during epilepsy surgery (five with CD34+ cells). Ex vivo multi-electrode array recording, immunolabelling, methylation microarray and single nuclei RNAseq were performed on BRAF wildtype MTLE-HS and BRAF V600E mutant non-expansive lesion of hippocampus and/or neocortex.
Results: We identified a BRAF V600E oncogenic variant in five MTLE-HS samples with CD34+ cells (19%) and in five neocortical samples with CD34+ cells (100%). Single nuclei RNAseq of resected samples revealed two unique clusters of abnormal cells (including CD34+ cells) associated with senescence and oligodendrocyte development in both hippocampal and neocortical BRAF V600E mutant samples. The co-expression of the oncogene-induced senescence marker p16 INK4A and the outer subventricular zone radial glia progenitor marker HOPX in CD34+ cells was confirmed by multiplex immunostaining. Pseudotime analysis showed that abnormal cells share a common lineage from progenitors to myelinating oligodendrocytes. Epilepsy surgery led to seizure freedom in eight of the 10 patients with BRAF mutant lesions.
Interpretation: BRAF V600E underlies a subset of MTLE-HS and epileptogenic non-expansive neocortical focal lesions. Detection of the oncogenic variant may help diagnosis and open perspectives for targeted therapies.
(© 2023 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)
Databáze: MEDLINE
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