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

Julie Lerond; Bertrand Mathon; Mélina Scopin; Lucia Nichelli; Justine Guégan; Céline Bertholle; Brigitte Izac; Muriel Andrieu; Thomas Gareau; Florian Donneger; Badreddine Mohand Oumoussa; Franck Letourneur; Suzanne Tran; Mathilde Bertrand; Isabelle Le Roux; Mehdi Touat; Sophie Dupont; Jean Christophe Poncer; Vincent Navarro; Franck Bielle

doi:10.1111/nan.12937

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

Neuropathol Appl Neurobiol. 2023 Oct;49(5):e12937. doi: 10.1111/nan.12937.

Authors

Julie Lerond¹, Bertrand Mathon², Mélina Scopin³, Lucia Nichelli⁴, Justine Guégan⁵, Céline Bertholle⁶, Brigitte Izac⁶, Muriel Andrieu⁶, Thomas Gareau⁵, Florian Donneger³, Badreddine Mohand Oumoussa⁷, Franck Letourneur⁶, Suzanne Tran⁸, Mathilde Bertrand⁵, Isabelle Le Roux¹, Mehdi Touat⁹, Sophie Dupont¹⁰, Jean Christophe Poncer³, Vincent Navarro¹¹, Franck Bielle^{8

12}

Affiliations

¹ Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, Sorbonne Université, Paris, France.
² AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Department of Neurosurgery, Sorbonne Université, Paris, France.
³ Institut du Fer à Moulin, Inserm, Sorbonne Université, Paris, France.
⁴ AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Department of Neuroradiology, Sorbonne Université, Paris, France.
⁵ Institut du Cerveau-Paris Brain Institute-ICM-Data Analysis Core platform, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Sorbonne Université, Paris, France.
⁶ CNRS, INSERM, Institut Cochin, Université Paris Cité, Paris, France.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ IAP-HP, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière, Rehabilitation Unit, Sorbonne Université, Paris, France.
¹¹ 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.
¹² AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Onconeurotek, Paris, France.

PMID: 37740653
DOI: 10.1111/nan.12937

Abstract

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.

Keywords: BRAF; CD34; HOPX; epilepsy; hippocampal sclerosis; methylation; senescence; somatic mosaicism.

MeSH terms

Epilepsies, Partial* / complications
Epilepsies, Partial* / genetics
Epilepsies, Partial* / pathology
Epilepsy* / pathology
Epilepsy, Temporal Lobe* / pathology
Hippocampus / pathology
Humans
Magnetic Resonance Imaging
Neocortex* / pathology
Proto-Oncogene Proteins B-raf / genetics
Sclerosis / pathology

Substances

Proto-Oncogene Proteins B-raf
BRAF protein, human

Abstract

MeSH terms

Substances

Grants and funding