title: Tumor cells with neuronal intermediate progenitor features define a subgroup of 1p/19q co-deleted anaplastic gliomas.
abstract: The integrated diagnosis of anaplastic oligodendroglioma, IDH mutant and 1p/19q co-deleted, grade III (O3id) is a histomolecular entity that WHO 2016 classification distinguished from other diffuse gliomas by specific molecular alterations. In contrast, its cell portrait is less well known. The present study is focused on intertumor and intratumor, cell lineage-oriented, heterogeneity in O3id. Based on pathological, transcriptomic and immunophenotypic studies, a novel subgroup of newly diagnosed O3idoverexpressing neuronal intermediate progenitor (NIP) genes was identified. This NIP overexpression pattern in O3idis associated with: (i) morphological and immunohistochemical similarities with embryonic subventricular zone, (ii) proliferating tumor cell subpopulation with NIP features including expression of INSM1 and no expression of SOX9, (iii) mutations in critical genes involved in NIP biology and, (iv) increased tumor necrosis. Interestingly, NIP tumor cell subpopulation increases in O3idrecurrence compared with paired newly diagnosed tumors. Our results, validated in an independent cohort, emphasize intertumor and intratumor heterogeneity in O3idand identified a tumor cell subpopulation exhibiting NIP characteristics that is potentially critical in oncogenesis of O3id. A better understanding of spatial and temporal intratumor cell heterogeneity in O3idwill open new therapeutic avenues overcoming resistance to current antitumor treatments.
authors.affiliation: Service de Neuropathologie Raymond Escourolle, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Paris, F-75013, France.|Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, F-75013, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Bielle
authors.affiliation: Service de Neuro-oncologie, Hospices Civils de Lyon, Hôpital Neurologique, Lyon, France.|Université Claude Bernard Lyon 1, Lyon, France.|Cancer Research Centre of Lyon, INSERM U1052, CNRS UMR5286, Lyon, France.
authors.forename: François
authors.initials: F
authors.lastname: Ducray
authors.affiliation: Service de Neuropathologie Raymond Escourolle, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Paris, F-75013, France.|Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, F-75013, France.|OncoNeuroTek, Institut du Cerveau et de la Moelle épinière, ICM, Paris, F-75013, France.
authors.forename: Karima
authors.initials: K
authors.lastname: Mokhtari
authors.affiliation: AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris, F-75013, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dehais
authors.affiliation: Hôpital Lariboisière, Département de Pathologie, AP-HP, Paris, France.
authors.forename: Homa
authors.initials: H
authors.lastname: Adle-Biassette
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, F-75013, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Carpentier
authors.affiliation: Service de Neuropathologie Raymond Escourolle, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Paris, F-75013, France.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Chanut
authors.affiliation: Hôpital Lariboisière, Département de Pathologie, AP-HP, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Polivka
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, F-75013, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Poggioli
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, F-75013, France.
authors.forename: Shai
authors.initials: S
authors.lastname: Rosenberg
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, F-75013, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Giry
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, F-75013, France.|OncoNeuroTek, Institut du Cerveau et de la Moelle épinière, ICM, Paris, F-75013, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Marie
authors.affiliation: Service de Neuropathologie Raymond Escourolle, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Paris, F-75013, France.|Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, F-75013, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Duyckaerts
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, F-75013, France.|AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris, F-75013, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Sanson
authors.affiliation: Département de Pathologie et Neuropathologie, Assistance Publique-Hôpitaux de Marseille, CHU Timone, Marseille, France.|Université Aix-Marseille, INSERM U911, Marseille, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Figarella-Branger
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, F-75013, France.|AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris, F-75013, France.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Idbaih
authors.affiliation: POLA Network investigators: Amiens: Christine Desenclos, Henri Sevestre; Angers: Philippe Menei, Audrey Rousseau; Besançon: Joel Godard, Gabriel Viennet; Bobigny: Antoine Carpentier; Bordeaux: Sandrine Eimer, Hugues Loiseau; Brest: Phong Dam-Hieu, Isabelle Quintin-Roué; Caen: Jean-Sebastien Guillamo, Emmanuelle Lechapt-Zalcman; Clermont-Ferrand:Jean-Louis Kemeny, Toufik Khallil; Clichy: Dominique Cazals-Hatem, Thierry Faillot; Cornebarrieu: Ioana Carpiuc, Pomone Richard; Créteil: Caroline Le Guerinel; Colmar: Claude Gaultier, Marie-Christine Tortel; Dijon: Marie-Hélène Aubriot-Lorton, François Ghiringhelli; Kremlin-Bicêtre: Clovis Adam, Fabrice Parker; Lille: Claude-Alain Maurage, Carole Ramirez; Limoges: Edouard Marcel Gueye, François Labrousse; Lyon: Anne Jouvet; Marseille: Olivier Chinot; Montpellier: Luc Bauchet, Valérie Rigau; Nancy: Patrick Beauchesne, Dr Guillaume Gauchotte; Nantes: Mario Campone, Delphine Loussouarn; Nice: Denys Fontaine, Fanny Vandenbos; Orléans: Claire Blechet, Mélanie Fesneau; Paris: Jean Yves Delattre (national coordinator of the network), Selma Elouadhani-Hamdi, Damien Ricard; Poitiers: Delphine Larrieu-Ciron, Pierre-Marie Levillain; Reims: Philippe Colin, Marie-Danièle Diebold; Rennes: Danchristian Chiforeanu, Elodie Vauléon; Rouen: Olivier Langlois, Annie Laquerrière; Saint-Etienne: Marie Janette Motsuo Fotso, Michel Peoc'h; Saint-Pierre de la réunion: Marie Andraud, Gwenaelle Runavot; Strasbourg: Marie-Pierre Chenard, Georges Noel; Suresnes: Dr Stéphane Gaillard, Dr Chiara Villa; Toulon: Nicolas Desse; Toulouse: Elisabeth Cohen-Moyal, Emmanuelle Uro-Coste; Villejuif: Frédéric Dhermain.
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology*; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1; D002888:Chromosomes, Human, Pair 19; D019295:Computational Biology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology*; D055495:Neurogenesis; D009837:Oligodendroglioma / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D012097:Repressor Proteins / Q000378:metabolism; D012189:Retrospective Studies; D055758:SOX9 Transcription Factor / Q000378:metabolism
chemical_list: D012097:Repressor Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C087342:INSM1 protein, human
keywords: 1p/19q co-deletion; anaplastic oligodendroglioma; embryonic subventricular zone; neuronal intermediate progenitor