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Your search keyword '"Basic and Translational Investigations"' showing total 13 results
Start Over Descriptor "Basic and Translational Investigations" Publisher hal ccsd
13 results on '"Basic and Translational Investigations"'

1. Mitochondrial DNA copy number as a prognostic marker is age-dependent in adult glioblastoma

Author

Baptiste Sourty, Laure-Marie Dardaud, Céline Bris, Valérie Desquiret-Dumas, Blandine Boisselier, Laëtitia Basset, Dominique Figarella-Branger, Alain Morel, Marc Sanson, Vincent Procaccio, Audrey Rousseau, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'Onco-neurologie = Département de neurologie 2 [CHU Pitié Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and HAL-SU, Gestionnaire

Subjects
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Basic and Translational Investigations, glioblastoma, AcademicSubjects/MED00300, AcademicSubjects/MED00310, methylation, mitochondrial DNA, prognosis, metabolism, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background Glioblastoma (GBM) is the most common and aggressive form of glioma. GBM frequently displays chromosome (chr) 7 gain, chr 10 loss and/or EGFR amplification (chr7+/chr10-/EGFRamp). Overall survival (OS) is 15 months after treatment. In young adults, IDH1/2 mutations are associated with longer survival. In children, histone H3 mutations portend a dismal prognosis. Novel reliable prognostic markers are needed in GBM. We assessed the prognostic value of mitochondrial DNA (mtDNA) copy number in adult GBM. Methods mtDNA copy number was assessed using real-time quantitative PCR in 232 primary GBM. Methylation of POLG and TFAM genes, involved in mtDNA replication, was assessed by bisulfite-pyrosequencing in 44 and 51 cases, respectively. Results Median age at diagnosis was 56.6 years-old and median OS, 13.3 months. 153/232 GBM (66 %) displayed chr7+/chr10-/EGFRamp, 23 (9.9 %) IDH1/2 mutation, 3 (1.3 %) H3 mutation and 53 (22.8 %) no key genetic alterations. GBM were divided into two groups, “Low” (n = 116) and “High” (n = 116), according to the median mtDNA/nuclear DNA ratio (237.7). There was no significant difference in OS between the two groups. By dividing the whole cohort according to the median age at diagnosis, OS was longer in the “High” vs “Low” subgroup (27.3 vs 15 months, P = .0203) in young adult GBM (n = 117) and longer in the “Low” vs “High” subgroup (14.5 vs 10.2 months, P = .0116) in older adult GBM (n = 115). POLG was highly methylated, whereas TFAM remained unmethylated. Conclusion mtDNA copy number may be a novel prognostic biomarker in GBM, its impact depending on age.

Published
2022

2. VCAM-1 targeted alpha-particle therapy for early brain metastases

Author

Ole Tietz, Laurent Chazalviel, Anne Marie Frelin-Labalme, Samuel Valable, Manuel Sarmiento Soto, Jérôme Toutain, Myriam Bernaudin, Elodie A. Pérès, Katherine A. Vallis, Didier Divoux, Aurélien Corroyer-Dulmont, Nicola R. Sibson, Nadia Falzone, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Hypoxie, physiopathologies cérébrovasculaire et tumorale (CERVOxy), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Department of Oncology [Oxford, UK] (CRUK/MRC), University of Oxford [Oxford], Grand Accélérateur National d'Ions Lourds (GANIL), Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), Brunaud, Carole, University of Oxford, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Couteau, Florence, Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), and Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Mice, Nude, Vascular Cell Adhesion Molecule-1, Breast Neoplasms, Antibodies, Targeted therapy, early brain metastases, Mice, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Cell Line, Tumor, Internal medicine, Carcinoma, medicine, AcademicSubjects/MED00300, Animals, Humans, External beam radiotherapy, Stage (cooking), 030304 developmental biology, VCAM-1, 0303 health sciences, alpha-particle therapy, Radiotherapy, Brain Neoplasms, business.industry, Brain, Histology, Lead Radioisotopes, Alpha Particles, medicine.disease, 3. Good health, Radiation therapy, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Basic and Translational Investigations, Toxicity, AcademicSubjects/MED00310, Female, Neurology (clinical), business
Abstract

Background Brain metastases (BM) develop frequently in patients with breast cancer. Despite the use of external beam radiotherapy (EBRT), the average overall survival is short (6 months from diagnosis). The therapeutic challenge is to deliver molecularly targeted therapy at an early stage when relatively few metastatic tumor cells have invaded the brain. Vascular cell adhesion molecule 1 (VCAM-1), overexpressed by nearby endothelial cells during the early stages of BM development, is a promising target. The aim of this study was to investigate the therapeutic value of targeted alpha-particle radiotherapy, combining lead-212 (212Pb) with an anti–VCAM-1 antibody (212Pb-αVCAM-1). Methods Human breast carcinoma cells that metastasize to the brain, MDA-231-Br-GFP, were injected into the left cardiac ventricle of nude mice. Twenty-one days after injection, 212Pb-αVCAM-1 uptake in early BM was determined in a biodistribution study and systemic/brain toxicity was evaluated. Therapeutic efficacy was assessed using MR imaging and histology. Overall survival after 212Pb-αVCAM-1 treatment was compared with that observed after standard EBRT. Results 212Pb-αVCAM-1 was taken up into early BM with a tumor/healthy brain dose deposition ratio of 6 (5.52e108 and 0.92e108) disintegrations per gram of BM and healthy tissue, respectively. MRI analyses showed a statistically significant reduction in metastatic burden after 212Pb-αVCAM-1 treatment compared with EBRT (P < 0.001), translating to an increase in overall survival of 29% at 40 days post prescription (P < 0.01). No major toxicity was observed. Conclusions The present investigation demonstrates that 212Pb-αVCAM-1 specifically accumulates at sites of early BM causing tumor growth inhibition.

Published
2019

3. A genome-wide association study identifies susceptibility loci for primary central nervous system lymphoma at 6p25.3 and 3p22.1: a LOC Network study

Author

Labreche, Karim, Daniau, Mailys, Sud, Amit, Law, Philip, Royer-Perron, Louis, Holroyd, Amy, Broderick, Peter, Went, Molly, Benazra, Marion, Ahle, Guido, Soubeyran, Pierre, Taillandier, Luc, Chinot, Olivier, Casasnovas, Olivier, Bay, Jacques-Olivier, Jardin, Fabrice, Oberic, Lucie, Fabbro, Michel, Damaj, Gandhi, Brion, Annie, Mokhtari, Karima, Philippe, Cathy, Sanson, Marc, Houillier, Caroline, Soussain, Carole, Hoang-Xuan, Khê, Houlston, Richard, Alentorn, Agusti, Moles-Moreau, Marie-Pierre, Gressin, Rémy, Morschhauser, Franck, Agapé, Philippe, Jaccard, Arnaud, Ghesquières, Hervé, Tempescul, Adrian, Gyan, Emmanuel, Marolleau, Jean-Pierre, Houot, Roch, Fornecker, Luc, Stefano, Anna-Luisa Di, Detrait, Ines, Rahimian, Amithys, Lathrop, Mark, Genet, Diane, Davi, Frederic, Cassoux, Nathalie, Touitou, Valérie, Choquet, Sylvain, Vital, Anne, Polivka, Marc, Figarella-Branger, Dominique, Benouaich-Amiel, Alexandra, Campello, Chantal, Charlotte, Fréderic, Martin-Duverneuil, Nadine, Feuvret, Loïc, Kas, Aurélie, Navarro, Soledad, Villa, Chiara, Bielle, Franck, Chrétien, Fabrice, Tortel, Marie Christine, Gauchotte, Guillaume, Uro-Coste, Emmanuelle, Godfrain, Catherine, Rigau, Valérie, Costopoulos, Myrto, Garff-Tavernier, Magalie Le, Meyronnet, David, Rousseau, Audrey, Adam, Clovis, Lamy, Thierry, Chabrot, Cécile, Boyle, Eileen, Blonski, Marie, Schmitt, Anna, The institute of cancer research [London], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Microsoft Research [Redmond], Microsoft Corporation [Redmond, Wash.], Cancer Genetics, Institute of cancer research, Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Plateforme de génétique moléculaire des cancers d'Aquitaine, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Laboratoire d'Hématologie [CHU Amiens], CHU Amiens-Picardie, Service d'hématologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université des sciences et de la Technologie d'Oran Mohamed Boudiaf [Oran] (USTO MB), Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CRLCC René Huguenin, Biologie des Interactions Neurones / Glie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'hématologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Biophysique, Médecine Nucléaire et Technologies Médicales (EA 1049), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service d'hématologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Service clinique des Maladies du Sang, CHU Pontchaillou [Rennes], Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), McGill University = Université McGill [Montréal, Canada], Institut Curie [Paris], Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Oto-Rhino-Laryngologie et de Chirurgie Cervico-Faciale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de mécanique des fluides de Toulouse (IMFT), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT), Service de Biopathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service d'hématologie clinique, Université de Rennes (UR)-Hôpital Pontchaillou, CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Hôpital Claude Huriez [Lille], CHU Lille, Service de Neuro-Oncologie [CHRU Nancy], UNICANCER, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), USTO (USTO), Centre de référence sur les démences rares et maladie de Pick, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Rangueil, Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], Service de Radiothérapie [CHU Pitié-Salpêtrière], Laboratoire d'Imagerie Biomédicale (LIB), Service de Neurochirurgie [CHU Pitié-Salpêtrière], Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Service de neuro-pathologie [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Institut Bergonié - CRLCC Bordeaux, Unité de transplantation médullaire et laboratoire d'oncologie moléculaire, CRLCC Jean Perrin, UNICANCER - Institut régional du Cancer [Montpellier] (ICM), Service hématologie Amiens, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hopital d'Amiens, Laboratoire de Spectrométrie de Masse BioOrganique, Département des Sciences Analytiques, Institut Pluridisciplinaire Hubert Curien (LSMBO-DSA-IPHC), Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université McGill, Service d'Hématologie Clinique [CHU Pitié-Salpêtrière], Institut Curie, Service d'Ophthalmologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Service d'Hépato-Gastroentérologie [CHU Pitié-Salpêtrière], Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Hôpital Claude Huriez, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Bergonié - Département de médecine, Université Bordeaux Segalen - Bordeaux 2-Centre régional de lutte contre le cancer [CRLCC], Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Radiothérapie [CHU Pitié Salpétrière], and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Central Nervous System, Cancer Research, Genome-wide association study, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Central Nervous System Neoplasms, 03 medical and health sciences, 0302 clinical medicine, primary CNS lymphoma, hemic and lymphatic diseases, medicine, Genetic predisposition, Humans, GWAS, 1000 Genomes Project, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, 0303 health sciences, Lymphoma, Non-Hodgkin, Primary central nervous system lymphoma, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.disease, cancer susceptibility, 3. Good health, Lymphoma, Oncology, 030220 oncology & carcinogenesis, Basic and Translational Investigations, Neurology (clinical), Lymphoma, Large B-Cell, Diffuse, Diffuse large B-cell lymphoma, Imputation (genetics), Genome-Wide Association Study
Abstract

BackgroundPrimary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin lymphoma. PCNSL is a distinct subtype of non-Hodgkin lymphoma, with over 95% of tumors belonging to the diffuse large B-cell lymphoma (DLBCL) group. We have conducted a genome-wide association study (GWAS) on immunocompetent patients to address the possibility that common genetic variants influence the risk of developing PCNSL.MethodsWe performed a meta-analysis of 2 new GWASs of PCNSL totaling 475 cases and 1134 controls of European ancestry. To increase genomic resolution, we imputed >10 million single nucleotide polymorphisms using the 1000 Genomes Project combined with UK10K as reference. In addition we performed a transcription factor binding disruption analysis and investigated the patterns of local chromatin by Capture Hi-C data.ResultsWe identified independent risk loci at 3p22.1 (rs41289586, ANO10, P = 2.17 × 10−8) and 6p25.3 near EXOC2 (rs116446171, P = 1.95 x 10−13). In contrast, the lack of an association between rs41289586 and DLBCL suggests distinct germline predisposition to PCNSL and DLBCL. We found looping chromatin interactions between noncoding regions at 6p25.3 (rs11646171) with the IRF4 promoter and at 8q24.21 (rs13254990) with the MYC promoter, both genes with strong relevance to B-cell tumorigenesis.ConclusionTo our knowledge this is the first study providing insight into the genetic predisposition to PCNSL. Our findings represent an important step in defining the contribution of common genetic variation to the risk of developing PCNSL.

Published
2019

4. The invasive proteome of glioblastoma revealed by laser-capture microdissection

Author

Daubon, Thomas, Guyon, Joris, Raymond, Anne-Aurélie, Dartigues, Benjamin, Rudewicz, Justine, Ezzoukhry, Zakaria, Dupuy, Jean-William, Herbert, John, Saltel, Frédéric, Bjerkvig, Rolf, Nikolski, Macha, Bikfalvi, Andreas, Nikolski, Macha, Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Bergen (UiB), Transbiomed : Biologie Fondamentale et Appliquée à la Médecine, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique de Bordeaux (CBIB), CGFB, Centre Génomique Fonctionnelle Bordeaux [Bordeaux] (CGFB), Institut Polytechnique de Bordeaux-Université de Bordeaux Ségalen [Bordeaux 2], Disease Gene Discovery Limited [London, UK], Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), KG Jebsen Brain Tumor Research Center, Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), Centre de recherche en pharmacologie - santé (CRPS), Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2

Subjects
patient-derived xenograft, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, proteomics analysis, glioblastoma, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, intratumor heterogeneity, [SDV.CAN]Life Sciences [q-bio]/Cancer, invasion, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Basic and Translational Investigations, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], ComputingMilieux_MISCELLANEOUS
Abstract

International audience; Background. Glioblastomas are heterogeneous tumors composed of a necrotic and tumor core and an invasive periphery.Methods. Here, we performed a proteomics analysis of laser-capture micro-dissected glioblastoma core and invasive areas of patient-derived xenografts.Results. Bioinformatics analysis identified enriched proteins in central and invasive tumor areas. Novel markers of invasion were identified, the genes proteolipid protein 1 (PLP1) and Dynamin-1 (DNM1), which were subsequently validated in tumors and by functional assays.Conclusions. In summary, our results identify new networks and molecules that may play an important role in glioblastoma development and may constitute potential novel therapeutic targets.

Published
2019

5. Identification of novel recurrent ETV6-IgH fusions in primary central nervous system lymphoma

Author

Dominique Figarella-Branger, Franck Bielle, Clovis Adam, Louis Royer-Perron, Guillaume Gauchotte, David Meyronet, Aurélie Bruno, Chiara Villa, Amithys Rahimian, Blandine Boisselier, Carole Soussain, Fabrice Chrétien, Khê Hoang-Xuan, Caroline Houillier, Sandrine Eimer, Mailys Daniau, Frederic Davi, Karima Mokhtari, Karim Labreche, Justine Guegan, Pierre de la Grange, Agusti Alentorn, Marc Polivka, Audrey Rousseau, Frédéric Lemoine, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), OncoNeuroTek [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], GenoSplice, Ltd, GenoSplice technology, GenoSplice [Paris], iCONICS, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’Anatomopathologie [Le Kremlin-Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hospices civils de Lyon, hôpital neurologique Pierre-Wertheimer, Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Pathologie [Hôpital Foch], Hôpital Foch [Suresnes], Centre Hospitalier Sainte Anne [Paris], Centre Hospitalier Universitaire de Bordeaux (CHU de Bordeaux), Département de Pathologie Cellulaire et Tissulaire [CHU Angers] (Laboratoire d’Histopathologie-Cytopathologie), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Hôpital René HUGUENIN (Saint-Cloud), This work is part of the national program Cartes d’Identité des Tumeurs (CIT) funded and developed by the Ligue nationale contre le cancer, the Institut National du Cancer, Association pour la recherche sur les tumeurs cérébrales (ARTC), Cancéropôle Île-de-France 'Emergence 2015-1' (2015-1-EMERG-05-INSERM 6-1), Ligue nationale contre le cancer (Comité du Val d’Oise, R14044DD), Ligue Nationale contre le cancer 'Recherche épidemiologique' (N° PRE2015.LNCC), Fondation pour la Recherche Médicale (FDT20140930968), and the program 'Investissements d’avenir' ANR-10-IAIHU-06, and the Institut National du Cancer (INCa) (Réseau Expert National LOC, Lymphomes Oculo-Cérébraux). This study was supported by the Lymphomes Oculo-Cérébraux (LOC) study group network (Réseau national de centres experts des lymphomes primitifs du système nerveux central), We would like to thank the French LOC Network investigators. Specimens from Marseille were retrieved from the AP-HM tumor bank AC 2013-1786, ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Incubateur et Pépinière d'Entreprises Paris-Salpêtrière (iPEPS-ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Male, Cancer Research, Oncogene Proteins, Fusion, MESH: Central Nervous System Neoplasms, Fusion gene, Central Nervous System Neoplasms, 0302 clinical medicine, hemic and lymphatic diseases, MESH: Middle Aged, medicine.diagnostic_test, Primary central nervous system lymphoma, RNA sequencing, ETV6-IgH, MESH: Follow-Up Studies, Middle Aged, Prognosis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Survival Rate, Oncology, fusion gene, MESH: Repressor Proteins, 030220 oncology & carcinogenesis, Basic and Translational Investigations, Female, Lymphoma, Large B-Cell, Diffuse, MESH: Biomarkers, Tumor, Haploinsufficiency, Immunoglobulin Heavy Chains, MESH: Immunoglobulin Heavy Chains, MESH: Proto-Oncogene Proteins c-ets, MESH: Survival Rate, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Prognosis, 03 medical and health sciences, primary CNS lymphoma, medicine, Biomarkers, Tumor, Humans, Survival rate, MESH: Humans, Proto-Oncogene Proteins c-ets, medicine.disease, MESH: Male, Lymphoma, haploinsufficiency, Repressor Proteins, ETV6, 030104 developmental biology, Cancer research, Immunoglobulin heavy chain, MESH: Lymphoma, Large B-Cell, Diffuse, Neurology (clinical), MESH: Female, Fluorescence in situ hybridization, Follow-Up Studies, MESH: Oncogene Proteins, Fusion
Abstract

International audience; Background: Primary central nervous system lymphoma (PCNSL) represents a particular entity within non-Hodgkin lymphomas and is associated with poor outcome. The present study addresses the potential clinical relevance of chimeric transcripts in PCNSL discovered by using RNA sequencing (RNA-seq).Methods: Seventy-two immunocompetent and newly diagnosed PCNSL cases were included in the present study. Among them, 6 were analyzed by RNA-seq to detect new potential fusion transcripts. We confirmed the results in the remaining 66 PCNSL. The gene fusion was validated by fluorescence in situ hybridization (FISH) using formalin-fixed paraffin-embedded (FFPE) samples. We assessed the biological and clinical impact of one new gene fusion.Results: We identified a novel recurrent gene fusion, E26 transformation-specific translocation variant 6-immunoglobulin heavy chain (ETV6-IgH). Overall, ETV6-IgH was found in 13 out of 72 PCNSL (18%). No fusion conserved an intact functional domain of ETV6, and ETV6 was significantly underexpressed at gene level, suggesting an ETV6 haploinsufficiency mechanism. The presence of the gene fusion was also validated by FISH in FFPE samples. Finally, PCNSL samples harboring ETV6-IgH showed a better prognosis in multivariate analysis, P = 0.03, hazard ratio = 0.33, 95% CI = 0.12-0.88. The overall survival at 5 years was 69% for PCNSL harboring ETV6-IgH versus 29% for samples without this gene fusion.Conclusions: ETV6-IgH is a new potential surrogate marker of PCNSL with favorable prognosis with ETV6 haploinsufficiency as a possible mechanism. The potential clinical impact of ETV6-IgH should be validated in larger prospective studies.

Published
2018

6. Identification and functional prediction of mitochondrial complex III and IV mutations associated with glioblastoma

Author

Stavros Polyzoidis, Helen L. Fillmore, Qian An, John McGeehan, Keyoumars Ashkan, Katie F. Stephenson, Geoffrey J. Pilkington, Samantha C. Higgins, D. Timothy J. Littlewood, Kathleen Keatley, Rhiannon E. Lloyd, William V. Holt, Brigitte Meunier, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biogenèse et fonctionnement des complexes OXPHOS mitochondriaux (BIOMIT), Département Biologie Cellulaire (BioCell), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
Nonsynonymous substitution, Male, Cancer Research, [SDV]Life Sciences [q-bio], APC-PAID, Pharmacy, Mitochondrion, medicine.disease_cause, Genome, mitochondrial DNA (mtDNA) mutation, Electron Transport Complex III, 0302 clinical medicine, EPRC, Genetics, 0303 health sciences, education.field_of_study, Mutation, Brain Neoplasms, Middle Aged, Heteroplasmy, 3. Good health, Mitochondrial, Molecular Docking Simulation, Mitochondrial respiratory chain, Oncology, functional prediction, 030220 oncology & carcinogenesis, Basic and Translational Investigations, Female, subgrouping, Adult, Mitochondrial DNA, Adolescent, Population, Biology, DNA, Mitochondrial, Electron Transport Complex IV, 03 medical and health sciences, medicine, Humans, EP/E500595/1, structural analysis, education, 030304 developmental biology, Aged, glioblastoma, RCUK, DNA, Neurology (clinical)
Abstract

Background - Glioblastoma (GBM) is the most common primary brain tumor in adults, with a dismal prognosis. Treatment is hampered by GBM's unique biology, including differential cell response to therapy. Although several mitochondrial abnormalities have been identified, how mitochondrial DNA (mtDNA) mutations contribute to GBM biology and therapeutic response remains poorly described. We sought to determine the spectrum of functional complex III and IV mtDNA mutations in GBM.Methods - The complete mitochondrial genomes of 10 GBM cell lines were obtained using next-generation sequencing and combined with another set obtained from 32 GBM tissues. Three-dimensional structural mapping and analysis of all the nonsynonymous mutations identified in complex III and IV proteins was then performed to investigate functional importance.Results - Over 200 mutations were identified in the mtDNAs, including a significant proportion with very low mutational loads. Twenty-five were nonsynonymous mutations in complex III and IV, 9 of which were predicted to be functional and affect mitochondrial respiratory chain activity. Most of the functional candidates were GBM specific and not found in the general population, and 2 were present in the germ-line. Patient-specific maps reveal that 43% of tumors carry at least one functional candidate.Conclusions - We reveal that the spectrum of GBM-associated mtDNA mutations is wider than previously thought, as well as novel structural-functional links between specific mtDNA mutations, abnormal mitochondria, and the biology of GBM. These results could provide tangible new prognostic indicators as well as targets with which to guide the development of patient-specific mitochondrially mediated chemotherapeutic approaches.

Published
2015

7. Mitotic index, microvascular proliferation, and necrosis define 3 groups of 1p/19q codeleted anaplastic oligodendrogliomas associated with different genomic alterations

Author

Dominique, Figarella-Branger, Karima, Mokhtari, Caroline, Dehais, Anne, Jouvet, Emmanuelle, Uro-Coste, Carole, Colin, Catherine, Carpentier, Fabien, Forest, Claude-Alain, Maurage, Jean-Michel, Vignaud, Marc, Polivka, Emmanuelle, Lechapt-Zalcman, Sandrine, Eimer, Gabriel, Viennet, Isabelle, Quintin-Roué, Marie-Hélène, Aubriot-Lorton, Marie-Danièle, Diebold, Delphine, Loussouarn, Catherine, Lacroix, Valérie, Rigau, Annie, Laquerrière, Fanny, Vandenbos, Sophie, Michalak, Henri, Sevestre, Michel, Peoch, François, Labrousse, Christo, Christov, Jean-Louis, Kemeny, Marie-Pierre, Chenard, Danchristian, Chiforeanu, François, Ducray, Ahmed, Idbaih, Frederic, Dhermain, Laboratoire d'anatomie pathologique - [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Pathologie et de Neuropathologie Est, Hospices Civils de Lyon (HCL), Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INSERM, U975, Université Paris 06, Service d’Anatomie et Cytologie Pathologiques, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service d'Anatomie Pathologique, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d’Anatomie Pathologique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'anatomie et cytologie pathologiques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Laboratoire d'Anatomie Pathologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Hypoxie, physiopathologies cérébrovasculaire et tumorale (CERVOxy), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Service de Pathologie-Neuropathologie, CHU de Bordeaux Pellegrin [Bordeaux], Histologie et Pathologie Moléculaire, Université Bordeaux Segalen - Bordeaux 2, Service Anatomie et Cytologie Pathologiques, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHRU Brest - Laboratoire d'Anatomo-Pathologie (CHU - AnaPath), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de Pathologie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire d'anatomie et cytologie pathologiques [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Service d'Anatomie Pathologique B, Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Anatomie et Cytologie Pathologique, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Laboratoire d'Anatomie et Cytologie Pathologiques, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), chu de nice, Hôpital Pasteur, Laboratoire Central d’Anatomo Pathologie, Hôpital Pasteur [Nice] (CHU), Département de pathologie cellulaire et tissulaire, CHU d'Angers, 4, rue Larrey, 49100 Angers, France., Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service d'Anatomie et Cytologie Pathologiques, CHU Amiens-Picardie, Service d'Anatomie Pathologique [CHU Limoges], CHU Limoges, Hôpital Henri Mondor, CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Laboratoire d'anatomie pathologique - Hôpital de Hautepierre Hôpitaux Universitaires de Strasbourg - Université de Strasbourg, Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Service de neuro-oncologie [Hôpital Pierre Wertheimer - HCL], Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neuropathologie Raymond Escourolle [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de neurologie 2 [CHU Pitié-Salpêtrière], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Etienne, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Service d'Anatomie et Cytologie Pathologique [Rouen], AP-HP Hôpital Henri Mondor (Créteil), Service d'anatomie et cytologie pathologiques [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Neuropathologie [CHU Pitié Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Nord [CHU - APHM]-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université

Subjects
Cancer Research, Pathology, medicine.medical_specialty, IDH1, Necrosis, Mitotic index, Proliferation index, [SDV]Life Sciences [q-bio], Oligodendroglioma, Biology, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Chromosome instability, medicine, Mitotic Index, Humans, Progression-free survival, ComputingMilieux_MISCELLANEOUS, Neovascularization, Pathologic, Brain Neoplasms, Brain, medicine.disease, Isocitrate Dehydrogenase, 3. Good health, Oncology, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Basic and Translational Investigations, Chromosome abnormality, Neurology (clinical), medicine.symptom, Chromosome Deletion, Chromosomes, Human, Pair 19, 030217 neurology & neurosurgery
Abstract

BACKGROUND: The aim of this study was to correlate histological features and molecular characteristics in anaplastic oligodendrogliomas (AO). METHODS: The histological characteristics of 203 AO patients enrolled in the French national network POLA were analyzed. The genomic profiles of 191 cases were studied using genomic arrays. IDH mutational status was assessed by immunohistochemistry and direct sequencing. RESULTS: 1p/19q co-deletion was present in 79% of cases and was associated with alpha-internexin expression (p < 10-4), IDH1/2 mutation (p < 10-4), chromosome 4 loss (p < 10-3), and better overall survival (p < 10-4). Based on mitotic index, microvascular proliferation (MVP) and necrosis, 3 groups of 1p/19q co-deleted AO were identified: AO with more than 5 mitoses per 10-HPF, no MVP and no necrosis, (1), AO with MVP and no necrosis (2) and AO with MVP and necrosis (3). Compared to group 1, group 2 and 3 AO had a higher mean Ki-67 proliferation index and a higher rate of 9p and 9q losses. Compared to group 2, group 3 AO had a higher number of chromosomal alterations including chromosome 4 loss. In the subgroup of 157 1p/19q co-deleted AO, chromosomal instability was associated with shorter progression free survival (p = 0.024) and shorter overall survival (p = 0.023). CONCLUSIONS: The present study shows that oligodendroglioma with classic histological features remains a molecularly heterogeneous entity and should be stratified according to 1p/19q status because of its major prognostic relevance. Moreover, 1p/19q co-deleted AO are also heterogeneous. Interestingly, mitotic index, MVP and necrosis help to classify them into three groups associated with distinct genomic alterations.

Published
2014

8. Association of matrix metalloproteinase 2 plasma level with response and survival in patients treated with bevacizumab for recurrent high-grade glioma

Author

Olivier Chinot, Mona Matta, Celine Boucard, Emeline Tabouret, Philippe Metellus, Françoise Boudouresque, Marc Sanson, Anderson Loundou, Antoine F. Carpentier, Maryline Barrie, Dominique Figarella-Branger, L'Houcine Ouafik, Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuro-Oncologie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Santé Publique et maladies Chroniques : Qualité de vie Concepts, Usages et Limites, Déterminants (SPMC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM), Service de neurologie [Hôpital Avicenne], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), INSERM UMR_S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie [CHU Marseille], Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Transfert d'Oncologie Biologique [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Service de neurochirurgie, and Ouafik, L'Houcine

Subjects
Adult, Male, Cancer Research, Bevacizumab, Population, Angiogenesis Inhibitors, [SDV.CAN]Life Sciences [q-bio]/Cancer, Vandetanib, Antibodies, Monoclonal, Humanized, Cediranib, chemistry.chemical_compound, Young Adult, [SDV.CAN] Life Sciences [q-bio]/Cancer, Glioma, Medicine, Humans, education, Survival analysis, ComputingMilieux_MISCELLANEOUS, Aged, education.field_of_study, business.industry, Brain Neoplasms, Kinase insert domain receptor, Middle Aged, medicine.disease, Survival Analysis, 3. Good health, Vascular endothelial growth factor, Treatment Outcome, Oncology, chemistry, Immunology, Basic and Translational Investigations, Cancer research, Matrix Metalloproteinase 2, Female, Neurology (clinical), Neoplasm Recurrence, Local, business, Glioblastoma, Biomarkers, medicine.drug
Abstract

Antiangiogenic agents that target the vascular endothelial growth factor (VEGF) pathway have been successfully developed and approved in the vast majority of cancers. As a consequence, an increasing use of antiangiogenic agents has been observed, leading to cost issues and reassessment of their benefit. However, activity on tumor response, and survival benefit of these agents, varies mostly among tumor types and with agents tested. Bevacizumab, a monoclonal antibody against VEGF, was the first antiangiogenic agent that has demonstrated a benefit on progression-free survival (PFS) with or without impact on survival, in patients with advanced and metastatic cancer.1 Glioblastoma multiforme (GBM) is a devastating disease, characterized by a highly angiogenic and invasive phenotype, suggesting a potential role for antiangiogenic strategies. Preclinical data as well as high levels of intratumoral VEGF expression have supported the evaluation of agents that target the VEGF pathway.2 Among them, bevacizumab has been recently approved by the FDA for patients with recurrent glioblastoma, based on a high response rate (RR) with prolonged PFS compared with historical controls3 and is under investigation in the first-line setting.4 Biomarkers able to predict response to antiangiogenic agents and particularly to bevacizumab are an unmet medical need for patients with cancer. The ideal biomarker should be easy to measure on multiple points upon treatment and standardized in their analysis.5 Baseline levels and/or variation of numerous intratumoral or circulating candidate prebiomarkers have been explored. However, to date their predictive significance has been generally weak and rarely confirmed among studies or compared with a cytotoxic treated population. In situ prebiomarkers such as VEGF, VEGF receptor (VEGFR) 2, and carbonic anhydrase 9, as well as plasma prebiomarkers such as VEGF, VEGFR1, intercellular adhesion molecule 1, and interleukin (IL)-6 and -8, have been reported to predict bevacizumab benefit, but this predictive value is generally weak and restricted to one end point (response, PFS, or overall survival [OS]).6 With other antiangiogenic agents such as cediranib in GBM and vandetanib in non–small-cell lung carcinoma, various prebiomarkers, including VEGF, VEGFR2, placenta growth factor (PlGF), basic fibroblast growth factor (bFGF), and matrix metalloproteinase (MMP) 2, present transition variations that have been related to either progression or survival.7,8 Given the remarkable but inconsistent activity of bevacizumab in GBM, we explored the value of selected plasma prebiomarkers to predict response and survival in patients treated with bevacizumab for recurrent high-grade glioma (HGG).

Published
2014

9. Impact of meriolins, a new class of cyclin-dependent kinase inhibitors, on malignant glioma proliferation and neo-angiogenesis

Author

Benoît Joseph, Vadim Lejoncour, Marie-Thérèse Schouft, François Liger, Céline Lecointre, Laurent Meijer, Gildas Lyvinec, Marie Jarry, Pierrick Gandolfo, Hélène Castel, Nadège Loaëc, Céline Malleval, Jérôme Honnorat, Laurence Desrues, Usr3151, Hal, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuroendocrinologie cellulaire et moléculaire, Synthèse de Molécules d'Intérêt Thérapeutique (SMITh), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Phophorylation de protéines et Pathologies Humaines (P3H), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff [Roscoff] (SBR), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Cancer Research, Pathology, medicine.medical_specialty, Cell cycle checkpoint, Angiogenesis, Blotting, Western, Mice, Nude, Apoptosis, Immunoenzyme Techniques, Mice, 03 medical and health sciences, 0302 clinical medicine, Cyclin-dependent kinase, Glioma, Human Umbilical Vein Endothelial Cells, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Phosphorylation, Rats, Wistar, Cells, Cultured, Cell Proliferation, 030304 developmental biology, Neurons, 0303 health sciences, Neovascularization, Pathologic, biology, Kinase, Cell growth, Cell Cycle, Cell cycle, Bridged Bicyclo Compounds, Heterocyclic, medicine.disease, Xenograft Model Antitumor Assays, Cyclin-Dependent Kinases, Rats, 3. Good health, Endothelial stem cell, Pyrimidines, Oncology, 030220 oncology & carcinogenesis, Basic and Translational Investigations, biology.protein, Cancer research, Neurology (clinical)
Abstract

International audience; Glioblastomas are the most frequent and most aggressive primary brain tumors in adults. The median overall survival is limited to a few months despite surgery, radiotherapy, and chemotherapy. It is now clearly established that hyperactivity of cyclin-dependent kinases (CDKs) is one of the processes underlying hyperproliferation and tumoral growth. The marine natural products meridianins and variolins, characterized as CDK inhibitors, display a kinase-inhibitory activity associated with cytotoxic effects. In order to improve selectivity and efficiency of these CDK inhibitors, a series of hybrid compounds called meriolins have been synthesized. The potential antitumoral activity of meriolins was investigated in vitro on glioma cell lines (SW1088 and U87), native neural cells, and a human endothelial cell line (HUV-EC-C). The impact of intraperitoneal or intratumoral administrations of meriolin 15 was evaluated in vivo on 2 different nude mice-xenografted glioma models. Meriolins 3, 5, and 15 exhibited antiproliferative properties with nanomolar IC50 and induced cell-cycle arrest and CDK inhibition associated with apoptotic events in human glioma cell lines. These meriolins blocked the proliferation rate of HUV-EC-C through cell cycle arrest and apoptosis. In vivo, meriolin 15 provoked a robust reduction in tumor volume in spite of toxicity for highest doses, associated with inhibition of cell division, activation of caspase 3, reduction of CD133 cells, and modifications of the vascular architecture. Meriolins, and meriolin 15 in particular, exhibit antiproliferative and proapoptotic activities on both glioma and intratumoral endothelial cells, constituting key promising therapeutic lead compounds for the treatment of glioblastoma.

Published
2014

10. Cells with intense EGFR staining and a high nuclear to cytoplasmic ratio are specific for infiltrative glioma: a useful marker in neuropathological practice

Author

Fanny Burel-Vandenbos, Maxime Benchetrit, Fabien Almairac, E. Fontas, Damien Ambrosetti, Laurent Turchi, Valérie Rigau, Jean-François Michiels, Thierry Virolle, Zoe Pedeutour, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)

Subjects
Adult, Male, Cancer Research, Pathology, medicine.medical_specialty, Cytoplasm, IDH1, Blotting, Western, Fluorescent Antibody Technique, Glial tumor, Biology, Immunoenzyme Techniques, 03 medical and health sciences, 0302 clinical medicine, Glioma, Biopsy, medicine, Biomarkers, Tumor, Tumor Cells, Cultured, Humans, Progenitor cell, Child, [SDV.BDD]Life Sciences [q-bio]/Development Biology, In Situ Hybridization, Fluorescence, Retrospective Studies, Cell Nucleus, medicine.diagnostic_test, Brain Neoplasms, medicine.disease, Flow Cytometry, 3. Good health, ErbB Receptors, Oncology, Gliosis, 030220 oncology & carcinogenesis, Basic and Translational Investigations, Immunohistochemistry, Female, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery, Immunostaining
Abstract

Infiltrative gliomas (IG), including astrocytomas, oligodendrogliomas, and glioblastomas, are the most common primary brain tumors in humans.1 IG display a poor prognosis, especially glioblastomas, which represent the most aggressive subtype.1 The tumors of this group are characterized by a pattern of infiltrative growth into the surrounding normal brain,2 making complete surgical excision very difficult. Recurrence or progression after surgery almost always occurs despite adjuvant treatment with radiotherapy and/or chemotherapy.1 Morphological patterns of IG are often heterogeneous, and the diagnosis may be challenging for pathologists.2 Glial tumor cells may also be difficult to distinguish from reactive cells on the basis of morphology alone. Reactive astrocytes may become very large and may even display pleomorphic nuclei resembling neoplastic tumor cells.3 The differential diagnosis between IG and gliosis can thus be difficult, especially in small biopsy samples.4 IG can also be difficult to differentiate from benign and/or curable noninfiltrative glial tumors, including pilocytic astrocytomas, gangliogliomas, and dysembryoplastic neuroepithelial tumors,1,2 and from demyelinating disease.5 It is therefore very important for pathologists to develop histological markers to identify infiltrating glioma cells. To date, no ideal marker has been identified for this purpose. In practice, the most useful markers are MIB1/Ki676,7 and p53,8,9 but these lack sensitivity and specificity.10 More recently, the mutated R132H form of isocitrate dehydrogenase 1 (IDH1), which can be specifically detected by immunohistochemistry,11,12 has been shown to be a good marker of grade II and grade III gliomas and of secondary glioblastomas.13–15 However IDH1 (R132H) is rare in primary glioblastomas16 and is not useful for the diagnosis of this subtype, which represents the most common IG. A marker specific for infiltrating cells, which are characteristic of IG regardless of grade or histological subtype, would be of value. Recently, we showed that the EGFR immunolabelling pattern can discriminate low-grade glioma from gliosis.17 The criterion that characterized low-grade gliomas was strong EGFR immunostaining in cells with a high nuclear to cytoplasmic ratio. EGFR overexpression is frequent in gliomas. In 40% of glioblastomas, EGFR overexpression is secondary to gene amplification and is often associated with expression of EGFRvIII, a constitutively activated mutated variant.18 Conversely, EGFR amplification is rare in low-grade gliomas,18–21 although protein overexpression has been detected with a frequency ranging from 11.5% to 100% of cases in the literature.19,20,22–24 The mechanism of this overexpression in low-grade IG remains unknown. Several ligands, including EGF and TGFα, may activate EGFR. The activation of EGFR is involved in several processes, including cell survival, differentiation, proliferation, and migration.25 Because EGFR has been shown to influence cell migration during the development of the central nervous system26–28 and in gliomas,29–31 we postulated that EGFR could be a marker of migrating cells, specific for IG. The aim of the present study was to assess whether elevated EGFR expression in cells with a high nuclear to cytoplasmic ratio, as we previously observed in low-grade glioma,17 may be a valuable criterion to discriminate infiltrative gliomas of any grade or histological subtype from noninfiltrative glial lesions. We also sought to further characterize these strongly EGFR-positive cells.

Published
2013

11. Detection of glioblastoma response to temozolomide combined with bevacizumab based on µMRI and µPET imaging reveals [$^{18}$F]-fluoro-L-thymidine as an early and robust predictive marker for treatment efficacy

Author

Simon Roussel, M Ibazizène, Myriam Lecocq, Jérôme Delamare, Edwige Petit, Andreas H. Jacobs, Elodie A. Pérès, Nathalie Varoqueaux, Jean-Sébastien Guillamo, Louisa Barré, Samuel Valable, Myriam Bernaudin, Aurélien Corroyer-Dulmont, Eric T. MacKenzie, Didier Divoux, Jérôme Toutain, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Roche SAS, Neuilly-sur-Seine, France, Laboratoire Roche SAS, European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-Universität Münster (WWU), This study was funded by the Institut National contre leCancer (INCa), Roche, the Centre National de laRecherche Scientifique (CNRS), the Ministe`re del’Enseignement Supe´rieur et de la Recherche (MESR),the Universite´ de Caen Basse-Normandie (UCBN), theConseil Regional de Basse-Normandie (CRBN), theEuropean Union –Fonds Europe´en de De´veloppementRe´gional (FEDER), and the Trans ChannelNeuroscience Network (TC2N), and Westfälische Wilhelms-Universität Münster = University of Münster (WWU)

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Pathology, Bevacizumab, Dacarbazine, [SDV]Life Sciences [q-bio], Antibodies, Monoclonal, Humanized, 030218 nuclear medicine & medical imaging, Immunoenzyme Techniques, Rats, Nude, 03 medical and health sciences, 0302 clinical medicine, Fluorodeoxyglucose F18, Internal medicine, Glioma, Antineoplastic Combined Chemotherapy Protocols, Temozolomide, medicine, Animals, Humans, Survival rate, Predictive marker, medicine.diagnostic_test, Brain Neoplasms, business.industry, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, Xenograft Model Antitumor Assays, Rats, Tumor Burden, 3. Good health, Survival Rate, Treatment Outcome, Positron emission tomography, Positron-Emission Tomography, 030220 oncology & carcinogenesis, Basic and Translational Investigations, Neurology (clinical), Radiopharmaceuticals, Glioblastoma, business, Biomarkers, medicine.drug
Abstract

International audience; The individualized care of glioma patients ought to benefit from imaging biomarkers as precocious predictors of therapeutic efficacy. Contrast enhanced MRI and [18F]-fluorodeoxyglucose (FDG) –PET are routinely used in clinical settings; their ability to forecast the therapeutic response is controversial. The objectives of our preclinical study were to analyze sensitive mMRI and/or mPET imaging biomarkers to predict the efficacy of anti-angiogenic and/or chemotherapeutic regimens. Human U87 and U251 orthotopic glioma models were implanted in nude rats. Temozolomide and/or bevacizumab were administered. mMRI (anatomical, diffusion, and microrheological parameters) and mPET ([$^{18}$F]-FDG and [$^{18}$F]-fluoro-L-thymidine [FLT]–PET) studies were undertaken soon (t1) after treatment initiation compared with late anatomical mMRI evaluation of tumor volume (t2) and overall survival. In both models, FDG and FLT uptakes were attenuated at t1 in response to temozolomide alone or with bevacizumab. The distribution of FLT, reflecting intratumoral heterogeneity, was also modified. FDG was less predictive for treatment efficacy than was FLT (also highly correlated with outcome, P < .001 for both models). Cerebral blood volume was significantly decreased by temozolomide 1 bevacizumab and was correlated with survival for rats with U87 implants. While FLT was highly predictive of treatment efficacy, a combination of imaging biomarkers was superior to any one alone (P < .0001 in both tumorswith outcome). Our results indicate that FLT is a sensitive predictor of treatment efficacy and that predictability is enhanced by a combination of imaging biomarkers. These findings may translate clinically in that individualized glioma treatments could be decided in given patients after PET/MRI examinations.

Published
2013

12. Cyclopamine cooperates with EGFR inhibition to deplete stem-like cancer cells in glioblastoma-derived spheroid cultures

Author

Marc-Antoine Belaud-Rotureau, Frédéric Dugay, Sandrine Eimer, Kelly Airiau, Véronique Quillien, Tony Avril, Francis Belloc, Laboratoire d'Histologie et de Pathologie moléculaire des tumeurs, Université Bordeaux Segalen - Bordeaux 2-EA 2406, Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Laboratoire d'Hématologie, Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux]-CHU Bordeaux [Bordeaux], Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Service de Biologie, CRLCC Eugène Marquis (CRLCC), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, Cyclopamine, [SDV]Life Sciences [q-bio], Blotting, Western, Fluorescent Antibody Technique, Apoptosis, Biology, Erlotinib Hydrochloride, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cancer stem cell, Cell Line, Tumor, Neurosphere, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Progenitor cell, In Situ Hybridization, Fluorescence, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, 030304 developmental biology, Comparative Genomic Hybridization, 0303 health sciences, Brain Neoplasms, Veratrum Alkaloids, Cell Differentiation, Drug Synergism, Flow Cytometry, Molecular biology, 3. Good health, ErbB Receptors, Oncology, chemistry, 030220 oncology & carcinogenesis, Basic and Translational Investigations, Cancer cell, Neoplastic Stem Cells, Quinazolines, Neurology (clinical), Erlotinib, Stem cell, Glioblastoma, medicine.drug
Abstract

Putative cancer stem cells have been identified in glioblastoma (GBM), associated with resistance to conventional therapies. Overcoming this resistance is a major challenge to manage this deadly brain tumor. Epidermal growth factor receptor (EGFR) is commonly amplified, over-expressed, and/or mutated in GBM, making it a compelling target for therapy. This study investigates the behavior of 3 primary neurosphere (NS) cell lines and their adherent counterparts originated from human GBM resections, when treated with EGFR–tyrosine kinase inhibitor erlotinib, associated or not with cyclopamine, a hedgehog pathway inhibitor. Adherent cells cultured in the presence of serum expressed the glial fibrillary acidic protein, whereas NS-forming cells cultured in serum-free medium expressed CD133, nestin, and Oct-4, markers of neural stem and progenitor cells. For the 3 adherent cell lines, erlotinib has a moderate effect (50% inhibitory concentration [IC50], >10 µM). Conversely, erlotinib induced a strong cell growth inhibition (IC50

Published
2012

13. Akt signaling pathway: a target for radiosensitizing human malignant glioma

Author

Jacques Chassagne, Gaëlle Loubeau, Andrei Tchirkov, Claudine Vermot-Desroches, Laurent Morel, Emmanuel Chautard, Pierre Verrelle, Thérapie ciblée combinatoire en Onco-Hématologie (EA3846), Université d'Auvergne - Clermont-Ferrand I (UdA), Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, CHAUTARD, Emmanuel, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)

Subjects
STAT3 Transcription Factor, Cancer Research, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Blotting, Western, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Radiation Tolerance, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Radioresistance, Glioma, medicine, Humans, STAT3, Protein kinase B, PI3K/AKT/mTOR pathway, 030304 developmental biology, 0303 health sciences, Brain Neoplasms, Akt/PKB signaling pathway, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, Oncology, 030220 oncology & carcinogenesis, Basic and Translational Investigations, Cancer research, biology.protein, Neurology (clinical), Signal transduction, Janus kinase, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract

International audience; Radiation therapy plays a central role in the treatment of glioblastoma, but it is not curative due to the high tumor radioresistance. Phosphatidyl-inositol 3-kinase/protein kinase B (Akt) and Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathways serve to block the apoptosis process, keeping cells alive in very toxic environments such as chemotherapy or ionizing radiation. In the present study, from a panel of 8 human malignant glioma cell lines, investigations on the relationship between intrinsic radioresistance and Akt or STAT3 basal activation were done. Secondly, the impact of down-modulation of Akt or STAT3 signaling on in vitro intrinsic radiosensitivity was evaluated. Using a clonogenic cell survival assay, our results revealed a significant correlation between the basal Akt activation and the surviving fraction at 2 Gy (SF2). In contrast, no correlation was found between STAT3 activation and SF2. According to this, down-modulation of Akt with a specific chemical inhibitor (Akt inhibitor IV) demonstrated a significant enhancement of radiation sensitivity on glioma cells in a clonogenic survival assay. On the contrary, down-modulation of STAT3 signaling with a specific chemical inhibitor (JSI-124) or a neutralizing gp130 antibody failed to radiosensitize glioma cells. These data indicate that the Akt intercept node could be a more relevant therapeutic target than STAT3 for radiosensitizing human malignant glioma.

Published
2010

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