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1. Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome

Author

Christel Depienne, Sorana Ciura, Oriane Trouillard, Delphine Bouteiller, Elsa Leitã;o, Caroline Nava, Boris Keren, Yannick Marie, Justine Guegan, Sylvie Forlani, Alexis Brice, Mathieu Anheim, Yves Agid, Paul Krack, Philippe Damier, François Viallet, Jean-Luc Houeto, Franck Durif, Marie Vidailhet, Yulia Worbe, Emmanuel Roze, Edor Kabashi, and Andreas Hartmann

Subjects
tourette syndrome, gene, variant, susceptibility factor, opioid receptor, zebrafish, oprk1, Diseases of the musculoskeletal system, RC925-935, Neurology. Diseases of the nervous system, RC346-429
Abstract

Background: Genes involved in Tourette syndrome (TS) remain largely unknown. We aimed to identify genetic factors contributing to TS in a French cohort of 120 individuals using a combination of hypothesis-driven and exome-sequencing approaches. Methods: We first sequenced exons of SLITRK1-6 and HDC in the TS cohort and subsequently sequenced the exome of 12 individuals harboring rare variants in these genes to find additional rare variants contributing to the disorder under the hypothesis of oligogenic inheritance. We further screened three candidate genes (OPRK1, PCDH10, and NTSR2) preferentially expressed in the basal ganglia, and three additional genes involved in neurotensin and opioid signaling (OPRM1, NTS, and NTSR1), and compared variant frequencies in TS patients and 788 matched control individuals. We also investigated the impact of altering the expression of Oprk1 in zebrafish. Results: Thirteen ultrarare missense variants of SLITRK1-6 and HDC were identified in 12 patients. Exome sequencing in these patients revealed rare possibly deleterious variants in 3,041 genes, 54 of which were preferentially expressed in the basal ganglia. Comparison of variant frequencies altering selected candidate genes in TS and control individuals revealed an excess of potentially disrupting variants in OPRK1, encoding the opioid kappa receptor, in TS patients. Accordingly, we show that downregulation of the Oprk1 orthologue in zebrafish induces a hyperkinetic phenotype in early development. Discussion: These results support a heterogeneous and complex genetic etiology of TS, possibly involving rare variants altering the opioid pathway in some individuals, which could represent a novel therapeutic target in this disorder.

Published
2019
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2. Genome-wide microarray expression and genomic alterations by array-CGH analysis in neuroblastoma stem-like cells.

Author

Raquel Ordóñez, Gabriel Gallo-Oller, Soledad Martínez-Soto, Sheila Legarra, Noémie Pata-Merci, Justine Guegan, Giselle Danglot, Alain Bernheim, Bárbara Meléndez, Juan A Rey, and Javier S Castresana

Subjects
Medicine, Science
Abstract

Neuroblastoma has a very diverse clinical behaviour: from spontaneous regression to a very aggressive malignant progression and resistance to chemotherapy. This heterogeneous clinical behaviour might be due to the existence of Cancer Stem Cells (CSC), a subpopulation within the tumor with stem-like cell properties: a significant proliferation capacity, a unique self-renewal capacity, and therefore, a higher ability to form new tumors. We enriched the CSC-like cell population content of two commercial neuroblastoma cell lines by the use of conditioned cell culture media for neurospheres, and compared genomic gains and losses and genome expression by array-CGH and microarray analysis, respectively (in CSC-like versus standard tumor cells culture). Despite the array-CGH did not show significant differences between standard and CSC-like in both analyzed cell lines, the microarray expression analysis highlighted some of the most relevant biological processes and molecular functions that might be responsible for the CSC-like phenotype. Some signalling pathways detected seem to be involved in self-renewal of normal tissues (Wnt, Notch, Hh and TGF-β) and contribute to CSC phenotype. We focused on the aberrant activation of TGF-β and Hh signalling pathways, confirming the inhibition of repressors of TGF-β pathway, as SMAD6 and SMAD7 by RT-qPCR. The analysis of the Sonic Hedgehog pathway showed overexpression of PTCH1, GLI1 and SMO. We found overexpression of CD133 and CD15 in SIMA neurospheres, confirming that this cell line was particularly enriched in stem-like cells. This work shows a cross-talk among different pathways in neuroblastoma and its importance in CSC-like cells.

Published
2014
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3. E4F1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure translation fidelity during brain development

Author

Michela Di Michele, Aurore Attina, Pierre-François Roux, Imène Tabet, Sophie Laguesse, Javier Florido, Morane Houdeville, Armelle Choquet, Betty Encislai, Giuseppe Arena, Carlo De Blasio, Olivia Wendling, François-Xavier Frenois, Laura Papon, Lucille Stuani, Maryse Fuentes, Céline Jahannault Talignani, Mélanie Rousseau, Justine Guégan, Yoan Buscail, Pierrick Dupré, Henri-Alexandre Michaud, Geneviève Rodier, Floriant Bellvert, Hanna Kulyk, Carole Ferraro Peyret, Hugo Mathieu, Pierre Close, Francesca Rapino, Cédric Chaveroux, Nelly Pirot, Lucie Rubio, Adeline Torro, Tania Sorg, Fabrice Ango, Christophe Hirtz, Vincent Compan, Elise Lebigot, Andrea Legati, Daniele Ghezzi, Laurent Nguyen, Alexandre David, Claude Sardet, Matthieu Lacroix, and Laurent Le Cam

Subjects
Science
Abstract

Abstract Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but the molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate metabolism and the regulation of the epitranscriptome that plays an essential role during brain development. Using genetically engineered mouse model and primary neuronal cells, we identify the transcription factor E4F1 as a key coordinator of AcetylCoenzyme A (AcCoA) production by the pyruvate dehydrogenase complex (PDC) and its utilization as an essential co-factor by the Elongator complex to acetylate tRNAs at the wobble position uridine 34 (U34). E4F1-mediated direct transcriptional regulation of Dlat and Elp3, two genes encoding key subunits of the PDC and of the Elongator complex, respectively, ensures proper translation fidelity and cell survival in the central nervous system (CNS) during mouse embryonic development. Furthermore, analysis of PDH-deficient cells highlight a crosstalk linking the PDC to ELP3 expression that is perturbed in LS patients.

Published
2025
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5. VEGF-C promotes brain-derived fluid drainage, confers neuroprotection, and improves stroke outcomes

Author

Ligia Simoes Braga Boisserand, Jean Bouchart, Luiz Henrique Medeiros Geraldo, Seyoung Lee, Basavaraju Sanganahalli Ganganna, Maxime Parent, Shenqi Zhang, Yuechuan Xue, Mario Skarica, Justine Guegan, Mingfeng Li, Xiodan Liu, Mathilde Poulet, Michael Askanase, Artem Osherov, Myriam Spajer, Maarie-Renee El Kamouh, Anne Eichmann, Kari K Alitalo, Jianbing Zhou, Nenad Sestan, Lauren Sansing, Helene Benveniste, Fahmeed Hyder, and jean-leon thomas

Subjects
Article
Abstract

Meningeal lymphatic vessels promote tissue clearance and immune surveillance in the central nervous system (CNS). Vascular endothelium growth factor-C (VEGF-C) is essential for meningeal lymphatic development and maintenance and has therapeutic potential for treating neurological disorders, including ischemic stroke. We have investigated the effects of VEGF-C overexpression on brain fluid drainage, single cell transcriptome in the brain, and stroke outcomes in adult mice. Intra-cerebrospinal fluid administration of an adeno-associated virus expressing VEGF-C (AAV-VEGF-C) increases the CNS lymphatic network. Post-contrast T1 mapping of the head and neck showed that deep cervical lymph node size and drainage of CNS-derived fluids were increased. Single nuclei RNA sequencing revealed a neuro-supportive role of VEGF-C via upregulation of calcium and brain-derived neurotrophic factor (BDNF) signaling pathways in brain cells. In a mouse model of ischemic stroke, AAV-VEGF-C pretreatment reduced stroke injury and ameliorated motor performances in the subacute stage. AAV-VEGF-C thus promotes CNS-derived fluid and solute drainage, confers neuroprotection, and reduces ischemic stroke damage. SHORT ABSTRACT: Intrathecal delivery of VEGF-C increases the lymphatic drainage of brain-derived fluids confers neuroprotection, and improves neurological outcomes after ischemic stroke.

Published
2023

6. Supplementary Figure 2 from MET Is a Potential Target across All Papillary Renal Cell Carcinomas: Result from a Large Molecular Study of pRCC with CGH Array and Matching Gene Expression Array

Author

Bernard Escudier, Jean-Jacques Patard, Sophie Gad, Sophie Couvé, Cedric Orear, Yves Allory, Vincent Molinie, Zahira Merabet, Philippe Camparo, Jean-Christophe Bernhard, Mathilde Sibony, Nathalie Rioux-Leclercq, Virginie Verkarre, Audrey Le Formal, Justine Guegan, and Laurence Albiges

Abstract

PDF file - 50KB, Correlation between copy number alteration (blue - gain/amplification, red - loss) and gene expression profiling. Gene expression level is represented (in grey box plot), according to copy number alteration (each blue circle representing a CGH array results, diameter of circle depicts amplitude of gain).

Published
2023
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7. Supplementary Figure 1 from MET Is a Potential Target across All Papillary Renal Cell Carcinomas: Result from a Large Molecular Study of pRCC with CGH Array and Matching Gene Expression Array

Author

Bernard Escudier, Jean-Jacques Patard, Sophie Gad, Sophie Couvé, Cedric Orear, Yves Allory, Vincent Molinie, Zahira Merabet, Philippe Camparo, Jean-Christophe Bernhard, Mathilde Sibony, Nathalie Rioux-Leclercq, Virginie Verkarre, Audrey Le Formal, Justine Guegan, and Laurence Albiges

Abstract

PDF file - 153KB, Correlation analysis of the expression level of 36 genes - involved in MET pathway - between the patients harboring a MET mutations, the 6 ccRCC samples, and normal kidney tissue samples.

Published
2023
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8. Supplementary Table 1, Figures 1 - 8 from Cisplatin Resistance Associated with PARP Hyperactivation

Author

Guido Kroemer, Maria Castedo, Jean-Charles Soria, Murat Saparbaev, Philippe Dessen, Catherine Brenner, Gen Sheng Wu, Kimitoshi Kohno, Parviz Behnam-Motlagh, Pauline Garcia, Abdul Qader Sukkurwala, Delphine Lissa, Cédric Oréar, Philippe Girard, Angélique Robin, Monique Talbot, David Pierre Enot, Justine Guegan, Ibtissam Talhaoui, Laura Senovilla, Oliver Kepp, Ken André Olaussen, Julien Adam, Lorenzo Galluzzi, Ilio Vitale, and Judith Michels

Abstract

PDF file - 490K, Supplementary Table S1. Systematic comparison of the effects of CDDP and PARP inhibitors on cancer cell lines used in this study. Supplementary Figure S1. Generation and characterization of CDDP-resistant human NSCLC cell clones. Supplementary Figure S2. Effects of CDDP and PARP inhibitors on the intracellular levels of poly(ADPribosyl) ated proteins in WT and CDDP-resistant NSCLC cells. Supplementary Figure S3. DNA damage as induced by PARP inhibitors is not a consequence of apoptotic caspase activation. Supplementary Figure S4. Markers of homologous recombination (HR) in CDDP-sensitive and CDDP-resistant A549 cells responding to PARP inhibitors. Supplementary Figure S5. DNA repair activity of A549 cell extracts towards dA�T- and THF�T-containing substrates. Supplementary Figure S6. DNA glycosylase activity of A549 cell extracts towards Hx�T- and U�G-containing substrates. Supplementary Figure S7. DNA repair activity of A549 cell extracts towards 5-OHC�T-and 8oxoG�C-containing substrates. Supplementary Figure S8. Expression levels and functional activity of XRCC1 and POL in CDDP-sensitive and CDDP-resistant cancer cells that overexpress PARP1 and contain high levels of poly(ADP-ribosyl)ated proteins.

Published
2023
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10. The antidiabetic drug glibenclamide exerts direct retinal neuroprotection

Author

Claire Gozalo, Laurent Jonet, Francine Behar-Cohen, Patricia Crisanti, Michèle Savoldelli, Zoubir Djerada, Elsa Kermorvant-Duchemin, Emilie Picard, Jacques Beltrand, Alexandre Moulin, Jean-Claude Jeanny, Alejandra Daruich, Justine Guegan, Lolita Radet, Kimberley Delaunay, Michel Polak, Marie-Christine Naud, and Marianne Berdugo

Subjects
Male, 0301 basic medicine, genetic structures, Administration, Oral, Pharmacology, Sulfonylurea Receptors, Glibenclamide, 0302 clinical medicine, Chlorocebus aethiops, Glyburide, Medicine, General Medicine, Diabetic retinopathy, Middle Aged, Potassium channel, 3. Good health, Neuroprotective Agents, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, Retinal Neurons, medicine.drug, endocrine system, Central nervous system, TRPM Cation Channels, Neuroprotection, Diabetes Mellitus, Experimental, 03 medical and health sciences, Retinal Diseases, Downregulation and upregulation, Physiology (medical), Animals, Humans, Hypoglycemic Agents, Potassium Channels, Inwardly Rectifying, Rats, Wistar, Retina, Diabetic Retinopathy, business.industry, Biochemistry (medical), Public Health, Environmental and Occupational Health, medicine.disease, eye diseases, Macaca fascicularis, 030104 developmental biology, Rats, Inbred Lew, Hyperglycemia, Sulfonylurea receptor, sense organs, business
Abstract

Sulfonylureas, widely used as hypoglycemic agents in adults with type 2 diabetes, have neuroprotective effects in preclinical models of central nervous system injury, and in children with neuropsychomotor impairments linked to neonatal diabetes secondary to ATP-sensitive potassium channel mutations. In the human and rodent retina, we show that the glibenclamide-activated channel sulfonylurea receptor 1 (SUR1) is expressed in the retina and enriched in the macula; we also show that it colocalizes with the potassium channel Kir6.2, and with the cation channel transporter TRPM4. Glibenclamide (glyburide), administered at doses that did not decrease the glycemia, or injected directly into the eye, protected the structure and the function of the retina in various models of retinal injury that recapitulate the pathogenic neurodegenerative events in the diabetic retina. The downregulation of SUR1 using a siRNA suppressed the neuroprotective effects of glibenclamide on excitotoxic stress-induced cell death. The glibenclamide effects include the transcriptional regulation of antioxidant and neuroprotective genes. Ocular glibenclamide could be repurposed for diabetic retinopathy.

Published
2021
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11. Molecular Profiling Reclassifies Adult Astroblastoma into Known and Clinically Distinct Tumor Entities with Frequent Mitogen-Activated Protein Kinase Pathway Alterations

Author

Franck Bielle, Mehdi Touat, Karima Mokhtari, Aurélien Nouet, Yannick Marie, Philipp Euskirchen, Audrey Rousseau, Luc Taillandier, William Boisseau, Justine Guegan, Marc Sanson, Caroline Dehais, Carine Karachi, Ahmed Idbaih, Nadine Martin-Duverneuil, Laurent Capelle, Khê Hoang-Xuan, Jean-Yves Delattre, Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-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), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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), Berlin Institute of Health (BIH), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Service de Neuropathologie [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), Service de Neurochirurgie [CHU Pitié-Salpêtrière], Service de Neuroradiologie [CHU Pitié-Salpêtrière], Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), and UNICANCER

Subjects
Adult, Male, Cancer Research, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Astroblastoma, Brain tumor, MN1‐BEND2, [SDV.CAN]Life Sciences [q-bio]/Cancer, DNA sequencing, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Neuro‐Oncology, Next‐generation sequencing, Aged, 030304 developmental biology, 0303 health sciences, biology, Brain Neoplasms, business.industry, Middle Aged, medicine.disease, Neoplasms, Neuroepithelial, 3. Good health, BRAF mutation, Oncology, Mitogen-activated protein kinase, Cancer research, biology.protein, Female, Mitogen-Activated Protein Kinases, business, 030217 neurology & neurosurgery, Recurrent Meningioma
Abstract

BackgroundAstroblastoma (ABM) is a rare glial brain tumor. Recurrent meningioma 1 (MN1) alterations have been recently identified in most pediatric cases. Adolescent and adult cases, however, remain molecularly poorly defined.Materials and MethodsWe performed clinical and molecular characterization of a retrospective cohort of 14 adult and 1 adolescent ABM.ResultsStrikingly, we found that MN1 fusions are a rare event in this age group (1/15). Using methylation profiling and targeted sequencing, most cases were reclassified as either pleomorphic xanthoastrocytomas (PXA)-like or high-grade glioma (HGG)-like. PXA-like ABM show BRAF mutation (6/7 with V600E mutation and 1/7 with G466E mutation) and CD34 expression. Conversely, HGG-like ABM harbored specific alterations of diffuse midline glioma (2/5) or glioblastoma (GBM; 3/5). These latter patients showed an unfavorable clinical course with significantly shorter overall survival (p = .021). Mitogen-activated protein kinase pathway alterations (including FGFR fusion, BRAF and NF1 mutations) were present in 10 of 15 patients and overrepresented in the HGG-like group (3/5) compared with previously reported prevalence of these alterations in GBM and diffuse midline glioma.ConclusionWe suggest that gliomas with astroblastic features include a variety of molecularly sharply defined entities. Adult ABM harboring molecular features of PXA and HGG should be reclassified. Central nervous system high-grade neuroepithelial tumors with MN1 alterations and histology of ABM appear to be uncommon in adults. Astroblastic morphology in adults should thus prompt thorough molecular investigation aiming at a clear histomolecular diagnosis and identifying actionable drug targets, especially in the mitogen-activated protein kinase pathway.Implications for PracticeAstroblastoma (ABM) remains a poorly defined and controversial entity. Although meningioma 1 alterations seem to define a large subset of pediatric cases, adult cases remain molecularly poorly defined. This comprehensive molecular characterization of 1 adolescent and 14 adult ABM revealed that adult ABM histology comprises several molecularly defined entities, which explains clinical diversity and identifies actionable targets. Namely, pleomorphic xanthoastrocytoma-like ABM cases show a favorable prognosis whereas high-grade glioma (glioblastoma and diffuse midline gliome)-like ABM show significantly worse clinical courses. These results call for in-depth molecular analysis of adult gliomas with astroblastic features for diagnostic and therapeutic purposes.

Published
2019
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12. Pathogenic Effects of Mineralocorticoid Pathway Activation in Retinal Pigment Epithelium

Author

Justine Guegan, Min Zhao, Emmanuelle Gelize, Say Viengchareun, Laura Kowalczuk, Francine Behar-Cohen, Yvan Arsenijevic, Tatiana Favez, Jérémie Canonica, Eric Pussard, Marc Lombès, Damien Le Menuet, Laurent Jonet, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Fondation Asile des aveugles - Hôpital Ophtalmique Jules-Gonin [Lausanne], 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), Signalisation Hormonale, Physiopathologie Endocrinienne et Métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), HAL-SU, Gestionnaire, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and 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)

Subjects
retina, Hydrocortisone, corticoids, eye, mineralocorticoid, retinal pigment epithelium, transcriptional regulation, Mice, chemistry.chemical_compound, 0302 clinical medicine, Mineralocorticoid receptor, Glucocorticoid receptor, Biology (General), Aldosterone, Spectroscopy, Barrier function, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, General Medicine, Extracellular Matrix, Computer Science Applications, Cell biology, Chemistry, medicine.anatomical_structure, Pluripotent Stem Cells, Epithelial-Mesenchymal Transition, QH301-705.5, medicine.drug_class, Mice, Transgenic, Article, Catalysis, Inorganic Chemistry, 03 medical and health sciences, Receptors, Glucocorticoid, Retinal Diseases, medicine, Animals, Humans, Physical and Theoretical Chemistry, QD1-999, Molecular Biology, 030304 developmental biology, Retina, Retinal pigment epithelium, Organic Chemistry, Retinal, Epithelium, eye diseases, Receptors, Mineralocorticoid, chemistry, Mineralocorticoid, 030221 ophthalmology & optometry, sense organs, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Glucocorticoids are amongst the most used drugs to treat retinal diseases of various origins. Yet, the transcriptional regulations induced by glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation in retinal pigment epithelium cells (RPE) that form the outer blood–retina barrier are unknown. Levels of endogenous corticoids, ligands for MR and GR, were measured in human ocular media. Human RPE cells derived from induced pluripotent stem cells (iRPE) were used to analyze the pan-transcriptional regulations induced by aldosterone—an MR-specific agonist, or cortisol or cortisol + RU486—a GR antagonist. The retinal phenotype of transgenic mice that overexpress the human MR (P1.hMR) was analyzed. In the human eye, the main ligand for GR and MR is cortisol. The iRPE cells express functional GR and MR. The subset of genes regulated by aldosterone and by cortisol + RU-486, and not by cortisol alone, mimics an imbalance toward MR activation. They are involved in extracellular matrix remodeling (CNN1, MGP, AMTN), epithelial–mesenchymal transition, RPE cell proliferation and migration (ITGB3, PLAUR and FOSL1) and immune balance (TNFSF18 and PTX3). The P1.hMR mice showed choroidal vasodilation, focal alteration of the RPE/choroid interface and migration of RPE cells together with RPE barrier function alteration, similar to human retinal diseases within the pachychoroid spectrum. RPE is a corticosteroid-sensitive epithelium. MR pathway activation in the RPE regulates genes involved in barrier function, extracellular matrix, neural regulation and epithelial differentiation, which could contribute to retinal pathology.

Published
2021
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13. Impact of a frequent nearsplice SOD1 variant in Amyotrophic Lateral Sclerosis: optimizing SOD1 genetic screening for gene therapy opportunities

Author

Stéphanie Millecamps, Aude-Marie Grapperon, Serge Lumbroso, François Salachas, Patrick Vourc'h, Aude Chiot, Delphine Bohl, Cécile Cazeneuve, Emilien Bernard, Anne-Laure Fauret-Amsellem, Kevin Mouzat, William Camu, Maria del Mar Amador, Christian S Lobsiger, Philippe Corcia, Beata Gyorgy, Séverine Boillée, Jean-Christophe Antoine, Shahram Attarian, Elisa Teyssou, Annie Verschueren, Yannick Marie, Claire Guissart, Jean-Philippe Camdessanché, Danielle Seilhean, Eric Leguern, François Muratet, Vincent Meininger, Justine Guegan, 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), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centres de référence pour la sclérose latérale amyotrophique [CHU Pitié-Salpêtrière], 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), Hôpital privé des Peupliers (Paris), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Centre Sclérose Latérale Amyotrophique et maladies du motoneurone [CHU de Saint-Étienne], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité fonctionnelle de neurogénétique moléculaire et cellulaire, 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 Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Gestionnaire, HAL Sorbonne Université 5, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Sclérose Latérale Amyotrophique et maladies du motoneurone [CHU Saint-Etienne], and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM)

Subjects
MESH: Mutation, MESH: Pedigree, Genetic enhancement, animal diseases, [SDV]Life Sciences [q-bio], SOD1, Disease, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, medicine.disease_cause, MESH: Phenotype, 03 medical and health sciences, 0302 clinical medicine, MESH: Aged, 80 and over, medicine, Missense mutation, MESH: Superroxide Dismutase-1, Amyotrophic lateral sclerosis, Gene, MESH: Amyotrophic Lateral Sclerosis, 030304 developmental biology, Genetics, MESH: Aged, MESH: Genetic Therapy, 0303 health sciences, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Middle Aged, MESH: Genetic Testing, nutritional and metabolic diseases, MESH: Adult, medicine.disease, Phenotype, MESH: Male, 3. Good health, nervous system diseases, [SDV] Life Sciences [q-bio], Psychiatry and Mental health, nervous system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Surgery, Neurology (clinical), MESH: Female, 030217 neurology & neurosurgery
Abstract

ObjectiveMutations in superoxide dismutase 1 gene (SOD1), encoding copper/zinc superoxide dismutase protein, are the second most frequent high penetrant genetic cause for amyotrophic lateral sclerosis (ALS) motor neuron disease in populations of European descent. More than 200 missense variants are reported along the SOD1 protein. To limit the production of these aberrant and deleterious SOD1 species, antisense oligonucleotide approaches have recently emerged and showed promising effects in clinical trials. To offer the possibility to any patient with SOD1-ALS to benefit of such a gene therapy, it is necessary to ascertain whether any variant of unknown significance (VUS), detected for example in SOD1 non-coding sequences, is pathogenic.MethodsWe analysed SOD1 mutation distribution after SOD1 sequencing in a large cohort of 470 French familial ALS (fALS) index cases.ResultsWe identified a total of 27 SOD1 variants in 38 families including two SOD1 variants located in nearsplice or intronic regions of the gene. The pathogenicity of the c.358–10T>G nearsplice SOD1 variant was corroborated based on its high frequency (as the second most frequent SOD1 variant) in French fALS, the segregation analysis confirmed in eight affected members of a large pedigree, the typical SOD1-related phenotype observed (with lower limb onset and prominent lower motor neuron involvement), and findings on postmortem tissues showing SOD1 misaccumulation.ConclusionsOur results highlighted nearsplice/intronic mutations in SOD1 are responsible for a significant portion of French fALS and suggested the systematic analysis of the SOD1 mRNA sequence could become the method of choice for SOD1 screening, not to miss these specific cases.

Published
2021
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14. Generation of excitatory and inhibitory neurons from common progenitors via Notch signaling in the cerebellum

Author

Andi H. Hansen, Natalia Mora, Natalia Danda, Justine Guegan, Luca Tiberi, Simon Hippenmeyer, Mathilde Bertrand, Marica Anderle, Tingting Zhang, Carmen Streicher, Tengyuan Liu, Ximena Contreras, Bassem A. Hassan, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institute of Science and Technology [Austria] (IST Austria), University of Trento [Trento], HAL-SU, Gestionnaire, 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), and Institute of Science and Technology [Klosterneuburg, Austria] (IST Austria)

Subjects
0301 basic medicine, DOUBLE MARKERS, EXPRESSION, Cerebellum, GLIOGENESIS, MOSAIC ANALYSIS, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Notch signaling pathway, Biology, Cell fate determination, Inhibitory postsynaptic potential, General Biochemistry, Genetics and Molecular Biology, NEUROGENESIS, 03 medical and health sciences, 0302 clinical medicine, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, Humans, human cerebellar organoids, SPECIFICATION, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Notch signaling, 030304 developmental biology, Progenitor, neural stem cells, Neurons, 0303 health sciences, Science & Technology, Receptors, Notch, Neurogenesis, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cell Differentiation, neuronal diversity, Cell Biology, STEM, Embryonic stem cell, mouse cerebellum, Neural stem cell, 030104 developmental biology, medicine.anatomical_structure, DIFFERENTIATION, MEDULLOBLASTOMA, Excitatory postsynaptic potential, Neuroscience, Life Sciences & Biomedicine, INTEGRATION, 030217 neurology & neurosurgery
Abstract

SUMMARYBrain neurons arise from relatively few progenitors capable of giving rise to an enormous diversity of neuronal types. Nonetheless, a cardinal feature of mammalian brain neurogenesis in both the cortex and the cerebellum is that excitatory neurons and inhibitory neurons derive from separate, spatially segregated, progenitors. Whether bi-potential progenitors with an intrinsic capacity to generate both excitatory and inhibitory lineages exist and how such a fate decision may be regulated is unknown. Using cerebellar development as a model, we discover that individual embryonic cerebellar progenitors give rise to both inhibitory and excitatory lineages. We find that gradations of Notch activity levels determine the fates of the progenitors and their daughters. Daughters with the highest levels of Notch activity retain the progenitor fate. Daughters with intermediate levels of Notch activity become fate restricted to generate inhibitory neurons, while daughters with very low levels of Notch signaling adopt the excitatory fate. Therefore, Notch mediated binary cell fate choice is a mechanism for regulating the ratio of excitatory to inhibitory neurons from common progenitors.Graphical summary

Published
2021
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15. Genetic screening of ANXA11 revealed novel mutations linked to Amyotrophic Lateral Sclerosis

Author

Selma Machat, Elisa Teyssou, Vincent Meininger, Yannick Marie, Géraldine Lautrette, Beata Gyorgy, Stéphanie Millecamps, Philippe Couratier, Séverine Boillée, Mélanie Ferrien, Danielle Seilhean, Cécile Cazeneuve, François Muratet, Thierry Larmonier, Justine Guegan, François Salachas, Pascal Cintas, Safaa Saker, Nadine Le Forestier, Maria-Del-Mar Amador, William Camu, Eric LeGuern, 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), Centres de référence pour la sclérose latérale amyotrophique [CHU Pitié-Salpêtrière], 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), Centre référent Sclérose Latérale Amyotrophique et autres maladies du motoneurone [CHU Limoges] (SLA CHU Limoges), CHU Limoges, Généthon, Unité fonctionnelle de neurogénétique moléculaire et cellulaire, 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 Sclérose Latérale amyotrophique [CHU Toulouse], Département Neurologie [CHU Toulouse], Pôle Neurosciences [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Neurosciences [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital privé des Peupliers (Paris), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neuropathologie [CHU Pitié Salpêtrière], Gestionnaire, HAL Sorbonne Université 5, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Sclérose Latérale Amyotrophique et maladies, Unité de neurophysiologie clinique [CHU Toulouse], and CHU Toulouse [Toulouse]

Subjects
0301 basic medicine, Male, Aging, Pathology, medicine.medical_specialty, Annexins, Datasets as Topic, ANXA11, frontotemporal dementia, 03 medical and health sciences, 0302 clinical medicine, Databases, Genetic, medicine, Humans, Exome, Motor neuron disease, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cognitive decline, Amyotrophic lateral sclerosis, Genetic Association Studies, neuropathology, business.industry, General Neuroscience, Neurodegeneration, Amyotrophic Lateral Sclerosis, FTD, Frontotemporal lobar degeneration, Motor neuron, Spinal cord, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Mutation, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), France, Geriatrics and Gerontology, Frontotemporal Lobar Degeneration, ALS, Annexin A11, business, 030217 neurology & neurosurgery, Developmental Biology, Frontotemporal dementia
Abstract

ANXA11 mutations have previously been discovered in amyotrophic lateral sclerosis (ALS) motor neuron disease. To confirm the contribution of ANXA11 mutations to ALS, a large exome data set obtained from 330 French patients, including 150 familial ALS index cases and 180 sporadic ALS cases, was analyzed, leading to the identification of 3 rare ANXA11 variants in 5 patients. The novel p.L254V variant was associated with early onset sporadic ALS. The novel p.D40Y mutation and the p.G38R variant concerned patients with predominant pyramidal tract involvement and cognitive decline. Neuropathologic findings in a p.G38R carrier associated the presence of ALS typical inclusions within the spinal cord, massive degeneration of the lateral tracts, and type A frontotemporal lobar degeneration. This mutant form of annexin A11 accumulated in various brain regions and in spinal cord motor neurons, although its stability was decreased in patients' lymphoblasts. Because most ANXA11 inclusions were not colocalized with transactive response DNA-binding protein 43 or p62 deposits, ANXA11 aggregation does not seem mandatory to trigger neurodegeneration with additional participants/partner proteins that could intervene.

Published
2021
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16. Mineralocorticoid Receptor Pathway and Its Antagonism in a Model of Diabetic Retinopathy

Author

Alexandre Moulin, Rinath Levy, Francine Behar-Cohen, Emmanuelle Gelize, Kimberley Delaunay, F. Azan, Min Zhao, Irene Bravo-Osuna, Marie-Christine Naud, Rocío Herrero-Vanrell, Justine Guegan, Patricia Lassiaz, Eric Pussard, Marianne Berdugo, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Université de Lausanne = University of Lausanne (UNIL), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Physiologie et physiopathologie endocriniennes (PHYSENDO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), and Gestionnaire, HAL Sorbonne Université 5

Subjects
Male, medicine.medical_specialty, Hydrocortisone, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Spironolactone, Retina, Diabetic nephropathy, chemistry.chemical_compound, Mineralocorticoid receptor, Polylactic Acid-Polyglycolic Acid Copolymer, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Animals, Humans, Mineralocorticoid Receptor Antagonists, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Diabetic Retinopathy, business.industry, Rats, Inbred Strains, Diabetic retinopathy, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Rats, Up-Regulation, Vitreous Body, Endocrinology, medicine.anatomical_structure, Receptors, Mineralocorticoid, chemistry, Diabetes Mellitus, Type 2, Gene Expression Regulation, Mineralocorticoid, Delayed-Action Preparations, Female, business, Retinopathy, Retinal Neurons
Abstract

Diabetic retinopathy remains a major cause of vision loss worldwide. Mineralocorticoid receptor (MR) pathway activation contributes to diabetic nephropathy but its role in retinopathy is unknown. In this study, we show that MR is overexpressed in the retina of type 2 diabetic Goto-Kakizaki (GK) rats and humans and, that cortisol is the MR ligand in human eyes. Lipocalin 2 and galectin 3, two biomarkers of diabetic complications regulated by MR are increased in GK and human retina. The sustained intraocular delivery of spironolactone, a steroidal mineralocorticoid antagonist, decreased the early and late pathogenic features of retinopathy in GK rats, such as retinal inflammation, vascular leakage and retinal edema through the up-regulation of genes encoding proteins known to intervene in vascular permeability such as Hey1, Vldlr, Pten, Slc7a1, Tjp1, Dlg1 and Sesn2 but did not decrease VEGF. Spironolactone also normalized the distribution of ion and water channels in macroglial cells. These results indicate that MR is activated in GK and human diabetic retina and that local MR antagonism could be a novel therapeutic option for diabetic retinopathy.

Published
2021
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17. Impact of a frequent nearsplice

Author

François, Muratet, Elisa, Teyssou, Aude, Chiot, Séverine, Boillée, Christian S, Lobsiger, Delphine, Bohl, Beata, Gyorgy, Justine, Guegan, Yannick, Marie, Maria Del Mar, Amador, Francois, Salachas, Vincent, Meininger, Emilien, Bernard, Jean-Christophe, Antoine, Jean-Philippe, Camdessanché, William, Camu, Cécile, Cazeneuve, Anne-Laure, Fauret-Amsellem, Eric, Leguern, Kevin, Mouzat, Claire, Guissart, Serge, Lumbroso, Philippe, Corcia, Patrick, Vourc'h, Aude-Marie, Grapperon, Shahram, Attarian, Annie, Verschueren, Danielle, Seilhean, and Stéphanie, Millecamps

Subjects
Adult, Aged, 80 and over, Male, Amyotrophic Lateral Sclerosis, DNA Mutational Analysis, Genetic Therapy, Middle Aged, Pedigree, Phenotype, Superoxide Dismutase-1, Mutation, Humans, Female, Genetic Testing, Aged
Abstract

Mutations in superoxide dismutase 1 gene (We analysed SOD1 mutation distribution after SOD1 sequencing in a large cohort of 470 French familial ALS (fALS) index cases.We identified a total of 27 SOD1 variants in 38 families including two SOD1 variants located in nearsplice or intronic regions of the gene. The pathogenicity of the c.358-10TG nearspliceOur results highlighted nearsplice/intronic mutations in

Published
2020

18. Primary CNS lymphoma patient-derived orthotopic xenograft model capture the biological and molecular characteristics of the disease

Author

Justine Guegan, Emmanuelle Menet, Mailys Daniau, Louis Royer-Perron, Frederic Davi, Matthieu Peyre, Khê Hoang-Xuan, Frederic Pouzoulet, Karima Mokhtari, Anne Schnitzler, Franck Assayag, Carole Soussain, Agusti Alentorn, Magali Le Garff-Tavernier, and Dalila Labiod

Subjects
0301 basic medicine, medicine.medical_treatment, Brain tumor, Mice, Nude, Targeted therapy, Central Nervous System Neoplasms, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Piperidines, hemic and lymphatic diseases, Parenchyma, medicine, Animals, Humans, Molecular Biology, business.industry, Adenine, breakpoint cluster region, Cell Biology, Hematology, Prognosis, medicine.disease, Primary tumor, Pathophysiology, Interleukin-10, Tumor Burden, Lymphoma, Disease Models, Animal, Pyrimidines, 030104 developmental biology, chemistry, Ibrutinib, Cancer research, Heterografts, Pyrazoles, Molecular Medicine, Lymphoma, Large B-Cell, Diffuse, Caudate Nucleus, business, 030215 immunology
Abstract

Primary CNS lymphomas (PCNSL) are rare and poor prognosis diffuse large B-cell lymphomas. Because of the brain tumor environment and the restricted distribution of drugs in the CNS, specific PCNSL patient-derived orthotopic xenograft (PDOX) models are needed for preclinical research to improve the prognosis of PCNSL patients. PCNSL patient specimens (n = 6) were grafted in the caudate nucleus of immunodeficient nude mice with a 83% rate of success, while subcutaneous implantation in nude mice of human PCNSL sample did not generate lymphoma, supporting the role of the brain microenvironment in the PCNSL physiopathology. PDOXs showed diffuse infiltration of B-cell lymphoma cells in the brain parenchyma. Each model had a unique mutational signature for genes in the BCR and NF-κB pathways and retained the mutational profile of the primary tumor. The models can be stored as cryopreserved biobank. Human IL-10 levels measured in the plasma of PCNSL-PDOX mice showed to be a reliable tool to monitor the tumor burden. Treatment response could be measured after a short treatment with the targeted therapy ibrutinib. In summary, we established a panel of human PCNSL-PDOX models that capture the histological and molecular characteristics of the disease and that proved suitable for preclinical experiments. Our methods of generation and characterization will enable the generation of additional PDOX-PCNSL models, essential tools for cognitive and preclinical drug discovery.

Published
2019
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19. Generation of neuronal diversity from common progenitors via Notch signaling in the cerebellum

Author

Andi H. Hansen, Tingting Zhang, Ximena Contreras, Mathilde Bertrand, Tengyuan Liu, Justine Guegan, Natalia Mora, Luca Tiberi, Bassem A. Hassan, Marica Anderle, Simon Hippenmeyer, and Carmen Streicher

Subjects
Cerebellum, 050208 finance, 05 social sciences, Notch signaling pathway, Cell fate determination, Biology, Inhibitory postsynaptic potential, Embryonic stem cell, Neural stem cell, medicine.anatomical_structure, nervous system, 0502 economics and business, medicine, 050207 economics, Progenitor cell, Neuroscience, Progenitor
Abstract

Summary The bewildering diversity of brain neurons arises from relatively few pluripotent progenitors through poorly understood mechanisms. The cerebellum is an attractive model to investigate mechanisms of neuronal diversification because the different subtypes of excitatory and inhibitory neurons are well described 1,2 . The cerebellum is a hub for control of motor function and contributes to a number of higher brain functions such as reward-related cognitive processes 3 . Deficits in cerebellar development lead to severe neurological disorders such as cerebellar ataxias 4 and medulloblastomas 5 , a heterogeneous and severe groups of childhood brain tumors, thus underlying the importance of understanding the cellular and molecular control of cerebellar development. In contrast to text book models, we report that excitatory and inhibitory cerebellar neurons derive from the same pluripotent embryonic cerebellar stem cells (eCSC). We find that the excitatory versus inhibitory fate decision of a progenitor is regulated by Notch signaling, whereby the cell with lower Notch activity adopts the excitatory fate, while the cell with higher Notch activity adopts the inhibitory fate. Thus, Notch-mediated binary cell fate choice is a conserved strategy for generating neuronal diversity from common progenitors that is deployed at different developmental time points in a context specific manner.

Published
2020
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20. PATH-16. MOLECULAR PATHOLOGY AND CLINICAL CHARACTERISTICS OF MMR DEFICIENCY (MMRd) IN DIFFUSE GLIOMAS

Author

Shannon Block, David A. Reardon, Alexandre Carpentier, Rameen Beroukhim, Mehdi Touat, Jean-Yves Delattre, Wenya Bi, Justine Guegan, Frédéric Beuvon, Marc Sanson, Ahmed Idbaih, Keith L. Ligon, Alex Duval, Pratiti Bandopadhayay, Sandro Santagata, Patrick Y. Wen, Florence Coulet, Karima Mokhtari, Marine Giry, Franck Bielle, and Erell Guillerm

Subjects
Cancer Research, Pathology, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, business.industry, Molecular pathology, Microsatellite instability, Signs and symptoms, MMR Deficiency, medicine.disease, digestive system diseases, Abstracts, Oncology, Glioma, medicine, Neurology (clinical), Msh2 gene, business
Abstract

BACKGROUND: MMR deficiency (MMRd) is found in a subset of gliomas. Emerging evidence indicates that MMRd could serve as predictive biomarker for both response to immunotherapy and resistance to alkylating agents. However, the molecular epidemiology, outcome, and the optimal diagnostic method of MMRd are poorly defined in gliomas. METHODS: A cohort of 350 adult gliomas was characterized as to WHO 2016 diagnosis, IDH1/2 sequencing, MGMT promoter methylation, prior treatment and outcome. Immunohistochemistry of MMR proteins (MSH2, MSH6, MLH1, PMS2) was performed in 260 tumors with available tissue. 100 tumors were analyzed with next generation targeted exome sequencing (NGS, Oncopanel) of 447 cancer genes, including full exon coverage of MMR genes. Comparisons between results from IHC, NGS and microsatellite instability (MSI) testing using pentaplex PCR amplification testing were incorporated to inform best practices. RESULTS: 53/260 tumors showed immunohistochemical (ie MMR protein staining loss) and/or molecular (ie presence of MMR pathogenic mutation with hypermutation) evidence of MMRd. No MSI was found by pentaplex PCR. 38/260 tumors harbored loss of protein expression of one or two MMR proteins: 15 showed loss of MSH6 protein (with/without concomitant MSH2 loss) and 23 had loss of PMS2 (with/without MLH1 loss). Analysis of 201 consecutive recurrent tumors from alkylator pre-treated patients showed significant association between MMRd and the presence of IDH1/2 mutation: MMRd in 20/90 (22.2%) of IDH1/2-mutant tumors vs 2/111 (1.8%) of IDH1/2-wild-type tumors (p

Published
2018

21. 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
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22. Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex

Author

Chantal M. E. Tallaksen, Alexandra Durr, Sophie Tezenas du Montcel, Silvia Fenu, Bertrand Sablonniere, Charles Duyckaerts, Christel Depienne, Alexis Brice, Justine Guegan, Giovanni Stevanin, Guillaume Banneau, Samia Ait Said, Mathieu Barbier, Marie-Lorraine Monin, Livia Parodi, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oslo University Hospital [Oslo], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Paris sciences et lettres (PSL), École pratique des hautes études (EPHE), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), and École Pratique des Hautes Études (EPHE)

Subjects
Adult, Male, 0301 basic medicine, Spastin, Genotype, Mutation, Missense, Pyramidal Tracts, Medizin, Physiology, Neuropathology, medicine.disease_cause, Severity of Illness Index, Frameshift mutation, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, medicine, Humans, Missense mutation, Age of Onset, Mutation, Spastic Paraplegia, Hereditary, business.industry, Middle Aged, Penetrance, 3. Good health, Phenotype, 030104 developmental biology, Spinocerebellar Tracts, Corticospinal tract, Disease Progression, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Age of onset, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

International audience; Hereditary spastic paraplegias (HSPs) are rare neurological disorders caused by progressive distal degeneration of the corticospinal tracts. Among the 79 loci and 65 spastic paraplegia genes (SPGs) involved in HSPs, mutations in SPAST, which encodes spastin, responsible for SPG4, are the most frequent cause of both familial and sporadic HSP. SPG4 is characterized by a clinically pure phenotype associated with restricted involvement of the corticospinal tracts and posterior columns of the spinal cord. It is rarely associated with additional neurological signs. However, both age of onset and severity of the disorder are extremely variable. Such variability is both intra- and inter-familial and may suggest incomplete penetrance, with some patients carrying mutations remaining asymptomatic for their entire life. We analysed a cohort of 842 patients with SPG4-HSP to assess genotype-phenotype correlations. Most patients were French (89%) and had a family history of SPG4-HSP (75%). Age at onset was characterized by a bimodal distribution, with high inter-familial and intra-familial variability, especially concerning first-degree relatives. Penetrance of the disorder was 0.9, complete after 70 years of age. Penetrance was lower in females (0.88 versus 0.94 in males, P = 0.01), despite a more diffuse phenotype with more frequent upper limb involvement. Seventy-seven per cent of pathogenic mutations (missense, frameshift, splice site, nonsense, and deletions) were located in the AAA cassette of spastin, impairing its microtubule-severing activity. A comparison of the missense and truncating mutations revealed a significantly lower age at onset for patients carrying missense mutations than those carrying truncating mutations, explaining the bimodal distribution of the age at onset. The age at onset for patients carrying missense mutations was often before 10 years, sometimes associated with intellectual deficiency. Neuropathological examination of a single case showed degeneration of the spinocerebellar and spinocortical tracts, as well as the posterior columns. However, there were numerous small-diameter processes among unusually large myelinated fibres in the corticospinal tract, suggesting marked regeneration. In conclusion, this large cohort of 842 individuals allowed us to identify a significantly younger age at onset in missense mutation carriers and lower penetrance in females, despite a more severe disorder. Neuropathology in one case showed numerous small fibres suggesting regeneration.

Published
2018
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23. MET Is a Potential Target across All Papillary Renal Cell Carcinomas: Result from a Large Molecular Study of pRCC with CGH Array and Matching Gene Expression Array

Author

Jean-Jacques Patard, Virginie Verkarre, Sophie Couvé, Nathalie Rioux-Leclercq, Jean-Christophe Bernhard, Philippe Camparo, Zahira Merabet, Bernard Escudier, Mathilde Sibony, Audrey Le Formal, Justine Guegan, Laurence Albiges, Sophie Gad, Yves Allory, Vincent Molinié, Cedric Orear, Oncologie génito-urinaire, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service d'Anatomie et de Cytologie Pathologiques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), PremUp Foundation, Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et Développement de Rennes (IGDR), 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 ), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'urologie, andrologie et transplantation rénale, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre de pathologie Amiens, Centre de pathologie Amiens - Picardie, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'anatomie pathologique, Hôpital Saint Joseph, Plateforme de Ressources Biologiques, Département de pathologie, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Plateforme de Génomique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Moléculaire, CHU Bordeaux [Bordeaux], Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [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 Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et cytologie pathologiques [CHU Tenon], 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) (APHP)-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Universités-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Plateforme de Génomique, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse ( AMMICa ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Cytokines et Immunologie des Tumeurs Humaines ( U753 ), and Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
Adult, Male, Cancer Research, DNA Copy Number Variations, Gene Expression, Biology, 03 medical and health sciences, Exon, 0302 clinical medicine, Germline mutation, medicine, Carcinoma, Cluster Analysis, Humans, Aged, Neoplasm Staging, 030304 developmental biology, Aged, 80 and over, Comparative Genomic Hybridization, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, Papillary renal cell carcinomas, Microarray analysis techniques, Gene Expression Profiling, Computational Biology, Cancer, Exons, Sequence Analysis, DNA, Middle Aged, Proto-Oncogene Proteins c-met, medicine.disease, Molecular biology, Carcinoma, Papillary, Kidney Neoplasms, 3. Good health, Gene expression profiling, Oncology, 030220 oncology & carcinogenesis, Mutation, Cancer research, Female, Neoplasm Grading, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Carrier Proteins, Protein Binding, Comparative genomic hybridization
Abstract

Purpose: Papillary renal cell carcinomas (pRCC) are the most common nonclear cell RCC subtype. Germline mutations of the MET oncogene at 7q31 have been detected in patients with hereditary type I pRCC and in 13% of sporadic type I pRCC. Recent report of MET inhibition strengthened the role of c-Met inhibition across pRCC. Experimental Design: We collected 220 frozen samples of sporadic pRCC through the French RCC Network and quality controlled for percentage of malignant cells >70%. Gene expression was assessed on 98 pRCC using human whole-genome Agilent 8 × 60K arrays. Copy number alterations were analyzed using Agilent Human 2 × 400K and 4× 180K array for type II pRCC and comparative genomic microarray analysis method for type I pRCC. MET gene sequencing was performed on type I pRCC. Results: MET expression level was high across all pRCC. We identified copy number alterations (gain) in 46% of type II pRCC and in 81% of type I pRCC. Correlation between DNA copy number alterations and mRNA expression level was highly significant. Eleven somatic mutations of MET gene were identified amongst 51 type I pRCC (21.6%), including 4 new mutations. We validated LRRK2 cokinase as highly correlated to MET expression. Conclusion: The present report expands the role of MET activation as a potential target across all pRCC subtypes. These data support investigating MET inhibitors in pRCC in correlation with MET activation status. Clin Cancer Res; 20(13); 3411–21. ©2014 AACR.

Published
2014
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24. Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma

Author

Rana Salam, Alexa Saliou, Franck Bielle, Mathilde Bertrand, Christophe Antoniewski, Catherine Carpentier, Agusti Alentorn, Laurent Capelle, Marc Sanson, Emmanuelle Huillard, Léa Bellenger, Justine Guégan, and Isabelle Le Roux

Subjects
Science
Abstract

Senescence can have beneficial and detrimental impact on cancer progression depending on the cellular context. Here the authors show that NRF2 regulates the senescence phenotype in malignant cells which consequently contribute to glioblastoma progression.

Published
2023
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25. Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Author

Amélie Piton, Melanie Bahlo, Paul J. Lockhart, Vesna Lukic, Caroline Nava, David J. Amor, Pierre Bitoun, Vicki Anderson, Fabien Lesne, Greta Gillies, Amanda G. Wood, Justine Guegan, Gail Robinson, Catherine Garel, Alexis Brice, Sarah E.M. Stephenson, Guy A. Rouleau, Aurélie Méneret, Delphine Héron, Kate Pope, Solveig Heide, Cyril Mignot, Emmanuel Roze, Angélique Quartier, Jean-Louis Mandel, Annalisa Paolino, Quentin Welniarz, Sylvie Odent, Florence Riant, George McGillivray, Linda J. Richards, Ilan Gobius, Elliott H. Sherr, Tania Attié-Bitach, Charles A. Galea, Timothy J. Edwards, Myriam Srour, Megan Spencer-Smith, Oriane Trouillard, Laura Morcom, Boris Keren, Christel Depienne, Marie Laure Moutard, Anne Faudet, Richard J. Leventer, Alissandra McIlroy, Agnès Rastetter, Thierry Billette de Villemeur, Simone Mandelstam, Jens Bunt, Martin B. Delatycki, Rick M. Tankard, Ashley P L Marsh, CHU Pitié-Salpêtrière [APHP], Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], 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)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], CHU Trousseau [APHP], Service de Pédiatrie [Jean Verdier], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Service de Radiologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique clinique [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-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), Montreal Neurological Hospital, McGill University Health Center [Montreal] (MUHC), CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Diagnostic Génétique, CHU Strasbourg-Hopital Civil, Service des Maladies du Système Nerveux [CHU Pitié-Salpêtrière], Laboratoire de Génétique Moléculaire [CHRU Strasbourg], CHRU Strasbourg, Bioinformatics division, The Walter & Eliza Hall Institute of Medical Research, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], 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), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Pierre et Marie Curie - Paris 6 (UPMC), 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)-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)-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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France (CdF (institution)), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Centre de Référence des Déficiences Intellectuelles de Causes Rares, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme ( GRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), 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 ) -Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris 13 ( UP13 ) -Hôpital Jean Verdier, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -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 ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Neuroscience Paris Seine ( NPS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), McGill University Health Center [Montreal, Canada] ( MUHC ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], 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)-CHU Pontchaillou [Rennes]-hôpital Sud, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), and 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)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, 0301 basic medicine, Developmental Disabilities, Penetrance, Receptors, Cell Surface, Biology, Nervous System Malformations, Corpus callosum, medicine.disease_cause, Mirror movements, Article, Corpus Callosum, 03 medical and health sciences, 0302 clinical medicine, Neural Stem Cells, Netrin, Intellectual disability, Genetics, medicine, Humans, Abnormalities, Multiple, Family, 10. No inequality, Agenesis of the corpus callosum, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Tumor Suppressor Proteins, Brain, DCC Receptor, medicine.disease, Phenotype, 030104 developmental biology, nervous system, Female, Agenesis of Corpus Callosum, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery
Abstract

International audience; Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.

Published
2017
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26. Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during oncogenesis

Author

Sophie Couvé, Hélène Le Jeune, David R. Mole, Karène Mahtouk, Gregory Nuel, Peter J. Ratcliffe, Anne Paule Gimenez-Roqueplo, Justine Guegan, Françoise Lasne, William G. Kaelin, Nathalie M. Mazure, Charline Ladroue, Jean Christophe Pagès, William Y. Kim, Patrick R. Benusiglio, Luba Tchertanov, Stéphane Richard, Brigitte Bressac-de Paillerets, Marion Le Gentil, Vladimir Lazar, Elodie Laine, Philippe Dessen, Betty Gardie, Christine Collin, Jean Feunteun, Sophie Gad, Bernard Lecomte, Institut National du Cancer [Boulogne Billancourt] (INC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Computationnelle et Quantitative = Laboratory of Computational and Quantitative Biology (LCQB), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Plateforme de Génomique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Université Paris Descartes - Paris 5 (UPD5)-Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS), Lineberger Comprehensive Cancer Center (UNC Lineberger), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Médecine générale, Virus, pseudo-virus: Morphogénèse et Antigénicité, Université de Tours-EA3856, Agence Française de Lutte contre le Dopage (AFLD), Institut Gustave Roussy (IGR), Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Angiogenesis Imaging UMR970, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), 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), Henry Wellcome Building for Molecular Physiology, University of Oxford [Oxford], Howard Hughes Medical Institute (HHMI), Génétique Oncologique EPHE, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), This work was supported by grants from the Ligue Nationale contre le Cancer (Comites du Cher et de l'Indre, de la Loire Atlantique et des Cotes d'Armor), the French NCI (INCa, PNES 'Kidney cancer'), the 'Association pour la Recherche sur le Cancer' (ARC), the 'Association VHL France,' the Region Pays de la Loire, as well as by the HypoxiaNet COST Action TD0901. S. Couve was supported by postdoctoral fellowships from the Fondation 'Cancer, Aidez la recherche!' and the 'Fondation Gustave Roussy.'The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact., Bernardo, Elizabeth, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Tours (UT)-EA3856, Université Nice Sophia Antipolis (1965 - 2019) (UNS), University of Oxford, Institut National du Cancer [Boulogne Billancourt] ( INC ), École pratique des hautes études ( EPHE ), Cytokines et Immunologie des Tumeurs Humaines ( U753 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Biologie Computationnelle et Quantitative = Laboratory of Computational and Quantitative Biology ( LCQB ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Plateforme de génomique, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse ( AMMICa ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Mathématiques Appliquées à Paris 5 ( MAP5 - UMR 8145 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National des Sciences Mathématiques et de leurs Interactions-Centre National de la Recherche Scientifique ( CNRS ), Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Agence Française de Lutte contre le Dopage ( AFLD ), Institut Gustave Roussy ( IGR ), Service de Génétique, Institut de cancérologie Gustave Roussy, Villejuif, France, Stabilité Génétique et Oncogenèse ( UMR 8200 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Recherche sur le Cancer et le Vieillissement ( IRCAN ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ), Howard Hugues Medical Institute, Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers, École Pratique des Hautes Études (EPHE), and 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)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, Pathology, medicine.medical_specialty, endocrine system diseases, Carcinogenesis, Mutant, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pheochromocytoma, Biology, Molecular Dynamics Simulation, medicine.disease_cause, Compound heterozygosity, urologic and male genital diseases, Polymorphism, Single Nucleotide, Article, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Malignant transformation, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Basic Helix-Loop-Helix Transcription Factors, Humans, Gene, neoplasms, Carcinoma, Renal Cell, 030304 developmental biology, 0303 health sciences, medicine.disease, Phenotype, female genital diseases and pregnancy complications, Kidney Neoplasms, 3. Good health, Oncology, Von Hippel-Lindau Tumor Suppressor Protein, 030220 oncology & carcinogenesis, Mutation, Cancer research, Signal Transduction
Abstract

The classic model of tumor suppression implies that malignant transformation requires full “two-hit” inactivation of a tumor-suppressor gene. However, more recent work in mice has led to the proposal of a “continuum” model that involves more fluid concepts such as gene dosage-sensitivity and tissue specificity. Mutations in the tumor-suppressor gene von Hippel-Lindau (VHL) are associated with a complex spectrum of conditions. Homozygotes or compound heterozygotes for the R200W germline mutation in VHL have Chuvash polycythemia, whereas heterozygous carriers are free of disease. Individuals with classic, heterozygous VHL mutations have VHL disease and are at high risk of multiple tumors (e.g., CNS hemangioblastomas, pheochromocytoma, and renal cell carcinoma). We report here an atypical family bearing two VHL gene mutations in cis (R200W and R161Q), together with phenotypic analysis, structural modeling, functional, and transcriptomic studies of these mutants in comparison with classical mutants involved in the different VHL phenotypes. We demonstrate that the complex pattern of disease manifestations observed in VHL syndrome is perfectly correlated with a gradient of VHL protein (pVHL) dysfunction in hypoxia signaling pathways. Thus, by studying naturally occurring familial mutations, our work validates in humans the “continuum” model of tumor suppression. Cancer Res; 74(22); 6554–64. ©2014 AACR.

Published
2014
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27. Genome-wide microarray expression and genomic alterations by array-CGH analysis in neuroblastoma stem-like cells

Author

Gabriel Gallo-Oller, Javier S. Castresana, Soledad Martínez-Soto, Alain Bernheim, Raquel Ordoñez, Justine Guegan, Bárbara Meléndez, G. Danglot, Noémie Pata-Merci, Juan A. Rey, and Sheila Legarra

Subjects
Etiology, Notch signaling pathway, lcsh:Medicine, Biology, Pathology and Laboratory Medicine, Research and Analysis Methods, Pediatrics, Neuroblastoma, Cancer stem cell, Cell Line, Tumor, Neurosphere, Molecular Cell Biology, Medicine and Health Sciences, Humans, Blastomas, lcsh:Science, Oligonucleotide Array Sequence Analysis, Cultured Tumor Cells, Multidisciplinary, Microarray analysis techniques, Gene Expression Profiling, lcsh:R, Wnt signaling pathway, Biology and Life Sciences, Cancers and Neoplasms, Cell Biology, Cell Cultures, Molecular biology, Hedgehog signaling pathway, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Gene expression profiling, Oncology, Pediatric Oncology, Cell culture, Neoplastic Stem Cells, Cancer research, Neuroblastoma Cells, lcsh:Q, Biological Cultures, Molecular Pathology, Genome-Wide Association Study, Signal Transduction, Research Article
Abstract

Neuroblastoma has a very diverse clinical behaviour: from spontaneous regression to a very aggressive malignant progression and resistance to chemotherapy. This heterogeneous clinical behaviour might be due to the existence of Cancer Stem Cells (CSC), a subpopulation within the tumor with stem-like cell properties: a significant proliferation capacity, a unique self-renewal capacity, and therefore, a higher ability to form new tumors. We enriched the CSC-like cell population content of two commercial neuroblastoma cell lines by the use of conditioned cell culture media for neurospheres, and compared genomic gains and losses and genome expression by array-CGH and microarray analysis, respectively (in CSC-like versus standard tumor cells culture). Despite the array-CGH did not show significant differences between standard and CSC-like in both analyzed cell lines, the microarray expression analysis highlighted some of the most relevant biological processes and molecular functions that might be responsible for the CSC-like phenotype. Some signalling pathways detected seem to be involved in self-renewal of normal tissues (Wnt, Notch, Hh and TGF-β) and contribute to CSC phenotype. We focused on the aberrant activation of TGF-β and Hh signalling pathways, confirming the inhibition of repressors of TGF-β pathway, as SMAD6 and SMAD7 by RT-qPCR. The analysis of the Sonic Hedgehog pathway showed overexpression of PTCH1, GLI1 and SMO. We found overexpression of CD133 and CD15 in SIMA neurospheres, confirming that this cell line was particularly enriched in stem-like cells. This work shows a cross-talk among different pathways in neuroblastoma and its importance in CSC-like cells.

Published
2014

28. Cisplatin resistance associated with PARP hyperactivation

Author

Pauline Garcia, Catherine Brenner, Kimitoshi Kohno, Gen Sheng Wu, Judith Michels, Guido Kroemer, Maria Castedo, Ken A. Olaussen, Julien Adam, Murat Saparbaev, Abdul Qader Sukkurwala, Laura Senovilla, Delphine Lissa, Oliver Kepp, Lorenzo Galluzzi, Ilio Vitale, Monique Talbot, Angélique Robin, Philippe Girard, Justine Guegan, Parviz Behnam-Motlagh, Jean-Charles Soria, Cedric Orear, Philippe Dessen, Ibtissam Talhaoui, David Enot, Apoptose, cancer et immunité (U848), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Images et Modèles, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), LIttoral ENvironnement et Sociétés - UMRi 7266 (LIENSs), Université de La Rochelle (ULR)-Centre National de la Recherche Scientifique (CNRS), AUTRES, Key Lab. Biopesticide & Chem. Biol., Minist. Educ., Fujian Agriculture and Forestry University (FAFU), Génomes et cancer (GC (FRE2939)), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Groupe Réparation de l'ADN, UMR 8113 CNRS, LBPA ENS Cachan, Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), 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)-Hospices Civils de Lyon (HCL)-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 Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), LIttoral ENvironnement et Sociétés - UMR 7266 (LIENSs), and La Rochelle Université (ULR)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, Lung Neoplasms, [SDV]Life Sciences [q-bio], Cell, Poly (ADP-Ribose) Polymerase-1, Apoptosis, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Poly (ADP-Ribose) Polymerase Inhibitor, Mice, 0302 clinical medicine, PARP1, Carcinoma, Non-Small-Cell Lung, Tumor Cells, Cultured, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, 3. Good health, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Female, Poly(ADP-ribose) Polymerases, medicine.drug, Programmed cell death, Poly ADP ribose polymerase, Blotting, Western, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Poly(ADP-ribose) Polymerase Inhibitors, Real-Time Polymerase Chain Reaction, 03 medical and health sciences, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, 030304 developmental biology, Cell Proliferation, Cisplatin, business.industry, Phenanthrenes, Xenograft Model Antitumor Assays, Drug Resistance, Neoplasm, Immunology, Cancer cell, Cancer research, business
Abstract

Non–small cell lung carcinoma patients are frequently treated with cisplatin (CDDP), most often yielding temporary clinical responses. Here, we show that PARP1 is highly expressed and constitutively hyperactivated in a majority of human CDDP-resistant cancer cells of distinct histologic origin. Cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PARhigh) responded to pharmacologic PARP inhibitors as well as to PARP1-targeting siRNAs by initiating a DNA damage response that translated into cell death following the activation of the intrinsic pathway of apoptosis. Moreover, PARP1-overexpressing tumor cells and xenografts displayed elevated levels of PAR, which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP1 expression itself. Thus, a majority of CDDP-resistant cancer cells appear to develop a dependency to PARP1, becoming susceptible to PARP inhibitor–induced apoptosis. Cancer Res; 73(7); 2271–80. ©2013 AACR.

Published
2013
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29. Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers

Author

Maria Vittoria Dieci, Caroline Even, Suzette Delaloge, Frédéric Commo, Laurence Albiges, Samar Alsafadi, Aicha Goubar, Véronique Scott, Jean-Charles Ahomadegbe, Vladimir Lazar, Justine Guegan, Coralie Falet, Virginie Quidville, and Fabrice Andre

Subjects
Acute promyelocytic leukemia, Antibodies, Monoclonal, Humanized Breast Neoplasms Carcinoma, Ductal, Breast Drug Resistance, Neoplasm Female Gene Amplification Humans Leukemia, Promyelocytic, Acute Middle Aged Receptors, Retinoic Acid Tretinoin Tumor Cells, Cultured, Cancer Research, Receptors, Retinoic Acid, Retinoic acid, Breast Neoplasms, Tretinoin, Retinoic acid receptor beta, Antibodies, Monoclonal, Humanized, chemistry.chemical_compound, Breast cancer, Leukemia, Promyelocytic, Acute, Tumor Cells, Cultured, Humans, Medicine, skin and connective tissue diseases, business.industry, Retinoic Acid Receptor alpha, Carcinoma, Ductal, Breast, Gene Amplification, Retinoic acid receptor gamma, Middle Aged, Trastuzumab, medicine.disease, Retinoid X receptor gamma, Retinoic acid receptor, Oncology, chemistry, Drug Resistance, Neoplasm, Retinoic acid receptor alpha, Cancer research, Female, business
Abstract

Starting from a clinical observation, a small subset of breast cancer patients presenting retinoic acid receptor alpha (RARA) amplification and overexpression was identified. Retinoic acid reduced cell viability of RARAamplified cell lines through interferon regulatory factor (IRF)-1 and caspase (CASP)-1 activation and RARAnonamplified cells were most likely resistant to all-trans-retinoic acid (ATRA). This study suggests that RARA-amplified breast cancers could be sensitive to retinoic acid. Background: Molecular segmentation of breast cancer allows identification of small groups of patients who present high sensitivity to targeted agents. A patient, with chemo- and trastuzumab-resistant HER2-overexpressing breast cancer, who presented concomitant acute promyelocytic leukemia, showed a response in her breast lesions to retinoic acid, arsenic, and aracytin. We therefore investigated whether RARA gene amplification could be associated with sensitivity to retinoic acid derivatives in breast cancers. Materials and Methods: Array comparative genomic hybridization and gene expression arrays were used to characterize RARA amplifications and expression in 103 breast cancer samples. In vitro activity of ATRA was characterized in T47D, SKBR3, and BT474 cell lines. Results: Retinoic acid receptor alpha was gained or amplified in 27% of HER2-positive and 13% of HER2-negative breast cancer samples. Retinoic acid receptor alpha can be coamplified with HER2. Retinoic acid receptor alpha copy number changes could be correlated with messenger RNA expression. All-trans-retinoic acid reduced cell viability of RARAamplified, but not RARA-normal, cell lines through apoptosis. Gene expression arrays showed that ATRA-induced apoptosis in RARA-amplified cell lines was related to an increase in CASP1 and IRF1. Conclusion: The results of this study suggest that breast cancers exhibiting RARA amplifications could be sensitive to retinoic acid. A phase II trial will evaluate this hypothesis in the clinical setting.

Published
2013

30. Differences in Transcription Patterns between Induced Pluripotent Stem Cells Produced from the Same Germ Layer Are Erased upon Differentiation

Author

Iryna Pirozhkova, Thomas Robert, Jörg Tost, Yegor S. Vassetzky, Gilles Carnac, Marc Lipinski, Elena S. Kim, Ana Barat, Dalila Laoudj-Chenivesse, Florence Busato, Petr Dmitriev, Justine Guegan, Chrystèle Bilhou-Nabera, Signalisation, noyaux et innovations en cancérologie (UMR8126), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Interactions moléculaires et cancer (IMC (UMR 8126)), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université de Paris (UP), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Passerieux, Emilie

Subjects
Cellular differentiation, Embryoid body, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Muscle Development, Myoblasts, Mice, 0302 clinical medicine, Molecular cell biology, Transduction, Genetic, Induced pluripotent stem cell, Cells, Cultured, Oligonucleotide Array Sequence Analysis, 0303 health sciences, Multidisciplinary, Stem Cells, Cell Differentiation, Medicine, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Stem cell, Cellular Types, Germ Layers, Research Article, Homeobox protein NANOG, KOSR, Science, Induced Pluripotent Stem Cells, DNA transcription, Kruppel-Like Transcription Factors, Biology, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, Kruppel-Like Factor 4, SOX2, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, Humans, Embryoid Bodies, Embryonic Stem Cells, 030304 developmental biology, Gene Expression Profiling, SOXB1 Transcription Factors, Mesenchymal Stem Cells, Fibroblasts, Molecular biology, Embryonic stem cell, Retroviridae, Gene expression, Octamer Transcription Factor-3, 030217 neurology & neurosurgery, Developmental Biology
Abstract

International audience; Little is known about differences between induced pluripotent stem cells produced from tissues originating from the same germ layer. We have generated human myoblast-derived iPS cells by retroviral transduction of human primary myoblasts with the OCT3/4, SOX2, KLF4 and MYC coding sequences and compared them to iPS produced from human primary fibroblasts. When cultivated in vitro, these iPS cells proved similar to human embryonic stem cells in terms of morphology, expression of embryonic stemness markers and gene promoter methylation patterns. Embryonic bodies were derived that expressed endodermal, mesodermal as well as ectodermal markers. A comparative analysis of transcription patterns revealed significant differences in the gene expression pattern between myoblast-and fibroblast-derived iPS cells. However, these differences were reduced in the mesenchymal stem cells derived from the two iPS cell types were compared. Citation: Pirozhkova I, Barat A, Dmitriev P, Kim E, Robert T, et al. (2013) Differences in Transcription Patterns between Induced Pluripotent Stem Cells Produced from the Same Germ Layer Are Erased upon Differentiation.

Published
2013
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31. Integrated molecular portrait of non-small cell lung cancers

Author

Philippe Dessen, Fabienne Dufour, Jacques Cadranel, Ludovic Lacroix, Philippe Vielh, Johanna Hasmats, Bastien Job, Jean-Charles Soria, Johan Hansson, Zsofia Balogh, Chen Suo, Janne Lehtiö, Hugues Ripoche, Cedric Orear, Vladimir Lazar, Yudi Pawitan, Joost van den Oord, Manfred Schmitt, Rudolf Napieralski, Fiona H Blackhall, Stefano Calza, Pierre Validire, Joakim Lundeberg, Benjamin Besse, Justine Guegan, Guillaume Meurice, Alexander M.M. Eggermont, and Philippe Girard

Subjects
Adult, Male, Lung Neoplasms, DNA Copy Number Variations, Biology, NSCLC, Bioinformatics, Carcinoma, Non-Small-Cell Lung, Gene expression, microRNA, Genetics, medicine, Carcinoma, Humans, Genetics(clinical), RNA, Messenger, Genetics (clinical), Aged, Aged, 80 and over, Lung, Gene Expression Profiling, LCC, Cancer, Genomics, Middle Aged, medicine.disease, AC, SCC, Human genetics, MicroRNAs, medicine.anatomical_structure, Cancer research, Adenocarcinoma, Female, DNA microarray, Systems biology, Research Article
Abstract

Background Non-small cell lung cancer (NSCLC), a leading cause of cancer deaths, represents a heterogeneous group of neoplasms, mostly comprising squamous cell carcinoma (SCC), adenocarcinoma (AC) and large-cell carcinoma (LCC). The objectives of this study were to utilize integrated genomic data including copy-number alteration, mRNA, microRNA expression and candidate-gene full sequencing data to characterize the molecular distinctions between AC and SCC. Methods Comparative genomic hybridization followed by mutational analysis, gene expression and miRNA microarray profiling were performed on 123 paired tumor and non-tumor tissue samples from patients with NSCLC. Results At DNA, mRNA and miRNA levels we could identify molecular markers that discriminated significantly between the various histopathological entities of NSCLC. We identified 34 genomic clusters using aCGH data; several genes exhibited a different profile of aberrations between AC and SCC, including PIK3CA, SOX2, THPO, TP63, PDGFB genes. Gene expression profiling analysis identified SPP1, CTHRC1and GREM1 as potential biomarkers for early diagnosis of the cancer, and SPINK1 and BMP7 to distinguish between AC and SCC in small biopsies or in blood samples. Using integrated genomics approach we found in recurrently altered regions a list of three potential driver genes, MRPS22, NDRG1 and RNF7, which were consistently over-expressed in amplified regions, had wide-spread correlation with an average of ~800 genes throughout the genome and highly associated with histological types. Using a network enrichment analysis, the targets of these potential drivers were seen to be involved in DNA replication, cell cycle, mismatch repair, p53 signalling pathway and other lung cancer related signalling pathways, and many immunological pathways. Furthermore, we also identified one potential driver miRNA hsa-miR-944. Conclusions Integrated molecular characterization of AC and SCC helped identify clinically relevant markers and potential drivers, which are recurrent and stable changes at DNA level that have functional implications at RNA level and have strong association with histological subtypes.

Published
2013

32. Multi-omics analysis of primary glioblastoma cell lines shows recapitulation of pivotal molecular features of parental tumors

Author

Camille Levasseur, Yannick Marie, Marc Sanson, Charlotte Schmitt, Shai Rosenberg, Keith L. Ligon, Maite Verreault, Khê Hoang-Xuan, Ahmed Idbaih, Karima Mokhtari, Jean-Yves Delattre, Jeremy Guehennec, Franck Bielle, Justine Guegan, 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), Service de Séquençage et de Génotypage, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de neurologie 2 [CHU Pitié-Salpêtrière], 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), Hadassah Hebrew University Medical Center [Jerusalem], HAL-UPMC, Gestionnaire, 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), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Service Commun de Biologie, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, 0301 basic medicine, Cancer Research, DNA Copy Number Variations, Somatic cell, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Druggability, [SDV.CAN]Life Sciences [q-bio]/Cancer, cell lines, Biology, Real-Time Polymerase Chain Reaction, Bioinformatics, Polymorphism, Single Nucleotide, Genome, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Biomarkers, Tumor, Tumor Cells, Cultured, cancer, Humans, Point Mutation, Exome, RNA, Messenger, Copy-number variation, Allele, genome, Gene, Exome sequencing, Aged, Brain Neoplasms, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Point mutation, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, High-Throughput Nucleotide Sequencing, Middle Aged, 3. Good health, 030104 developmental biology, Oncology, Basic and Translational Investigations, Cancer research, Female, Neurology (clinical), Glioblastoma
Abstract

International audience; Background. Glioblastoma (GBM) is the deadliest primary brain cancer in adults. Emerging innovative therapies hold promise for personalized cancer treatment. Improving therapeutic options depends on research relying on relevant preclinical models. In this line we have established in the setting of the GlioTex project (GBM and Experimental Therapeutics) a GBM patient-derived cell line (GBM-PDCL) library. A multi-omic approach was used to determine the molecular landscape of PDCL and the extent to which they represent GBM tumors.Methods. Single nucleotide polymorphism array, expression arrays, exome sequencing, and RNA sequencing were used to measure and compare the molecular landscapes of 20 samples representing 10 human GBM tumors and paired GBM-PDCLs.Results. Copy number variations were similar for a median of 85% of the genome and for 59% of the major focal events. Somatic point mutations were similar in a median of 41%. Mutations in GBM driver and “druggable” genes were maintained in 67% of events. Mutations that were not conserved in the PDCL were mainly low allelic fraction and/or non-driver mutations. Based on RNA expression profiling, PDCLs cluster closely to their parental tumor with overexpression of pathways associated with cancer progression in PDCL.Conclusions. Overall, PDCLs recapitulate pivotal molecular alterations of paired-parental tumors supporting their use as a preclinical model of GBM. However, some driver aberrations are lost or gained in the passage from tumor to PDCL. Our results support using PDCL as a relevant preclinical model of GBM. Further investigations of changes between PDCLs and their parental tumor may provide insights into GBM biology.

Published
2016
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33. Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models

Author

Arnaud Petit, Clarisse Thiollier, Paola Rivera-Munoz, Françoise Pflumio, Daniel Gautheret, Justine Guegan, William Vainchenker, Paola Ballerini, Judith Landman-Parker, Philippe Dessen, Yannis Duffourd, Cécile K. Lopez, Isabelle Radford, M'Boyba Diop, John D. Crispino, Olivier Bluteau, Yann Lécluse, Thomas Mercher, Beat Bornhauser, Stéphane de Botton, Jean-Pierre Bourquin, Cathy Ignacimouttou, Olivier Bernard, Dirk Reinhardt, Sandrine Poglio, Vinciane Mabialah, Nicole Dastugue, Anne Laure Bauchet, Bastien Gerby, Qiang Wen, Institut Gustave Roussy (IGR), Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service MIRCEN (MIRCEN), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Hannover Medical School [Hannover] (MHH), Universität Zürich [Zürich] = University of Zurich (UZH), Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire d'Hématologie, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Hématopoïèse normale et pathologique (U1170 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Images et Modèles, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique des tumeurs (U985), Institut Gustave Roussy (IGR)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Claude Bernard Lyon 1 (UCBL), 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)-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 Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Cancérologie de Toulouse (CRCT), 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)-Centre National de la Recherche Scientifique (CNRS), Service de Chimie Moléculaire (SCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Plateforme de génomique, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bases fondamentales et stratégies nouvelles en cancérologie (BFSNC - IFR54), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-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 Trousseau [APHP], CEA Direction des Sciences du Vivant (CEA/DSV), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of Zurich, Mercher, Thomas, Gerby, Bastien, Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-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 Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital Armand-Trousseau [Paris], University of Zürich [Zürich] (UZH), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-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 Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Oncogene Proteins, Fusion, [SDV]Life Sciences [q-bio], Kaplan-Meier Estimate, Mice, SCID, Bioinformatics, Fusion gene, Mice, Acute megakaryoblastic leukemia, 0302 clinical medicine, Aurora Kinases, Leukemia, Megakaryoblastic, Acute, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Immunology and Allergy, ComputingMilieux_MISCELLANEOUS, Aurora Kinase A, Oligonucleotide Array Sequence Analysis, 0303 health sciences, High-Throughput Nucleotide Sequencing, GATA1, Azepines, Genomics, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Leukemia, 030220 oncology & carcinogenesis, 2723 Immunology and Allergy, Female, Molecular Sequence Data, Immunology, Kruppel-Like Transcription Factors, Aurora A kinase, 610 Medicine & health, [SDV.CAN]Life Sciences [q-bio]/Cancer, Protein Serine-Threonine Kinases, Biology, Article, 03 medical and health sciences, Chromosome 16, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Animals, Humans, Amino Acid Sequence, Gene, Aged, 030304 developmental biology, 2403 Immunology, Base Sequence, Gene Expression Profiling, Infant, medicine.disease, Xenograft Model Antitumor Assays, Repressor Proteins, Gene expression profiling, Pyrimidines, 10036 Medical Clinic, Cancer research
Abstract

A CBFA2T3-GLIS2 fusion gene was identified in 31% of non–Down syndrome AMKL., Acute megakaryoblastic leukemia (AMKL) is a heterogeneous disease generally associated with poor prognosis. Gene expression profiles indicate the existence of distinct molecular subgroups, and several genetic alterations have been characterized in the past years, including the t(1;22)(p13;q13) and the trisomy 21 associated with GATA1 mutations. However, the majority of patients do not present with known mutations, and the limited access to primary patient leukemic cells impedes the efficient development of novel therapeutic strategies. In this study, using a xenotransplantation approach, we have modeled human pediatric AMKL in immunodeficient mice. Analysis of high-throughput RNA sequencing identified recurrent fusion genes defining new molecular subgroups. One subgroup of patients presented with MLL or NUP98 fusion genes leading to up-regulation of the HOX A cluster genes. A novel CBFA2T3-GLIS2 fusion gene resulting from a cryptic inversion of chromosome 16 was identified in another subgroup of 31% of non–Down syndrome AMKL and strongly associated with a gene expression signature of Hedgehog pathway activation. These molecular data provide useful markers for the diagnosis and follow up of patients. Finally, we show that AMKL xenograft models constitute a relevant in vivo preclinical screening platform to validate the efficacy of novel therapies such as Aurora A kinase inhibitors.

Published
2012
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34. A pair of co-opted retroviral envelope syncytin genes is required for formation of the two-layered murine placental syncytiotrophoblast

Author

Francis Harper, Cécile Vernochet, Thierry Heidmann, Anne Dupressoir, Gérard Pierron, Philippe Dessen, and Justine Guegan

Subjects
Placenta, Mutant, Connexin, Mice, Transgenic, Pregnancy Proteins, Biology, Epigenesis, Genetic, Mice, Open Reading Frames, Syncytiotrophoblast, Pregnancy, medicine, Animals, Humans, Epigenetics, Gene, Mice, Knockout, Genetics, Genome, Multidisciplinary, Gene Products, env, Trophoblast, Embryo, Trophoblasts, Cell biology, Retroviridae, medicine.anatomical_structure, PNAS Plus, embryonic structures, Pregnancy, Animal, Female, Rabbits
Abstract

In most mammalian species, a critical step of placenta development is the fusion of trophoblast cells into a multinucleated syncytiotrophoblast layer fulfilling essential fetomaternal exchange functions. Key insights into this process came from the discovery of envelope genes of retroviral origin, the syncytins , independently acquired by the human ( syncytin-1 and - 2 ), mouse ( syncytin-A and - B ), and rabbit ( syncytin-Ory1 ) genomes, with fusogenic properties and placenta-specific expression. We previously showed that mouse syncytin-A is essential for the formation of one of the two syncytiotrophoblast layers and for embryo survival. Here, we have generated syncytin-B KO mice and demonstrate that syncytin-B null placenta displays impaired formation of syncytiotrophoblast layer II (ST-II), with evidence of unfused apposed cells, and enlargement of maternal lacunae disrupting the placenta architecture. Unexpectedly, syncytin-B null embryos are viable, with only limited late-onset growth retardation and reduced neonate number. Microarray analyses identified up-regulation of the connexin 30 gene in mutant placentae, with the protein localized at the fetomaternal interface, suggesting gap junction-mediated compensatory mechanisms. Finally, double-KO mice demonstrate premature death of syncytin-A null embryos if syncytin-B is deleted, indicating cooperation between ST-I and ST-II. These findings establish that both endogenous retrovirus-derived syncytin genes contribute independently to the formation of the two syncytiotrophoblast layers during placenta formation, demonstrating a major role of retroviral gene capture, through convergent evolution, to generate multiple placental structures. Although some are absolutely required for completion of pregnancy, others are still amenable to “epigenetic” compensations, thus illustrating the complexity of the molecular machinery that developed during placental evolution.

Published
2011
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35. GENO-33PATIENT DERIVED GLIOBLASTOMA CELL LINES RECAPITULATE PARENTAL TUMORS' MOLECULAR LANDSCAPE

Author

Justine Guegan, Khê Hoang-Xuan, Jean-Yves Delattre, Shai Rosenberg, Camille Levasseur, Jeremy Guehennec, Charlotte Schmitt, Maite Verreault, Ahmed Idbaih, Karima Mokhtari, Yannick Marie, and Marc Sanson

Subjects
Cancer Research, Glioblastoma cell, business.industry, Biology, medicine.disease, Text mining, Oncology, Cell culture, medicine, Cancer research, Neurology (clinical), business, Abstracts from the 20th Annual Scientific Meeting of the Society for Neuro-Oncology, Glioblastoma
Published
2015
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36. A Comprehensive Study of the VHL-R200W Chuvash Polycythemia Mutation Reveals a Gradual Dysregulation of the Hypoxia Pathway in Oncogenesis

Author

Philippe Dessen, Betty Gardie, William G. Kaelin, Elodie Laine, Sophie Gad, H Le Jeune, Brigitte Bressac-de Paillerets, Stéphane Richard, Sophie Couvé, Luba Tchertanov, Pages J-C., Jean Feunteun, B Lecomte, Sylvie Hermouet, K Mahtouk, Patrick R. Benusiglio, Charline Ladroue, Justine Guegan, Peter J. Ratcliffe, and David R. Mole

Subjects
Genetics, Tumor suppressor gene, Immunology, Haplotype, EPAS1, Cell Biology, Hematology, Biology, medicine.disease, medicine.disease_cause, Biochemistry, Pheochromocytoma, Germline mutation, medicine, Von Hippel–Lindau disease, Allele, Carcinogenesis
Abstract

Context : Germline mutations in genes involved in the hypoxia sensing pathway (VHL, PHD2/EGLN1, HIF2A/EPAS1) predispose patients to erythrocytosis associated with normal or high serum erythropoietin level. The more frequent mutation, VHL-R200W (R200W), has been identified in homozygous carriers with a congenital erythrocytosis named Chuvash polycythemia. Survival in the Chuvash patients was found to be reduced compared to control groups due to higher rates of arterial and venous thromboses, and to haemorrhagic events. Noteworthily, a characteristic of these patients and their parents, heterozygous for the mutation, is the total absence of tumor development as the opposite of heterozygous carriers of other VHL mutations. Indeed, VHL is a tumor suppressor gene and heterozygous carriers of VHLmutations have von Hippel-Lindau disease and are at high risk of multiple tumors (e.g. CNS hemangioblastomas, pheochromocytoma, renal cell carcinoma). The absence of tumor development in patients with congenital erythrocytosis remained unexplained. The R200W mutation is transmitted within a 340-kilobases haplotype inherited 14,000 to 62,000 years ago from a single founder event. The absence of tumor development in patients carrying the R200W mutation raised the possibility of the presence of a protective element within this core haplotype. Objective: The purpose of this study was to determine the mechanisms underlying the absence of tumor development in patients carrying the R200W mutation, healthy (heterozygous carriers) or with congenital erythrocytosis (homozygous). Methods: We report here one particular family carring a heterozygous R200W mutation associated, for the first time, with a typical von Hippel-Lindau disease (with pheochromocytoma, hemangioblastoma and renal cell carcinoma) (Olswang et al., 1998). We performed a comprehensive study with genotyping, phenotypic analysis, structural modeling, functional and transcriptomic studies of the R200W mutant in comparison to classical mutants involved in von Hippel-Lindau disease. For the first time, the use of inducible expression vectors encoding untagged VHL in the functional studies allowed the observation of very subtle effects. Results: We show that the R200W mutation alone is definitely not associated with the von Hippel Lindau disease because this particular family actually carries another pathogenic mutation, VHL-R161Q, on the same VHL allele, and the double mutated allele segregates with disease. Our genotyping showed that the doubled mutations lies on the Chuvash core haplotype transmitted with the R200W mutation. We can thus conclude that this haplotype does not contain any protective elements against cancer development and that the VHLmutations are, by themselves, predominantly responsible for manifestations of the von Hippel-Lindau disease. Functional studies demonstrate that the function of the R200W mutation is close to the wild type protein and the severity of disease manifestations observed in VHL syndrome is perfectly correlated with a gradient of pVHL dysfunction in hypoxia signaling pathways. Conclusion: We show that the R200W mutation associated with congenital erythrocytosis is at the bottom of an oncogenic gradient. These results validate for the first time in humans the recently proposed “continuum” model of tumor suppression, which differs from the classical Knudson’s two-hit model and implies that subtle gene dosage-sensitivity may underlie tumor predisposition. This model may be of major importance in our understanding of tumor risk in patients with erythrocytosis carrying germline mutations in other genes belonging the HIF pathway. Indeed, in rare cases, PHD2 and HIF2A pathogenic mutations also predispose patients to pheochromocytomas or paragangliomas development. Disclosures No relevant conflicts of interest to declare.

Published
2014
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37. Abstract 3051: Genome-wide microarray expression and genomic alteration by array-CGH analysis in neuroblastoma stem-like cells

Author

Soledad Martínez, Noémie Pata-Merci, Sheila Legarra, Xing Fan, Justine Guegan, Javier S. Castresana, Juan A. Rey, Gabriel Gallo, G. Danglot, Alain Bernheim, and Raquel Ordoñez

Subjects
Genetics, Cancer Research, education.field_of_study, biology, Microarray analysis techniques, Population, Wnt signaling pathway, medicine.disease, Hedgehog signaling pathway, Oncology, GLI1, Cancer stem cell, Neurosphere, Neuroblastoma, biology.protein, Cancer research, medicine, education
Abstract

Neuroblastoma, the most common extracranial malignant solid tumor in childhood has a very diverse clinical behaviour: from spontaneous regression to a very aggressive malignant progression and resistance to chemotherapy. This heterogeneous clinical behaviour might be due to molecular differences in tumor cell subpopulations. The cancer stem cells (CSC) model proposes the existence of a subpopulation within the tumor with stem-like cell properties: a significant proliferation capacity, a unique self-renewal capacity, and therefore, a higher ability to form new tumors. We enriched the stem-like cell population content of two commercial neuroblastoma cell lines (SKNDZ and SIMA) by the use of conditioned cell culture media for neurospheres, and compared genome expression and genomic gains and losses appearing in neurospheres versus the alterations appearing in standard tumor cells, by microarray analysis and array-CGH, respectively. Array-CGH did not show any significant differences between standard and neurosphere-forming cell lines, both in SKNDZ and in SIMA. The microarray expression analysis highlighted some of the most relevant biological processes and molecular functions that might be responsible for the stem-cell like phenotype. As expected, some signalling pathways detected were involved in self-renewal of normal tissues (Wnt, Notch, Hedgehog and TGF-β) and seem to contribute to CSC phenotype when deregulated. Among them, we focused on the aberrant activation of Hedgehog and TGF-β signalling pathways. We confirmed the inhibition of repressors of TGF-β pathway, as SMAD6 and SMAD7 by quantitative PCR. The analysis of the Sonic Hedgehog pathway showed overexpression of PTCH1, GLI1 and SMO. We analyzed two CSC surface markers, and found overexpression of CD133 and CD15 in SIMA neurospheres, confirming that this cell line was particularly enriched in stem-like cells. This work shows a cross-talk of different pathways in neuroblastoma, and the importance of it in stem-like cells, as confirmed by the overexpression observed in JAG1, one of the targets of TGF-β and also the main activator of Notch signalling pathway. Further analysis based on this work could identify possible new targets for molecular CSC therapies against neuroblastoma, highlighting the importance of redirecting current cancer treatments towards CSC to achieve total elimination of tumor cell population and improve treatment effectiveness. Citation Format: Raquel Ordoñez, Gabriel Gallo, Soledad Martínez, Sheila Legarra, Noémie Pata-Merci, Justine Guegan, Giselle Danglot, Xing Fan, Juan A. Rey, Alain Bernheim, Javier S. Castresana. Genome-wide microarray expression and genomic alteration by array-CGH analysis in neuroblastoma stem-like cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3051. doi:10.1158/1538-7445.AM2014-3051

Published
2014
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38. Radiosensitization by a novel Bcl-2 and Bcl-XL inhibitor S44563 in small-cell lung cancer

Author

Paule Opolon, Berthier Lk, Stéphane Depil, Justine Guegan, Jean-Luc Perfettini, Delphine Dugue, Eric Deutsch, Geneste O, Guido Kroemer, Jean-Charles Soria, A. Gombos, Yohann Loriot, Pierre Mordant, and Alain Pierré

Subjects
Cancer Research, Radiation-Sensitizing Agents, Lung Neoplasms, medicine.medical_treatment, Immunology, bcl-X Protein, Mice, Nude, Bcl-xL, Apoptosis, Radiation Tolerance, Cellular and Molecular Neuroscience, Mice, In vivo, medicine, Animals, Humans, Radiosensitivity, Lung cancer, Clonogenic assay, neoplasms, Cell Proliferation, Cisplatin, Sulfonamides, biology, NF-kappa B, Cell Biology, medicine.disease, Molecular biology, Combined Modality Therapy, Small Cell Lung Carcinoma, Xenograft Model Antitumor Assays, respiratory tract diseases, Radiation therapy, Proto-Oncogene Proteins c-bcl-2, biology.protein, Cancer research, Original Article, Female, Heterocyclic Compounds, 3-Ring, medicine.drug
Abstract

Radiotherapy has a critical role in the treatment of small-cell lung cancer (SCLC). The effectiveness of radiation in SCLC remains limited as resistance results from defects in apoptosis. In the current study, we investigated whether using the Bcl-2/Bcl-XL inhibitor S44563 can enhance radiosensitivity of SCLC cells in vitro and in vivo. In vitro studies confirmed that S44563 caused SCLC cells to acquire hallmarks of apoptosis. S44563 markedly enhanced the sensitivity of SCLC cells to radiation, as determined by a clonogenic assay. The combination of S44563 and cisplatin-based chemo-radiation showed a significant tumor growth delay and increased overall survival in mouse xenograft models. This positive interaction was greater when S44563 was given after the completion of the radiation, which might be explained by the radiation-induced overexpression of anti-apoptotic proteins secondary to activation of the NF-κB pathway. These data underline the possibility of combining IR and Bcl-2/Bcl-XL inhibition in the treatment of SCLC as they underscore the importance of administering conventional and targeted therapies in an optimal sequence.

Published
2014

39. Abstract 413: Genome-wide microarray expression and array-CGH analysis in neuroblastoma stem-like cells by use of the neurosphere-formation assay

Author

Gabriel Gallo, Justine Guegan, Noémie Pata-Merci, Gisèle Danglot, Alain Bernheim, Xing Fan, Javier S. Castresana, and Sheila Legarra

Subjects
Genetics, Cancer Research, Cell signaling, Cell cycle, Biology, medicine.disease, genomic DNA, Oncology, Cell culture, Neurosphere, Neuroblastoma, Gene expression, Cancer research, medicine, DNA microarray
Abstract

In this work, we aimed at analyzing genome-wide gene expression and DNA gains and losses in neuroblastoma cell lines and in neurospheres containing stem-like cells. SKNDZ and SIMA neuroblastoma cell lines were grown in DMEM cell culture medium, and in DMEM-F12 selective serum free medium (with EGF, bFGF and B27; to induce the neurosphere-forming phenotype). After RNA and genomic DNA extractions from the 4 cell lines (2 standard, 2 neurosphere-forming cell lines), expression microarrays and array-CGH analyses were performed (Aligent Technologies). Array-CGH did not show any significant differences between standard and neurosphere-forming cell lines, both in SKNDZ and in SIMA. Microarray expression analysis demonstrated a total of 425 upregulated and 170 downregulated genes in neurosphere-forming cell lines. The differentially expressed genes were classified using the PANTHER classification system (www.pantherdb.org). As a result, apoptosis, cell adhesion, cell communication, cell cycle, and immune system processes appeared upregulated and downregulated in neurospheres. Some of those genes participate in pathways related with cancer (Table 1). In conclusion, the stem-like phenotype does not seem to be linked to anatomic changes at the level of deletions/gains of DNA, but to changes in expression of genes, like those of the TGF-beta, Notch and Sonic Hedgehog pathways. Those pathways, specially TGF-beta, widely described as an important therapeutic target against cancer, should be further studied to determine their real implication in the neurosphere-formation process in neuroblastoma, and therefore, as candidate targets for the treatment of neuroblastoma stem-like cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 413. doi:1538-7445.AM2012-413

Published
2012
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40. Exome Sequencing Reveals Signal Transduction Genes Involved in Impulse Control Disorders in Parkinson's Disease

Author

Sabine Prud'hon, Samir Bekadar, Agnès Rastetter, Justine Guégan, Florence Cormier-Dequaire, Lucette Lacomblez, Graziella Mangone, Hana You, Mailys Daniau, Yannick Marie, Hélène Bertrand, Suzanne Lesage, Sophie Tezenas Du Montcel, Mathieu Anheim, Alexis Brice, Fabrice Danjou, and Jean-Christophe Corvol

Subjects
Parkinson's disease (PD), dopamine agonists (DA), impulse control disorders (ICD), pharmacogenetics, exome sequencing, Neurology. Diseases of the nervous system, RC346-429
Abstract

Introduction: Impulse control disorders (ICDs) frequently complicate dopamine agonist (DA) therapy in Parkinson's disease (PD). There is growing evidence of a high heritability for ICDs in the general population and in PD. Variants on genes belonging to the reward pathway have been shown to account for part of this heritability. We aimed to identify new pathways associated with ICDs in PD.Methods: Thirty-six Parkinsonian patients on DA therapy with (n = 18) and without ICDs (n = 18) matched on age at PD's onset, and gender was selected to represent the most extreme phenotypes of their category. Exome sequencing was performed, and variants with a strong functional impact in brain-expressed genes were selected. Allele frequencies and their distribution in genes and pathways were analyzed with single variant and SKAT-O tests. The 10 most associated variants, genes, and pathways were retained for replication in the Parkinson's progression markers initiative (PPMI) cohort.Results: None of markers tested passed the significance threshold adjusted for multiple comparisons. However, the “Adenylate cyclase activating” pathway, one of the top associated pathways in the discovery data set (p = 1.6 × 10−3) was replicated in the PPMI cohort and was significantly associated with ICDs in a post hoc pooled analysis (combined p-value 3.3 × 10−5). Two of the 10 most associated variants belonged to genes implicated in cAMP and ERK signaling (rs34193571 in RasGRF2, p = 5 × 10−4; rs1877652 in PDE2A, p = 8 × 10−4) although non-significant after Bonferroni correction.Conclusion: Our results suggest that genes implicated in the signaling pathways linked to G protein-coupled receptors participate to genetic susceptibility to ICDs in PD.

Published
2020
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41. Comparative Analysis of Urso- and Tauroursodeoxycholic Acid Neuroprotective Effects on Retinal Degeneration Models

Author

Alejandra Daruich, Emilie Picard, Justine Guégan, Thara Jaworski, Léa Parenti, Kimberley Delaunay, Marie-Christine Naud, Marianne Berdugo, Jeffrey H. Boatright, and Francine Behar-Cohen

Subjects
UDCA, TUDCA, retina, retinal detachment, retinal degeneration, neuroprotection, Medicine, Pharmacy and materia medica, RS1-441
Abstract

Ursodeoxycholic (UDCA) and tauroursodeoxycholic (TUDCA) acids have shown neuroprotective properties in neurodegenerative diseases, but differential effects of the two bile acids have been poorly explored. The aim of this study was to evaluate the neuroprotective effects of UDCA versus TUDCA in a neuroretinal degeneration model and to compare transcriptionally regulated pathways. The WERI-Rb-1 human cone-like cell line and retinal explants were exposed to albumin and TUDCA or UDCA. Viability, cell death, and microglial activation were quantified. Transcriptionally regulated pathways were analyzed after RNA sequencing using the edgeR bioconductor package. Pre-treatment of cone-like cells with UDCA or TUDCA significantly protected cells from albumin toxicity. On retinal explants, either bile acid reduced apoptosis, necroptosis, and microglia activation at 6 h. TUDCA induced the regulation of 463 genes, whilst 31 genes were regulated by UDCA. Only nineteen common genes were regulated by both bile acids, mainly involved in iron control, cell death, oxidative stress, and cell metabolism. As compared to UDCA, TUDCA up-regulated genes involved in endoplasmic reticulum stress pathways and down-regulated genes involved in axonal and neuronal development. Either bile acid protected against albumin-induced cell loss. However, TUDCA regulated substantially more neuroprotective genes than UDCA.

Published
2022
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42. Contribution of captured retroviral envelope genes, the 'synctins' to the formation of the mouse placenta

Author

Cécile Vernochet, Philippe Dessen, Justine Guegan, Anne Dupressoir, Francis Harper, Gérard Pierron, and Thierry Heidmann

Subjects
Genetics, lcsh:Immunologic diseases. Allergy, Fetus, Embryogenesis, Mutant, Placentation, Trophoblast, Biology, Phenotype, Cell biology, medicine.anatomical_structure, Syncytiotrophoblast, Infectious Diseases, Placenta, Virology, embryonic structures, medicine, Oral Presentation, lcsh:RC581-607, reproductive and urinary physiology
Abstract

Background In most mammalian species, a key process of placentation is the fusion of trophoblast cells into a multinucleated syncytiotrophoblast layer at the fetomaternal interface. Envelope proteins of retroviral origin, the syncytins, specifically expressed in the placenta and with in vitro cell-cell fusogenic activity, have been suspected to be involved in this process [1-5]. In mice, inactivation of syncytin-A resulted in impaired formation of the syncytiotrophoblast layer I (facing the maternal blood lacuna) and in embryonic death [6], demonstrating that it is required for placenta development. Here, the effect of the inactivation of the second murine syncytin gene, syncytin-B, is described. Materials and methods We generated syncytin-B mutant mice, and embryos homozygous mutant for syncytin-B or for both syncytinA and -B were obtained at different gestational stages, through time mating intercrosses. The placentae of syncytin-B null embryos were examined using histological analyses and refined electron microscopy analyses of the fetomaternal interface. Genes whose expression is modified in null placenta were identified using microarrays analyses and their expression was localized by immunohistochemistry. Results Syncytin-B null placenta disclose defects in formation of the syncytiotrophoblast layer II (facing the fetal blood vessels), with enlarged maternal lacuna disrupting the placenta architecture. At variance with the syncytin-A phenotype, syncytin-B null embryos are viable, although they still display late-onset embryonic growth retardation and a significant perinatal death rate. Interestingly, double SynA/SynB KO embryos die earlier than do embryos deficient for syncytin-A alone, suggesting cooperative interactions. Finally, an induction of connexin-30 expression was observed in the syncytin-B null placenta, with the protein being detected at the fetomaternal interface, suggesting a compensatory process whereby impaired syncytialization is counteracted by a gap junction mediated, cell-cell communication. Conclusions

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