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1. IGF2 promotes growth of adrenocortical carcinoma cells, but its overexpression does not modify phenotypic and molecular features of adrenocortical carcinoma.

Author: Marine Guillaud-Bataille, Bruno Ragazzon, Aurélien de Reyniès, Claire Chevalier, Isabelle Francillard, Olivia Barreau, Virginie Steunou, Johann Guillemot, Frédérique Tissier, Marthe Rizk-Rabin, Fernande René-Corail, Abir Al Ghuzlan, Guillaume Assié, Xavier Bertagna, Eric Baudin, Yves Le Bouc, Jérôme Bertherat, and Eric Clauser
Subjects: Medicine, Science
Abstract: Insulin-like growth factor 2 (IGF2) overexpression is an important molecular marker of adrenocortical carcinoma (ACC), which is a rare but devastating endocrine cancer. It is not clear whether IGF2 overexpression modifies the biology and growth of this cancer, thus more studies are required before IGF2 can be considered as a major therapeutic target. We compared the phenotypical, clinical, biological, and molecular characteristics of ACC with or without the overexpression of IGF2, to address these issues. We also carried out a similar analysis in an ACC cell line (H295R) in which IGF2 expression was knocked down with si- or shRNA. We found no significant differences in the clinical, biological and molecular (transcriptomic) traits between IGF2-high and IGF2-low ACC. The absence of IGF2 overexpression had little influence on the activation of tyrosine kinase pathways both in tumors and in H295 cells that express low levels of IGF2. In IGF2-low tumors, other growth factors (FGF9, PDGFA) are more expressed than in IGF2-high tumors, suggesting that they play a compensatory role in tumor progression. In addition, IGF2 knock-down in H295R cells substantially impaired growth (>50% inhibition), blocked cells in G1 phase, and promoted apoptosis (>2-fold). Finally, analysis of the 11p15 locus showed a paternal uniparental disomy in both IGF2-high and IGF2-low tumors, but low IGF2 expression could be explained in most IGF2-low ACC by an additional epigenetic modification at the 11p15 locus. Altogether, these observations confirm the active role of IGF2 in adrenocortical tumor growth, but also suggest that other growth promoting pathways may be involved in a subset of ACC with low IGF2 expression, which creates opportunities for the use of other targeted therapies.
Published: 2014
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2. TREM-1 orchestrates angiotensin II–induced monocyte trafficking and promotes experimental abdominal aortic aneurysm

Author: Laurie Soulat-Dufour, Alexandre Boissonnas, Giulia Chinetti, Florence Pinet, Ludivine Laurans, Fabien Lareyre, Andreas Giraud, Léa Guyonnet, Soraya Taleb, Bruno Esposito, Coralie L. Guerin, Marc Derive, Sylvie Lang, Juliette Raffort, José Vilar, Alain Tedgui, Marie Vandestienne, Jean-Sébastien Silvestre, Amir Boufenzer, Hafid Ait-Oufella, Ziad Mallat, Icía Santos-Zas, Rida Al-Rifai, Yujiao Zhang, Patrick Bruneval, Jérémie Joffre, Eric Clauser, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of California [San Francisco] (UC San Francisco), University of California (UC), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 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)-Université Côte d'Azur (UCA), INOTREM SA, Faculté de Médecine [Nancy], Université de Lorraine (UL)-Université de Lorraine (UL), Institut Curie [Paris], Innovations thérapeutiques en hémostase (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Luxembourg Institute of Health (LIH), Service de Cardiologie [CHU Saint-Antoine], CHU Saint-Antoine [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), University of Cambridge [UK] (CAM), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pinet, Florence, Mallat, Ziad [0000-0003-0443-7878], Apollo - University of Cambridge Repository, Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), and ANR-18-CE14-0009,TETRAAA,EXploration et modulation du récépteur TREM-1 dans la maldie anévrysmale aortique(2018)
Subjects: 0301 basic medicine, Mice, Knockout, ApoE, Interleukin-1beta, Inflammation, macromolecular substances, Monocytes, Proinflammatory cytokine, Mice, 03 medical and health sciences, Aortic aneurysm, 0302 clinical medicine, Downregulation and upregulation, Cell migration/adhesion, Cell Movement, Vascular Biology, medicine.artery, Animals, Humans, Medicine, Innate immunity, Aorta, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Tumor Necrosis Factor-alpha, business.industry, Angiotensin II, Monocyte, General Medicine, medicine.disease, Triggering Receptor Expressed on Myeloid Cells-1, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, cardiovascular system, Cancer research, Matrix Metalloproteinase 2, Tumor necrosis factor alpha, medicine.symptom, business, Gene Deletion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article, Aortic Aneurysm, Abdominal
Abstract: International audience; The triggering receptor expressed on myeloid cells 1 (TREM-1) drives inflammatory responses in several cardiovascular diseases but its role in abdominal aortic aneurysm (AAA) remains unknown. Our objective was to explore the role of TREM-1 in a mouse model of angiotensin II-induced (AngII-induced) AAA. TREM-1 expression was detected in mouse aortic aneurysm and colocalized with macrophages. Trem1 gene deletion (Apoe-/-Trem1-/-), as well as TREM-1 pharmacological blockade with LR-12 peptide, limited both AAA development and severity. Trem1 gene deletion attenuated the inflammatory response in the aorta, with a reduction of Il1b, Tnfa, Mmp2, and Mmp9 mRNA expression, and led to a decreased macrophage content due to a reduction of Ly6Chi classical monocyte trafficking. Conversely, antibody-mediated TREM-1 stimulation exacerbated Ly6Chi monocyte aorta infiltration after AngII infusion through CD62L upregulation and promoted proinflammatory signature in the aorta, resulting in worsening AAA severity. AngII infusion stimulated TREM-1 expression and activation on Ly6Chi monocytes through AngII receptor type I (AT1R). In human AAA, TREM-1 was detected and TREM1 mRNA expression correlated with SELL mRNA expression. Finally, circulating levels of sTREM-1 were increased in patients with AAA when compared with patients without AAA. In conclusion, TREM-1 is involved in AAA pathophysiology and may represent a promising therapeutic target in humans.
Published: 2021
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3. Aldosterone-Producing Adenoma With a Somatic KCNJ5 Mutation Revealing APC-Dependent Familial Adenomatous Polyposis

Author: Eric Clauser, Sheerazed Boulkroun, Julien Vouillarmet, Myriam Decaussin-Petrucci, Maria-Christina Zennaro, Jean-Louis Peix, Pierre Lantelme, Julia Graeppi-Dulac, Charles Thivolet, Fabio L. Fernandes-Rosa, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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), and Université de Lyon-Institut National de la Recherche Agronomique (INRA)
Subjects: 0301 basic medicine, Aldosterone synthase, Adenoma, Adult, Male, Pathology, medicine.medical_specialty, Heterozygote, Adenomatous polyposis coli, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Adenomatous Polyposis Coli Protein, Adrenal Gland Neoplasms, Loss of Heterozygosity, 030209 endocrinology & metabolism, Biochemistry, Familial adenomatous polyposis, Diagnosis, Differential, Hypertension, Malignant, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Primary aldosteronism, Internal medicine, Hyperaldosteronism, Medicine, Humans, Aldosterone, biology, Adrenal Hyperplasia, Congenital, business.industry, Biochemistry (medical), Adrenalectomy, medicine.disease, 030104 developmental biology, chemistry, Adenomatous Polyposis Coli, G Protein-Coupled Inwardly-Rectifying Potassium Channels, Macronodular Adrenal Hyperplasia, Mutation, biology.protein, business
Abstract: Context: Recurrent somatic mutations in KCNJ5, CACNA1D, ATP1A1, and ATP2B3 have been identified in aldosterone-producing adenomas (APAs). The question as to whether they are responsible for both nodulation and aldosterone production is not solved. Case Description: We describe the case of a young patient who was diagnosed with severe arterial hypertension due to primary aldosteronism at age 26 years, followed by hemorrhagic stroke 4 years later. Abdominal computed tomography showed bilateral macronodular adrenal hyperplasia. Identification of lateralized aldosterone secretion led to right adrenalectomy, followed by normalization of biochemical and hormonal parameters and amelioration of blood pressure. The resected adrenal showed three nodules, one of them expressing aldosterone synthase and harboring a somatic KNCJ5 mutation. A Weiss revisited index of 3 of the APA prompted us to perform a second 18F-2-fluoro-2-deoxy-D-glucose-positron emission tomography after surgery, which revealed abnormal rectal activity despite the absence of clinical symptoms. Gastrointestinal exploration showed multiple polyps with severe dysplasia, and the diagnosis of familial adenomatous polyposis was established in the presence of a germline heterozygous APC gene mutation. Sequencing of somatic DNA from the APA and a second adrenal nodule revealed biallelic APC inactivation due to loss of heterozygosity in both nodules. Conclusions: This case report underlines the need for establishing the frequency of germline APC variants in patients with primary aldosteronism and bilateral macronodular adrenal hyperplasia because their presence may predispose to APA development and severe hypertension well before the first familial adenomatous polyposis symptoms appear. From a mechanistic point of view, it supports a two-hit model for APA development, whereby the first hit drives increased cell proliferation whereas the second hit specifies the pattern of hormonal secretion.
Published: 2016
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4. Unraveling the intrafamilial correlations and heritability of tumor types in MEN1: a Groupe d'étude des Tumeurs Endocrines study

Author: Catherine Cardot-Bauters, Olivier Chabre, B. Delemer, Emilie Castermans, Eric Clauser, Michel Rodier, Georges Weryha, M.F. Odou, Alain Calender, F. Borson-Chazot, Abderrahmane Bourredjem, F Schillo, H. Du Boullay, Jean-Marc Kuhn, Véronique Kerlan, Anne Barlier, Catherine Lombard-Bohas, P. Lecomte, S. Giraud, B. Goichot, Albert Beckers, Sophie Christin-Maitre, I. Guilhem, F. Archambeaud, A. Tabarin, Hélène Bihan, Eric Pasmant, Jean-Louis Sadoul, Philippe Chanson, Patricia Niccoli, Julien Thevenon, Jérôme Bertherat, Vincent Rohmer, Pierre Goudet, Marc Le Renard, Lionel Groussin, P. Caron, N. Bourcigaux, Christine Binquet, Eric Baudin, Bruno Vergès, Laurence Faivre, Philippe Ruszniewski, M. Le Bras, 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, Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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, equipe 4, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Service de gastro-entérologie et assistance nutritive, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Endocrinologie - Diabète - Nutrition [Reims], Université de Reims Champagne-Ardenne (URCA)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), centre hospitalier universitaire de liège, Service d'endocrinologie clinique, CHU Pontchaillou [Rennes], Service d'Endocrinologie (ANGERS - Endocrino), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de médecine interne et de nutrition, Hôpital de Hautepierre [Strasbourg], Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de consultations de pathologies professionnelles [CHRU Nancy] (CCPP), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Endocrinologie [CHRU Nancy], Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Cyanobactéries des milieux aquatiques tropicaux peu profonds. Rôles et contrôles (CYROCO), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), 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-Université de Lyon-Centre Léon Bérard [Lyon]-Hôpital Edouard Herriot [CHU - HCL], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), FHU TRANSLAD (CHU de Dijon), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Edouard Herriot [CHU - HCL], Laboratoire des Procédés d'Élaboration des Réactifs Fonctionnels (PERF), Ecole Nationale Supérieure de Chimie de Lille (ENSCL), Eq 4, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Centre de médecine nucléaire, Fédération d'endocrinologie-Groupement hospitalier Lyon-Est-Fédération d'endocrinologie-Groupement hospitalier Lyon-Est, CHU Lyon, Service d'Endocrinologie (GRENOBLE - Endocrino), CHU Grenoble, Institut Cochin (UMR_S567 / UMR 8104), Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Pierre Aigrain (LPA), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université de Brest (UBO)-Université de Brest (UBO), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Agence nationale de la sécurité des systèmes d'information (ANSSI), Service d'Ophtalmologie (CHU de Dijon), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP]
Subjects: Oncology, Adult, Male, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Adrenal Gland Neoplasm, Adrenal Gland Neoplasms, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Pituitary neoplasm, Neuroendocrine tumors, Metastasis, Cohort Studies, Young Adult, Endocrinology, Age Distribution, Internal medicine, medicine, Multiple Endocrine Neoplasia Type 1, Humans, MEN1, Genetic Predisposition to Disease, Pituitary Neoplasms, Expressivity (genetics), Child, ComputingMilieux_MISCELLANEOUS, [SDV.BA]Life Sciences [q-bio]/Animal biology, Pituitary tumors, Bronchial Neoplasms, Infant, Newborn, Infant, General Medicine, Thymus Neoplasms, Heritability, Middle Aged, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Pedigree, Pancreatic Neoplasms, Neuroendocrine Tumors, Parathyroid Neoplasms, Child, Preschool, Female, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: BackgroundMEN1, which is secondary to the mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence of direct genotype-phenotype correlations. The existence of a higher risk of death in the Groupe d'étude des Tumeurs Endocrines-cohort associated with a mutation in the JunD interacting domain suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intrafamilial correlations and heritability of the six main tumor types in MEN1.MethodsThe study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs) and pituitary, adrenal, bronchial, and thymic (thNET) tumors and the presence of metastasis. Intrafamilial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software.ResultsIntrafamilial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and thNETs. The heritability of these three tumor types was consistently strong and significant with 64% (s.e.m.=0.13; Ps.e.m.=0.21; Ps.e.m.=0.41; P=0.006) for thNETs.ConclusionThe present study shows the existence of modifying genetic factors for thymus, adrenal, and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step toward personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.
Published: 2015
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5. IGF2 Promotes Growth of Adrenocortical Carcinoma Cells, but Its Overexpression Does Not Modify Phenotypic and Molecular Features of Adrenocortical Carcinoma

Author: Fernande René-Corail, Abir Al Ghuzlan, Marine Guillaud-Bataille, Yves Le Bouc, Johann Guillemot, Eric Clauser, Eric Baudin, Olivia Barreau, Marthe Rizk-Rabin, Isabelle Francillard, Jérôme Bertherat, Guillaume Assié, Aurélien de Reyniès, Claire Chevalier, Virginie Steunou, Bruno Ragazzon, Xavier Bertagna, Frédérique Tissier, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service d'explorations fonctionnelles [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-Sorbonne Université, Service de Biologie Hormonale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pôle Endocrinologie-Diabétologie Adultes-Enfants, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Saint-Vincent de Paul, Centre de Recherche Saint-Antoine (UMRS893), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), INSERM, Assistance Publique Hôpitaux de Paris., Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Service d'Anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière] (ACP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Programme'Cartes d'Identité des Tumeurs ' ( CIT ), Ligue Nationale Contre le Cancer, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Hôpital Saint-Vincent de Paul, Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Laboratoire d'Explorations Fonctionnelles Endocriniennes, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Service d'Anatomie Pathologique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Institut Gustave Roussy ( IGR ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Service d'Anatomie et cytologie pathologiques = Service de Pathologie [CHU Pitié-Salpêtrière] (ACP), Bos, Mireille, Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP]
Subjects: Male, endocrine system diseases, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Gene Expression, Apoptosis, Small hairpin RNA, Endocrinology, Molecular Cell Biology, Basic Cancer Research, Medicine and Health Sciences, Adrenocortical Carcinoma, Adrenocortical carcinoma, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, Multidisciplinary, Genomics, Middle Aged, Prognosis, female genital diseases and pregnancy complications, 3. Good health, Gene Expression Regulation, Neoplastic, Phenotype, Oncology, Cell Processes, Gene Knockdown Techniques, Medicine, Female, Signal transduction, Anatomy, Tyrosine kinase, Transcriptome Analysis, Research Article, Signal Transduction, Adult, animal structures, Adolescent, Science, Endocrine System, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cell Growth, Genomic Imprinting, Young Adult, FGF9, Insulin-Like Growth Factor II, Cell Line, Tumor, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Genetics, Cancer Genetics, Cancer Detection and Diagnosis, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Aged, Cell Proliferation, Cell growth, Growth factor, Chromosomes, Human, Pair 11, Biology and Life Sciences, Computational Biology, Cell Biology, DNA Methylation, medicine.disease, Genome Analysis, Molecular biology, G1 Phase Cell Cycle Checkpoints, Tumor progression, Genetic Loci, Cancer research, Adrenal Cortex, Genome Expression Analysis
Abstract: International audience; Insulin-like growth factor 2 (IGF2) overexpression is an important molecular marker of adrenocortical carcinoma (ACC), which is a rare but devastating endocrine cancer. It is not clear whether IGF2 overexpression modifies the biology and growth of this cancer, thus more studies are required before IGF2 can be considered as a major therapeutic target. We compared the phenotypical, clinical, biological, and molecular characteristics of ACC with or without the overexpression of IGF2, to address these issues. We also carried out a similar analysis in an ACC cell line (H295R) in which IGF2 expression was knocked down with si- or shRNA. We found no significant differences in the clinical, biological and molecular (transcriptomic) traits between IGF2-high and IGF2-low ACC. The absence of IGF2 overexpression had little influence on the activation of tyrosine kinase pathways both in tumors and in H295 cells that express low levels of IGF2. In IGF2-low tumors, other growth factors (FGF9, PDGFA) are more expressed than in IGF2-high tumors, suggesting that they play a compensatory role in tumor progression. In addition, IGF2 knock-down in H295R cells substantially impaired growth (>50% inhibition), blocked cells in G1 phase, and promoted apoptosis (>2-fold). Finally, analysis of the 11p15 locus showed a paternal uniparental disomy in both IGF2-high and IGF2-low tumors, but low IGF2 expression could be explained in most IGF2-low ACC by an additional epigenetic modification at the 11p15 locus. Altogether, these observations confirm the active role of IGF2 in adrenocortical tumor growth, but also suggest that other growth promoting pathways may be involved in a subset of ACC with low IGF2 expression, which creates opportunities for the use of other targeted therapies.
Published: 2014
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6. A Feminizing Adrenocortical Carcinoma in the Context of a Late Onset 21-Hydroxylase Deficiency

Author: Jean Guibourdenche, Mathilde Sibony, Estelle Louiset, Wiebke Arlt, Charlotte Waintrop, Rossella Libé, Eric Clauser, Lionel Groussin, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU), Neuroendocrinologie cellulaire et moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM), La grossesse normale et pathologique: développement et fonctions du placenta et de l'utérus (UMR_S 767), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Université Paris Descartes - Paris 5 (UPD5)-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)-Centre National de la Recherche Scientifique (CNRS), CHU Cochin [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: Male, MESH: Adrenal Hyperplasia, Congenital, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Late onset, Context (language use), MESH: Adrenal Cortex Neoplasms, Biochemistry, MESH: Adrenocortical Carcinoma, Endocrinology, Internal medicine, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Adrenocortical Carcinoma, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Adrenocortical carcinoma, Feminization, MESH: Feminization, ComputingMilieux_MISCELLANEOUS, Aged, MESH: Age Factors, MESH: Aged, MESH: Humans, Adrenal Hyperplasia, Congenital, Biochemistry (medical), Age Factors, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Adrenal Cortex Neoplasms, MESH: Male, 3. Good health, Gynecomastia, MESH: Gynecomastia
Abstract: French COMETE Network (R.L.), 75014 Paris, France; Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine (W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom; INSERM U982 (E.L.), Differenciation & Communication Neuronale & Neuroendocrine, Universite de Rouen, 76821 Mont-Saint-Aignan, France; Departments of Endocrinology (C.W., L.G.), Hormonal Biology (J.G.), Pathology (M.S.), and Oncogenetics (E.C.), Hopital Cochin, Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France; and INSERM U1016 (L.G.), Institut Cochin, 75014 Paris, France
Published: 2014
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7. Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe d'etude des Tumeurs Endocrines (GTE) cohort study

Author: Bruno Vergès, Albert Beckers, Brigitte Delemer, Vincent Rohmer, Arnaud Murat, Jean-Marc Kuhn, Philippe Ruszniewski, Christine Binquet, Julien Thevenon, Philippe Caron, Georges Weryha, Michel Rodier, Sophie Giraud, F. Archambeaud, I. Guilhem, Morgane Le Bras, Philippe Chanson, Béatrice Parfait, Jean-Louis Sadoul, Lionel Groussin, Patricia Niccoli, Catherine Cardot-Bauters, Philippe Bouchard, Eric Baudin, Françoise Duron, Michel Renard, Hélène Bihan, Véronique Kerlan, P. Lecomte, Catherine Lombard-Bohas, Abderrahmane Bourredjem, Anne Barlier, Emilie Castermans, Françoise Borson-Chazot, Bernard Goichot, Olivier Chabre, Antoine Tabarin, Alain Calender, Laurence Faivre, Hélène Du Boullay, Pierre Goudet, Eric Clauser, Alfred Penfornis, Marie-Françoise Odou, Université Joseph Fourier - Grenoble 1 ( UJF ), Immunovirologie et polymorphisme génétique, Université de Nantes ( UN ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de médecine nucléaire, Fédération d'endocrinologie-Groupement hospitalier Lyon-Est, Centre de recherche en neurobiologie - neurophysiologie de Marseille ( CRN2M ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ), Service d'Endocrinologie ( BORDEAUX - Endocrino ), CHU Bordeaux [Bordeaux], Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux ( Inserm U745 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Biologie du Cancer et de l'Infection ( BCI - UMR S1036 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Grenoble Alpes ( UGA ), Service d'Endocrinologie ( LIEGE - Endocrino ), Université de Liège, Department of Gastroenterology, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Beaujon, Pathologie et virologie moléculaire ( PVM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'Endocrinologie - Diabète - Nutrition [Reims], Université de Reims Champagne-Ardenne ( URCA ) -Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims ( CHU Reims ), Laboratoire Microorganismes : Génome et Environnement ( LMGE ), Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Universitaire [Rennes], Service d'Endocrinologie ( ANGERS - Endocrino ), CHU Angers, Département de Médecine Interne et Nutrition, CHU Strasbourg, Service d'Endocrinologie ( TOULOUSE - Endocrino ), CHU Toulouse [Toulouse], Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Université Paris-Sud - Paris 11 ( UP11 ) -IFR93-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ), Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Service d'Endocrinologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Service d'Endocrinologie ( TOURS - Endocrino ), CHRU Tours, Service de diabétologie - endocrinologie, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( PCVP / CARDIO ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Conservatoire National des Arts et Métiers - Paris ( CNAM Paris ), Conservatoire National des Arts et Métiers [CNAM] ( CNAM ), Unité de Recherche en Epidémiologie Nutritionnelle ( UREN ), Institut National de la Recherche Agronomique ( INRA ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Médecine interne B, Endocrinologie, Diabète, Maladies métaboliques [CHU Limoges], CHU Limoges, Groupe d'Etude de la Thrombose de Bretagne Occidentale ( GETBO ), Université de Brest ( UBO ), Service d'Endocrinologie ( CHRU - Endocrino ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Service de Diabétologie, Service des maladies métaboliques et endocriniennes, Hôpital Universitaire Carémeau [Nîmes], Service d'Endocrinologie ( NICE - Endocrino ), CHU Nice, Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ) -Centre National de la Recherche Scientifique ( CNRS ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( EA 3920) ( PCVP / CARDIO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ) -Université Bourgogne Franche-Comté [COMUE] ( UBFC ), Université Joseph Fourier - Grenoble 1 (UJF), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Service d'Endocrinologie (BORDEAUX - Endocrino), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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 Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Endocrinologie (LIEGE - Endocrino), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pathologie et virologie moléculaire (PVM (UMR_7151)), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université de Reims Champagne-Ardenne (URCA)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Université d'Auvergne - Clermont-Ferrand I (UdA), Service d'Endocrinologie (ANGERS - Endocrino), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service d'Endocrinologie (TOULOUSE - Endocrino), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Endocrinologie (TOURS - Endocrino), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Diabétologie - Endocrinologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( EA 3920) (PCVP / CARDIO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Service d'Endocrinologie (CHRU - Endocrino), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service d'Endocrinologie (NICE - Endocrino), Centre Hospitalier Universitaire de Nice (CHU Nice), Université de Nantes (UN), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Beaujon, Pathologie et virologie moléculaire (PVM), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université de Brest (UBO), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Fédération d'endocrinologie, Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Centre National de la Recherche Scientifique (CNRS), Service Endocrinologie, maladies métaboliques et nutrition [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( UR 3920) (PCVP / CARDIO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO)
Subjects: Oncology, Male, endocrine system diseases, Proto-Oncogene Proteins c-jun, [SDV]Life Sciences [q-bio], Disease, medicine.disease_cause, MESH: Protein Structure, Tertiary, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, MESH : Female, Genetics (clinical), Mutation, General Medicine, MESH: Follow-Up Studies, MESH : Risk Factors, 3. Good health, 030220 oncology & carcinogenesis, Cohort, MESH : Proto-Oncogene Proteins, Female, MESH : Mutation, MESH : Protein Structure, Tertiary, MESH : Proto-Oncogene Proteins c-jun, MESH : Multiple Endocrine Neoplasia Type 1, Cohort study, medicine.medical_specialty, endocrine system, MESH: Mutation, Genetic counseling, MESH : Male, MESH: Multiple Endocrine Neoplasia Type 1, 030209 endocrinology & metabolism, Biology, 03 medical and health sciences, Internal medicine, Proto-Oncogene Proteins, Genetics, medicine, Multiple Endocrine Neoplasia Type 1, Humans, MEN1, Family, Molecular Biology, MESH: Family, MESH: Humans, MESH: Proto-Oncogene Proteins c-jun, [ SDV ] Life Sciences [q-bio], Proportional hazards model, MESH : Humans, Cancer, MESH : Follow-Up Studies, medicine.disease, MESH: Male, Protein Structure, Tertiary, MESH: Proto-Oncogene Proteins, Cancer research, MESH : Family, MESH: Female, Follow-Up Studies
Abstract: International audience; Multiple endocrine neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Although genotype-phenotype studies have so far failed to identify any statistical correlations, some families harbor recurrent tumor patterns. The function of MENIN is unclear, but has been described through the discovery of its interacting partners. Mutations in the interacting domains of MENIN functional partners have been shown to directly alter its regulation abilities. We report on a cohort of MEN1 patients from the Groupe d'étude des Tumeurs Endocrines. Patients with a molecular diagnosis and a clinical follow-up, totaling 262 families and 806 patients, were included. Associations between mutation type, location or interacting factors of the MENIN protein and death as well as the occurrence of MEN1-related tumors were tested using a frailty Cox model to adjust for potential heterogeneity across families. Accounting for the heterogeneity across families, the overall risk of death was significantly higher when mutations affected the JunD interacting domain (adjusted HR = 1.88: 95%-CI = 1.15-3.07). Patients had a higher risk of death from cancers of the MEN1 spectrum (HR = 2.34; 95%-CI = 1.23-4.43). This genotype-phenotype correlation study confirmed the lack of direct genotype-phenotype correlations. However, patients with mutations affecting the JunD interacting domain had a higher risk of death secondary to a MEN1 tumor and should thus be considered for surgical indications, genetic counseling and follow-up.
Published: 2013
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8. Systematic Analysis of G Protein-Coupled Receptor Gene Expression in Adrenocorticotropin-Independent Macronodular Adrenocortical Hyperplasia Identifies Novel Targets for Pharmacological Control of Adrenal Cushing’s Syndrome

Author: Guillaume Assié, Hervé Lefebvre, Jérôme Bertherat, Nathalie Sturm, Eric Clauser, Jean-Jacques Feige, Fernande René-Corail, Michaël Thomas, Lionel Groussin, Estelle Louiset, Olivier Chabre, Nadia Cherradi, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Angiogenèse hormono-regulée et angiogenèse tumorale (LAPV), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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 Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Cochin [AP-HP], Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: Cortisol secretion, medicine.medical_specialty, Adenoma, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Gene Expression, Context (language use), 030209 endocrinology & metabolism, Biology, Biochemistry, Clonidine, G Protein-Coupled Receptor Gene, Receptors, G-Protein-Coupled, [SHS]Humanities and Social Sciences, 03 medical and health sciences, Translational Highlights from Jcem, Drug Delivery Systems, 0302 clinical medicine, Endocrinology, Adrenocorticotropic Hormone, Receptors, Adrenergic, alpha-2, Internal medicine, Adrenergic alpha-2 Receptor Agonists, medicine, Humans, Pituitary Neoplasms, Cushing Syndrome, Molecular Biology, Antihypertensive Agents, Cells, Cultured, Oligonucleotide Array Sequence Analysis, Hydrocortisone, G protein-coupled receptor, 030304 developmental biology, 0303 health sciences, Hyperplasia, 030219 obstetrics & reproductive medicine, Gene Expression Profiling, Biochemistry (medical), General Medicine, medicine.disease, 3. Good health, Gene expression profiling, ACTH-Secreting Pituitary Adenoma, Macronodular Adrenal Hyperplasia, Adrenal Cortex, hormones, hormone substitutes, and hormone antagonists, medicine.drug
Abstract: Stimulation of cortisol secretion through abnormally expressed G protein-coupled receptors (GPCRs) is a frequent feature of ACTH-independent macronodular adrenal hyperplasia (AIMAH). This has opened a pharmacological strategy that targets GPCRs for the treatment of Cushing's syndrome in AIMAH. However, only few drugs are available for the presently described GPCRs.The objective of the study was to identify new GPCR targets for the pharmacological treatment of adrenal Cushing's syndrome.We designed a cDNA chip containing 865 nucleotidic sequences of GPCRs. mRNAs were extracted from three normal adrenals, 18 AIMAHs, four adrenals from Cushing's disease patients, and 13 cortisol-secreting adenomas. A set of GPCR mRNAs that showed significantly higher or lower expression in AIMAH than in normal adrenal were studied by quantitative RT-PCR analysis. Analysis of protein expression and function were performed on selected GPCRs.The study was conducted at a tertiary care center and basic research laboratories.The ACTH MC2 receptor showed a low expression in 15 of 18 AIMAHs samples, whereas several previously undescribed GPCR genes were found highly expressed in a subset of AIMAH, such as the receptors for motilin (MLNR; three of 18 AIMAHs) and γ-aminobutyric acid (GABBR1; five of 18 AIMAHs), and the α2A adrenergic receptor (ADRA2A; 13 of 18 AIMAHs), on which we focused our attention. Western blot and immunochemistry analyses showed expression of ADRA2A protein in AIMAH but not in normal adrenal cortex. The ADRA2A agonist clonidine enhanced both basal and stimulated cortisol production. Clonidine-induced increase in basal cortisol levels was blocked by the ADRA2A antagonist yohimbine.ADRA2A is a potential target for pharmacological treatment of Cushing's syndrome linked to AIMAH.
Published: 2010
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9. ACTH-Independent Cushing’s Syndrome with Bilateral Micronodular Adrenal Hyperplasia and Ectopic Adrenocortical Adenoma

Author: Estelle Louiset, Eric Clauser, Jean-Marc Kuhn, Philippe Grise, Françoise Gobet, Juliette Cariou, Constantine A. Stratakis, Hervé Lefebvre, Jérôme Bertherat, Anya Rothenbuhler, Anelia Horvath, Rossella Libé, Sylvie Renouf, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), CHU Cochin [AP-HP], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Université Paris Descartes - Paris 5 (UPD5)-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)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Service d'endocrinologie pédiatrique [CHU Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Section on Endocrinology and Genetics, National Institutes of Health (NIH)-National Institute of Child Health and Human Development, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Physiologie et Toxicologie Expérimentales, Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and 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)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Pathology, medicine.medical_specialty, endocrine system, Adenoma, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, education, Drug Resistance, 030209 endocrinology & metabolism, Adrenocorticotropic hormone, Choristoma, Clinical Case Seminar, Biochemistry, Adrenocortical adenoma, 03 medical and health sciences, Cushing syndrome, 0302 clinical medicine, Endocrinology, Adrenocorticotropic Hormone, Internal medicine, Adrenal Glands, medicine, Humans, Conn Syndrome, Cushing Syndrome, Hyperplasia, business.industry, Adrenal cortex, Biochemistry (medical), Adrenal Cortex Neoplasm, medicine.disease, Adrenal Cortex Neoplasms, 3. Good health, Radiography, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Adrenocortical Adenoma, Female, Kidney Diseases, business, hormones, hormone substitutes, and hormone antagonists
Abstract: Bilateral micronodular adrenal hyperplasia and ectopic adrenocortical adenoma are two rare causes of ACTH-independent Cushing's syndrome.The aim of the study was to evaluate a 35-yr-old woman with ACTH-independent hypercortisolism associated with both micronodular adrenal hyperplasia and ectopic pararenal adrenocortical adenoma.In vivo and in vitro studies were performed in a University Hospital Department and academic research laboratories.Mutations of the PRKAR1A, PDE8B, and PDE11A genes were searched for in leukocytes and adrenocortical tissues. The ability of adrenal and adenoma tissues to synthesize cortisol was investigated by immunohistochemistry, quantitative PCR, and/or cell culture studies.Detection of 17alpha-hydroxylase and 21-hydroxylase immunoreactivities, quantification of CYP11B1 mRNA in adrenal and adenoma tissues, and measurement of cortisol levels in supernatants by radioimmunological assays were the main outcomes.Histological examination of the adrenals revealed nonpigmented micronodular cortical hyperplasia associated with relative atrophy of internodular cortex. No genomic and/or somatic adrenal mutations of the PRKAR1A, PDE8B, and PDE11A genes were detected. 17alpha-Hydroxylase and 21-hydroxylase immunoreactivities as well as CYP11B1 mRNA were detected in adrenal and adenoma tissues. ACTH and dexamethasone activated cortisol secretion from adenoma cells. The stimulatory action of dexamethasone was mediated by a nongenomic effect involving the protein kinase A pathway.This case suggests that unknown molecular defects can favor both micronodular adrenal hyperplasia and ectopic adrenocortical adenoma associated with Cushing's syndrome.
Published: 2010
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10. Sheep 5HT2A receptors: partial cloning of the coding sequence and mRNA localization by in situ hybridization in the ewe hypothalamus

Author: Colette Auzan, Eric Clauser, Philippe Chemineau, J. Pelletier, A. Daveau, Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), ProdInra, Migration, and Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Histology, Mammillary body, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Hypothalamus, In situ hybridization, [INFO] Computer Science [cs], Biology, Pathology and Forensic Medicine, LOCALISATION, 03 medical and health sciences, 0302 clinical medicine, Complementary DNA, Animals, Humans, Receptor, Serotonin, 5-HT2A, [INFO]Computer Science [cs], RNA, Messenger, Cloning, Molecular, In Situ Hybridization, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cloning, 0303 health sciences, Sheep, Base Sequence, Nucleic acid sequence, Sequence Analysis, DNA, Cell Biology, Molecular biology, Rats, [SDV] Life Sciences [q-bio], Receptors, Serotonin, Median eminence, Pars tuberalis, Partial cloning, 030217 neurology & neurosurgery
Abstract: Serotonin and serotonin receptors of class II (5HT2-R) are thought to be involved in the neural mechanisms which regulate the LH release associated with photoperiodic changes in sheep. A specific premammillary hypothalamic area displaying a significant binding of 3H-ketanserin, a potent 5HT2-R antagonist, was previously identified. The aim of the present study was to ascertain by in situ hybridization (ISH) that 5HT2-R mRNA-containing cells were also present in this specific hypothalamic area. Total RNA was prepared from sheep pars tuberalis/median eminence, and a cDNA fragment of 546 bp was amplified by reverse transcriptase polymerase chain reaction (RT-PCR) using degenerated primers deduced from the human and rat 5HT2A-R sequences. After cloning and sequencing, the sheep nucleotide sequence had the highest homology (85.1-92.3%) with the other known mammalian 5HT2-R or 5HT2A-R sequences. Homology with other 5HT-R subtypes or other monoamine receptors was much lower, 60% at maximum. After ISH using sense and antisense 35S-riboprobes, specific labelling was found in different parts of the hypothalamus, especially in the mammillary bodies where the binding was higher. Within the hypothalamus, the density of labelled cells, mainly neurons, varied considerably. It was maximal in the mammillary bodies and also in a restricted ventral region of the premammillary hypothalamus located from about 500/700 micrometer to 1200/1400 micrometer in front of the mammillary recess, where 3H-ketanserin binding was previously reported.(1) the structural study of the sequence indicated that the new cloned cDNA corresponds to the sheep 5HT2-R class and, probably, to the 5HT2A-R subtype and (2) the ISH studies revealed that a restricted area of the premammillary hypothalamus shows a large number of 5HT2-R mRNA-containing neurons.
Published: 1999

11. The pituitary V3 vasopressin receptor and the corticotroph phenotype in ectopic ACTH syndrome

Author: S. Jegou, Xavier Bertagna, P René, Jean-Pierre Luton, Colette Auzan, F Lenne, Hubert Vaudry, Y de Keyzer, Jean-Marc Kuhn, and Eric Clauser
Subjects: Adenoma, medicine.medical_specialty, endocrine system, Receptors, Vasopressin, Pro-Opiomelanocortin, Molecular Sequence Data, Carcinoid Tumor, Biology, Pituitary neoplasm, Receptors, Corticotropin-Releasing Hormone, Proopiomelanocortin, Internal medicine, medicine, Humans, ACTH receptor, Pituitary Neoplasms, RNA, Messenger, Vasopressin receptor, Arginine vasopressin receptor 1B, Base Sequence, Pituitary tumors, Bronchial Neoplasms, General Medicine, medicine.disease, ACTH Syndrome, Ectopic, Endocrinology, Phenotype, biology.protein, Corticotropic cell, hormones, hormone substitutes, and hormone antagonists, Research Article
Abstract: Ectopic ACTH secretion occurs in highly differentiated and rather indolent tumors like bronchial carcinoids or, in contrast, in various types of aggressive and poorly differentiated neuroendocrine tumors. We explored this phenomenon using the recently cloned human pituitary V3 vasopressin receptor as an alternate molecular marker of the corticotroph phenotype. Expression of V3 receptor, corticotrophin releasing hormone (CRH) receptor, and proopiomelanocortin (POMC) genes was examined in tumors of pituitary and nonpituitary origin. A comparative RT-PCR approach revealed signals for both V3 receptor and CHR receptor mRNAs in 17 of 18 ACTH-secreting pituitary adenomas, and 6 of 6 normal pituitaries; in six growth hormone- or prolactin-secreting adenomas, a very faint V3 receptor signal was observed in three cases, and CRH receptor signal was undetected in all. Six of eight bronchial carcinoids responsible for the ectopic ACTH syndrome had both POMC and V3 receptor signals as high as those in ACTH-secreting pituitary adenomas; in contrast, no POMC signal and only a very faint V3 receptor signal were detected in six of eight nonsecreting bronchial carcinoids. Northern blot analysis showed V3 receptor mRNA of identical size in ACTH-secreting bronchial carcinoids and pituitary tumors. Other types of nonpituitary tumors responsible for ectopic ACTH syndrome presented much lower levels of both POMC and V3 receptor gene expression than those found in ACTH-secreting bronchial carcinoids. In contrast with the V3 receptor, CRH receptor mRNA was detected in the majority of neuroendocrine tumors irrespective of their POMC status. These results show that expression of the V3 receptor gene participates in the corticotroph phenotype. Its striking association with ACTH-secreting bronchial carcinoids defines a subset of nonpituitary tumors in which ectopic POMC gene expression is but one aspect of a wider process of corticotroph cell differentiation, and opens new possibilities of pharmacological investigations and even manipulations of this peculiar ACTH hypersecretory syndrome.
Published: 1996

12. Dinucleotide repeat polymorphism in the human angiotensinogen gene

Author: Eric Clauser, Yu.V. Kotelevtsev, Florent Soubrier, and Pierre Corvol
Subjects: Genetics, Polymorphism, Genetic, Base Sequence, Molecular Sequence Data, Angiotensinogen, Biology, Dinucleotide Repeat, Molecular biology, Polymerase Chain Reaction, White People, law.invention, Gene mapping, Genetic marker, law, Chromosomes, Human, Pair 1, Angiotensinogen gene, Humans, Restriction fragment length polymorphism, Allele, Allele frequency, Polymerase chain reaction, Alleles, Repetitive Sequences, Nucleic Acid
Published: 1991

13. Internalization of the rat AT1a and AT1b receptors: pharmacological and functional requirements

Author: Eric Clauser, Catherine Monnot, Pierre Corvol, Betty Teutsch, and Sophie Conchon
Subjects: Agonist, medicine.medical_specialty, Angiotensin receptor, medicine.drug_class, media_common.quotation_subject, education, Biophysics, Tetrazoles, CHO Cells, Biology, Biochemistry, Losartan, Angiotensin Receptor Antagonists, Structural Biology, Internal medicine, Cricetinae, Genetics, medicine, Animals, Internalization, Receptor, Molecular Biology, media_common, G protein-coupled receptor, Angiotensin II receptor type 1, Receptors, Angiotensin, Dose-Response Relationship, Drug, Angiotensin II, Biphenyl Compounds, Antagonist, Imidazoles, Biological Transport, Cell Biology, Recombinant Proteins, Cell biology, Rats, Endocrinology, G-protein coupled receptor, hormones, hormone substitutes, and hormone antagonists
Abstract: The capacity of the angiotensin II (AngII) agonist [Sar1]AngII, the antagonist [Sar1-I1e8]AngII and the non-peptidic antagonist DuP753 to undergo receptor internalization were studied in Chinese hamster ovary cells expressing rat AngII type 1a or 1b receptors (AT1a or AT1b) or a mutant of AT1a (Asn74) unable to couple G-protein. In this expression system, the ligand-induced internalization of rat AT1a and AT1b are similar. Moreover, peptidic ligands, either the agonist or antagonist, induce a significant internalization of AT1 receptors, but the non-peptidic antagonist DuP753 is far less potent. Finally, the normal internalization of the mutant Asn74 demonstrates that receptor activation and G-protein coupling are not required for AT1ainternalization.
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14. Expression and characterization of recombinant human angiotensinogen in a heterologous eukaryotic cell line

Author: Pierre Corvol, Isabelle Gaillard, Lei Wei, Eric Clauser, Baracco, Chantal, and Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: endocrine system, [SDV]Life Sciences [q-bio], Biophysics, Angiotensinogen, Biology, Transfection, Biochemistry, law.invention, Cell Line, 03 medical and health sciences, Structure-Activity Relationship, Cricetulus, law, Complementary DNA, Cricetinae, Renin–angiotensin system, Animals, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, [SDV.BV] Life Sciences [q-bio]/Vegetal Biology, cardiovascular diseases, Molecular Biology, Chromatography, High Pressure Liquid, 030304 developmental biology, Gel electrophoresis, 0303 health sciences, Expression vector, urogenital system, Chinese hamster ovary cell, 030302 biochemistry & molecular biology, Cell Biology, DNA, Molecular biology, Recombinant Proteins, [SDV] Life Sciences [q-bio], Cell culture, Recombinant DNA, Female, hormones, hormone substitutes, and hormone antagonists, Plasmids, circulatory and respiratory physiology
Abstract: Transfection of Chinese hamster ovary cells with an expression plasmid containing a full length human angiotensinogen cDNA has provided cell lines that secrete recombinant angiotensinogen in large quantities. This angiotensinogen is immunologically identical to plasma angiotensinogen and can be cleaved by human kidney renin (EC 3.4.23.15.). The peptide liberated by renin cleavage is immunologically identical to standard angiotensin I and shows a retention time on isocratic reversed-phase high-pressure liquid chromatography identical to that of standard angiotensin I. The heterogeneity of recombinant angiotensinogen on sodium dodecyl sulfate-polyacrylamide gel electrophoresis differs from that of plasma angiotensinogen. Treatment with endoglycosidases demonstrated that this difference is restricted to that of N-glycans and that N-glycans correspond to the quasi-totality of the carbohydrate content of both recombinant and plasma angiotensinogens. The development of a system capable of expressing human angiotensinogen cDNA in mammalian cells and the ability to obtain the corresponding angiotensinogen in large quantities will allow new studies on structure-function relationships of this protein.
Published: 1988
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15. Replacement of insulin receptor tyrosine residues 1162 and 1163 does not alter the mitogenic effect of the hormone

Author: Gilles Ponzio, Chantal Filloux, Eric Clauser, Bernard Rossi, Colette Auzan, Jean-Olivier Contreres, and A Debant
Subjects: DNA Replication, Multidisciplinary, biology, Chinese hamster ovary cell, GRB10, Ribosomal Protein S6 Kinases, Deoxyglucose, IRS2, Receptor tyrosine kinase, Receptor, Insulin, Cell Line, Insulin receptor, Biochemistry, Solubility, Insulin receptor substrate, Cricetinae, ROR1, biology.protein, Animals, Tyrosine, Tyrosine kinase, Protein Kinases, Research Article
Abstract: Chinese hamster ovary transfectants that express insulin receptors in which tyrosine residues 1162 and 1163 were replaced by phenylalanine exhibit a total inhibition of the insulin-mediated tyrosine kinase activity toward exogenous substrates [histone, casein, and poly(Glu/Tyr)]; this latter activity is associated with total inhibition of the hypersensitivity reported for insulin in promoting 2-deoxyglucose uptake. We now present evidence that the twin tyrosines also control the insulin-mediated stimulation of glycogen synthesis. Surprisingly, this type of Chinese hamster ovary transfectant is as hypersensitive to insulin for its mitogenic effect as are Chinese hamster ovary cells expressing many intact insulin receptors. Such data suggest that (i) the insulin mitogenic effect routes through a different pathway than insulin uses to activate the transport and metabolism of glucose and (ii) the mitogenic effect of insulin is not controlled by the twin tyrosines. At the molecular level, the solubilized mutated receptor has no insulin-dependent tyrosine kinase activity, whereas this receptor displays measurable insulin-stimulated phosphorylation of its beta subunit in 32P-labeled cells. We therefore propose that the autocatalytic phosphorylating activity of the receptor reports a cryptic tyrosine kinase activity that cannot be visualized by the use of classical exogenous substrates.
Published: 1988

16. K011 Effet d’un gain de fonction du récepteur AT1a sur la régulation cardiovasculaire des souris mutées

Author: Véronique Baudrie, Eric Clauser, Dominique Laude, C. Petrel, Jean-Luc Elghozi, and K. Palma Rigo
Subjects: business.industry, Medicine, General Medicine, Cardiology and Cardiovascular Medicine, business, Molecular biology
Abstract: Cette etude est realisee chez des souris knock-in qui expriment un gain de fonction du recepteur AT1A de l’angiotensine II (AngII). Des resultats preliminaires ont montre que ces animaux mutants (AT1AMUT) avaient une elevation modere et permanente de la pression arterielle (PA) (+ 20mmHg) associee a une prolongation des effets presseurs de l’AngII (Billet et al. J Clin Invest 2007, 117 : 1914-1925). L’objectif de ce travail est de caracteriser au plan fonctionnel cardio-vasculaire les souris mutees. La PA est mesuree en continu par telemetrie durant 48 heures chez 5 mâles sauvages (AT1AWT) et 5 mâles mutes. L’intervalle entre deux battements cardiaques (intervalle pulse, IP) est converti en frequence cardiaque (FC). Les variabilites de la PA systolique (PAS) et de l’IP sont etudiees par l’analyse spectrale. La sensibilite du baroreflexe spontane est exprimee par le gain de la fonction de transfert entre la PAS et l’IP. La double mutation induit le jour comme la nuit une augmentation de la PAS et une augmentation de la FC (PAS jour : AT1AMUT 127.9 ± 5.9, AT1AWT 104.9 ± 5.4 mmHg ; PAS nuit AT1AMUT 141.4 ± 6.1, AT1AWT 115.2 ± 6.6 mmHg ; FC jour : AT1AMUT 481.3 ± 18.4, AT1AWT 409.7 ± 6.0 bat/min ; FC nuit AT1AMUT 551.1 ± 14.9, AT1AWT 467.6 ± 5.9 bat/min). L’activite motrice des souris n’est pas modifiee par la mutation. L’AT1AMUT presente une augmentation significative de la variabilite de PAS la nuit qui n’est pas observee chez l’AT1AWT. La variabilite de IP est significativement reduite par la mutation le jour. Le Gain des zones LF et de HF est significativement reduit chez AT1AMUT, le jour et la nuit. Cette double mutation, associee a un gain de fonction du recepteur AT1A, induit ainsi une elevation de la PA accompagnee d’une diminution de la sensibilite du baroreflexe spontane. L’elevation tensionnelle pourrait resulter d’un mecanisme peripherique, avec une vasoconstriction liee a l’activation du recepteur AT1A, ou d’un mecanisme central : inhibition du baroreflexe par une activation des recepteurs AT1A cerebraux. L’AngII est en effet connue pour inhiber le baroreflexe, ce qui pourrait induire une activation sympathique elevant la PA. * Projet soutenu par l’attribution d’une Allocation Doctorale Region Ile-de-France.
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16 results on '"Eric, Clauser"'

1. IGF2 promotes growth of adrenocortical carcinoma cells, but its overexpression does not modify phenotypic and molecular features of adrenocortical carcinoma.

2. TREM-1 orchestrates angiotensin II–induced monocyte trafficking and promotes experimental abdominal aortic aneurysm

3. Aldosterone-Producing Adenoma With a Somatic KCNJ5 Mutation Revealing APC-Dependent Familial Adenomatous Polyposis

4. Unraveling the intrafamilial correlations and heritability of tumor types in MEN1: a Groupe d'étude des Tumeurs Endocrines study

5. IGF2 Promotes Growth of Adrenocortical Carcinoma Cells, but Its Overexpression Does Not Modify Phenotypic and Molecular Features of Adrenocortical Carcinoma

6. A Feminizing Adrenocortical Carcinoma in the Context of a Late Onset 21-Hydroxylase Deficiency

7. Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe d'etude des Tumeurs Endocrines (GTE) cohort study

8. Systematic Analysis of G Protein-Coupled Receptor Gene Expression in Adrenocorticotropin-Independent Macronodular Adrenocortical Hyperplasia Identifies Novel Targets for Pharmacological Control of Adrenal Cushing’s Syndrome

9. ACTH-Independent Cushing’s Syndrome with Bilateral Micronodular Adrenal Hyperplasia and Ectopic Adrenocortical Adenoma

10. Sheep 5HT2A receptors: partial cloning of the coding sequence and mRNA localization by in situ hybridization in the ewe hypothalamus

11. The pituitary V3 vasopressin receptor and the corticotroph phenotype in ectopic ACTH syndrome

12. Dinucleotide repeat polymorphism in the human angiotensinogen gene

13. Internalization of the rat AT1a and AT1b receptors: pharmacological and functional requirements

14. Expression and characterization of recombinant human angiotensinogen in a heterologous eukaryotic cell line

15. Replacement of insulin receptor tyrosine residues 1162 and 1163 does not alter the mitogenic effect of the hormone

16. K011 Effet d’un gain de fonction du récepteur AT1a sur la régulation cardiovasculaire des souris mutées

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16 results on '"Eric, Clauser"'

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