Author: "Betty Gardie" / Topic: biology - Searchworks@Jio Institute Digital Library Search Results

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1. Involvement of PBRM1 in VHL disease‑associated clear cell renal cell carcinoma and its putative relationship with the HIF pathway

Author: Virginie Verkarre, Sophie Couvé, Guillaume Meurice, Betty Gardie, Bin Tean Teh, Baptiste Nguyen, Flore Renaud, Stéphane Richard, Sophie Ferlicot, Bastien Job, Melanie Da Costa, Benjamin Grandon, Véronique Duchatelle, Nathalie Droin, Sophie Gad, Vincent Molinié, Katia Posseme, Gwénaël Le Teuff, and Arnaud Mejean
Subjects: polybromo 1 somatic mutation, BAF180, Cancer Research, endocrine system diseases, Tumor suppressor gene, Oncogene, Cancer, von Hippel-Lindau disease, Articles, clear cell renal cell carcinoma, Biology, urologic and male genital diseases, medicine.disease, female genital diseases and pregnancy complications, PBRM1, Clear cell renal cell carcinoma, Von Hippel-Lindau germline mutation, Germline mutation, Oncology, Hypoxia-inducible factors, medicine, Cancer research, hypoxia inducible factor 1, hypoxia inducible factor 2, Von Hippel–Lindau disease
Abstract: Von Hippel-Lindau (VHL) disease is the main cause of inherited clear-cell renal cell carcinoma (ccRCC) and is caused by germline mutations in the VHL tumor suppressor gene. Bi-allelic VHL alterations lead to inactivation of pVHL, which plays a major role by downstream activation of the hypoxia inducible factor (HIF) pathway. Somatic VHL mutations occur in 80% of sporadic ccRCC cases and the second most frequently mutated gene is polybromo 1 (PBRM1). As there is currently no data regarding PBRM1 involvement in VHL disease-associated ccRCC, the aim of the present study was to assess the PBRM1 mutational status, and PBRM1 and HIF expression in VHL disease-associated ccRCC series compared with a sporadic series. PBRM1 gene was screened by Sanger sequencing for 23 VHL-disease-associated ccRCC and 22 sporadic ccRCC cases. Immunohistochemical studies were performed to detect the expression of PBRM1, HIF1 and HIF2 for all cases. In VHL-associated tumors, 13.0% (n=3/23) had PBRM1 somatic mutations and 17.4% (n=4/23) had a loss of PBRM1 nuclear expression. In sporadic cases, 27.3% (n=6/22) showed PBRM1 somatic mutations and 45.5% (n=10/22) had a loss of PBRM1 nuclear expression. Loss of PBRM1 was associated with an advanced tumor stage. HIF1-positive tumors were observed more frequently in the VHL-associated ccRCC than in the sporadic series. Furthermore, in the VHL cohort, PBRM1 expression appeared to be associated more with HIF1 than with HIF2. Given that hereditary tumors tend to be less aggressive, these results would suggest that co-expression of PBRM1 and HIF1 may have a less oncogenic role in VHL-associated ccRCC.
Published: 2021
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2. Germline mutation in the NBR1 gene involved in autophagy detected in a family with renal tumors

Author: Katia Posseme, Sophie Giraud, Pauline Garnier, Bastien Job, Sophie Gad, Betty Gardie, Brigitte Bressac-de Paillerets, Stéphane Richard, Flore Renaud, Nathalie Droin, Virginie Verkarre, Florine Adolphe, Sophie Ferlicot, Marc Deloger, and Sophie Couvé
Subjects: Adult, Male, Cancer Research, Cell, Biology, urologic and male genital diseases, medicine.disease_cause, Germline, Frameshift mutation, Germline mutation, Genetics, medicine, Autophagy, Humans, Genetic Predisposition to Disease, Folliculin, Molecular Biology, Gene, Carcinoma, Renal Cell, Exome sequencing, Germ-Line Mutation, Aged, Mutation, Intracellular Signaling Peptides and Proteins, Middle Aged, Prognosis, female genital diseases and pregnancy complications, Kidney Neoplasms, Pedigree, medicine.anatomical_structure, Cancer research, Female, Follow-Up Studies
Abstract: Hereditary Renal Cell Carcinomas (RCC) are caused by mutations in predisposing genes, the major ones including VHL, FLCN, FH and MET. However, many families with inherited RCC have no germline mutation in these genes. Using Whole Exome Sequencing on germline DNA from a family presenting three different histological renal tumors (an angiomyolipoma, a clear-cell RCC and an oncocytic papillary RCC), we identified a frameshift mutation in the Neighbor of BRCA1 gene 1 (NBR1), segregating with the tumors. NBR1 encodes a cargo receptor protein involved in autophagy. Genetic and functional analyses suggested a pathogenic impact of the mutation. Indeed, functional study performed in renal cell lines showed that the mutation alters NBR1 interactions with some of its partners (such as p62/SQSTM1), leading to a dominant negative effect. This results in an altered autophagic process and an increased proliferative capacity in renal cell lines. Our study suggests that NBR1 may be a new predisposing gene for RCC, however its characterization needs to be further investigated in order to confirm its role in renal carcinogenesis.
Published: 2020

3. Absence of CALR Mutations in Idiopathic Erythrocytosis Patients with Low Serum Erythropoietin Levels

Author: Mary Frances McMullin, Amy Graham, François Girodon, Sophie Laird, Betty Gardie, Céline Garrec, Robert J. G. Cuthbert, Mark Catherwood, and Nicholas C.P. Cross
Subjects: medicine.medical_specialty, Serum erythropoietin, biology, Erythrocyte indices, business.industry, Hematology, General Medicine, 03 medical and health sciences, Disease susceptibility, 0302 clinical medicine, Endocrinology, Erythropoietin, 030220 oncology & carcinogenesis, Internal medicine, Mutation (genetic algorithm), biology.protein, medicine, Idiopathic erythrocytosis, business, Calreticulin, 030215 immunology, medicine.drug
Published: 2018
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4. Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome

Author: Wallid Deb, Bertrand Cariou, Arnaud Wiedemann, Julien Thevenon, Rhonda E. Schnur, Vincent Ramaekers, Alexandre N. Datta, Richard Redon, Solène Conrad, Natacha Sloboda, Benjamin Cogné, François Feillet, Geneviève Baujat, Bertrand Isidor, Pierre Vabres, Tawfeg Ben-Omran, Marie Vincent, Flora Breheret, Dorothea Wand, Aline Delignières, Laurence Faivre, Betty Gardie, Xavier Balguerie, Anne-Claire Bursztejn, Marion Lenglet, Lionel Van Maldergem, Sébastien Küry, Antonin Lamaziere, Virginie Carmignac, Eva Trochu, Sébastien Barbarot, Marie-Cécile Nassogne, Erin Torti, Yue Si, Paul Kuentz, Thomas Besnard, Jean-Louis Guéant, Alice Goldenberg, Stéphane Bézieau, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie pédiatrique, Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Rouen, Hamad medical corporation, Centre Hospitalier Universitaire de Nancy (CHU Nancy), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Bourgogne Franche-Comté [COMUE] (UBFC), University of Basel (Unibas), Hôpital Bretagne Atlantique, Partenaires INRAE, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Université Catholique de Louvain = Catholic University of Louvain (UCL), Centre Hospitalier Universitaire de Liège (CHU-Liège), Gene Dx, Centre de Génétique, and Hôpital St-Antoine
Subjects: Male, Developmental Disabilities, Intellectual disability, cholesterol pathway, Whole Exome Sequencing, chemistry.chemical_compound, Missense mutation, Age of Onset, Child, Intramolecular Transferases, Genetics (clinical), Exome sequencing, Genetics, Sanger sequencing, 0303 health sciences, biology, Lanosterol, 030305 genetics & heredity, LSS, 3. Good health, Pedigree, Cholesterol, Phenotype, intellectual disability, Child, Preschool, Allelic Imbalance, Congenital cataracts, symbols, Female, Squalene, early-onset epileptic encephalopathy, 03 medical and health sciences, symbols.namesake, Cholesterol pathway, Exome Sequencing, medicine, Humans, 030304 developmental biology, Epilepsy, Infant, Alopecia, alopecia, medicine.disease, Early-onset epileptic encephalopathy, chemistry, Mutation, biology.protein, Hypotrichosis, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Lanosterol synthase
Abstract: International audience; Purpose Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features. Methods Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individuals either by exome sequencing or LSS Sanger sequencing. Splicing defects were assessed by transcript analysis and minigene assay. Results We reported ten APMR individuals from six unrelated families with biallelic variants in LSS. We additionally identified one affected individual with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. Quantification of cholesterol and its precursors did not reveal noticeable imbalance. Conclusion In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol. Our data suggest LSS as a major gene causing a rare recessive neuroectodermal syndrome.
Published: 2019
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5. Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease

Author: Mathias Vilaine, Céline Garrec, Pierre Lindenbaum, Sophie Couvé, Mathilde Pacault, Laurence Heidet, Stéphane Bézieau, Celeste Bento, David Hoogewijs, Helene Dreau, Yannick Arlot-Bonnemains, Nelly Burnichon, Marion Lenglet, Richard van Wijk, Maria-Luigia Randi, Alexandre Buffet, Florence Robriquet, Fabrice Airaud, Holger Cario, Nicolas Janin, Melissa M. Pentony, Erika Kvikstad, Stéphane Richard, Karim Bouchireb, Antonis Kattamis, Jean-Michaël Mazzella, Carme Camps, Sylvie Job, Sophie Ferlicot, Anne Couturier, Richard Redon, Maria Caterina Putti, Thomas Besnard, Joachim R. Göthert, Klaus-Michael Debatin, Betty Gardie, Sophie Deveaux, Franck Chesnel, Solenne Dumont, Jenny C. Taylor, Marine Cornec, Bin Tean Teh, François Girodon, Vincent Bours, Sophie Gad, Anne-Paule Gimenez-Roqueplo, Sabine Irtan, Klaus Schwarz, Elpis Mantadakis, Samantha J. L. Knight, Brigitte Bressac-de Paillerets, Molecular Mechanisms of Chronic Inflammation in Hematological Diseases (CRCINA-ÉQUIPE 16), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Universität Ulm - Ulm University [Ulm, Allemagne], Institute for Clinical Transfusion Medicine and Immunogenetics [Ulm, Germany], German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen, University of Oxford, Oxford NIHR Biomedical Research Centre, 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 ), Université de Fribourg = University of Fribourg (UNIFR), 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), 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), Immunologie intégrative des tumeurs (UMR 1186), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Oxford University Hospitals NHS Trust, Centre de Références Cancers Rares (PREDIR), INCA, Hôpital Bicêtre, Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Hôpitaux Universitaires Paris-Sud Bicêtre (APHP), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker] (MARHEA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neurochirurgie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université Sorbonne Paris Cité (USPC), Democritus University of Thrace (DUTH), Universitätsklinikum Ulm - University Hospital of Ulm, Centre hospitalier universitaire de Nantes (CHU Nantes), Université Paris-Saclay, National Heart Centre Singapore (NHCS), Service d'hématologie biologique [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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, laboratory of Excellence GR-Ex, Paris, France, Università degli Studi di Padova = University of Padua (Unipd), C.H.U. Sart Tilman [Liège], University Medical Center [Utrecht], University Hospital [Essen, Germany], National and Kapodistrian University of Athens (NKUA), Cliniques Universitaires Saint-Luc [Bruxelles], Centro Hospitalar e Universitário [Coimbra], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], 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 ), Zürich Center for Integrative Human Physiology (ZIHP), Universität Zürich [Zürich] = University of Zurich (UZH)-Institute of Physiology, Faculté de Médecine, Université de Ngozi, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), 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), Laboratoire de Génétique Oncologique [Villejuif], École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Department of Medicine, Karolinska Institutet [Stockholm], National Haemoglobinopathy Reference Laboratory, Molecular Haematology, Haemophilia Centre, Churchill Hospital, John Radcliffe Hospital [Oxford University Hospital], Centre Expert National Cancer Rares PREDIR, Service d'Urologie, CHU de Bicêtre, Le Kremlin-Bicêtre, Service Genetique, 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), Service d’Anatomie Cytologie Pathologiques, Hôpital Bicêtre, Assistance Publique - Hôpitaux de Paris (AP-HP), 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), Department of Pediatrics and Adolescent Medicine, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de biologie et pathologie médicales [Gustave Roussy], Van Andel Research Institute, Grand Rapids, Michigan, Van Andel Institute [Grand Rapids], Service d'hématologie biologique (CHU de Dijon), Utrecht University [Utrecht], First Department of Paediatrics, Athens University, Thalassaemia Unit, 'Aghia Sofia' Children's Hospital, Centre Hospitalier Universitaire de Liège (CHU-Liège), SAFRAN Group, Service Génétique, Union nationale des coopératives d’élevage et d’insémination animale (UNCEIA), Rare Adrenal Cancer Network COMETE, CHATEL, Stephanie, University of Fribourg, and UCL - (SLuc) Centre de génétique médicale UCL
Subjects: 0301 basic medicine, Adult, Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Heterozygote, von Hippel-Lindau Disease, Adolescent, endocrine system diseases, Biochemistry, Immunology, Hematology, Cell Biology, RNA Splicing, [SDV]Life Sciences [q-bio], Medizin, Polycythemia, Biology, medicine.disease_cause, urologic and male genital diseases, 03 medical and health sciences, Exon, Young Adult, medicine, Humans, Genetic Predisposition to Disease, Von Hippel–Lindau disease, Child, Gene, neoplasms, Genetics, Mutation, Intron, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Exons, Middle Aged, medicine.disease, Exon skipping, female genital diseases and pregnancy complications, 3. Good health, Pedigree, [SDV] Life Sciences [q-bio], 030104 developmental biology, Von Hippel-Lindau Tumor Suppressor Protein, RNA splicing, Female, Synonymous substitution
Abstract: International audience; Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau (VHL) gene. Since this discovery, additional VHL mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. VHL is a major tumor suppressor gene, mutations in which were first described in patients presenting with von Hippel-Lindau disease, which is characterized by the development of highly vascularized tumors. Here, we identified a new VHL cryptic-exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. More importantly, we identified mutations in E1' in seven families with erythrocytosis (one homozygous case and six compound-heterozygous cases with a mutation in E1' in addition to a mutation in VHL coding sequences) and in one large family with typical VHL disease but without any alteration in the other VHL exons. In this study we have shown that the mutations induced a dysregulation of the VHL splicing with excessive retention of E1' and are associated with a downregulation of VHL protein expression. In addition, we have demonstrated a pathogenic role for synonymous mutations in VHL-Exon 2 that alter splicing through E2-skipping in five families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially impact splicing, correlating with phenotype severity. This study demonstrates that cryptic-exon-retention or exon-skipping are new VHL alterations and reveals a novel complex splicing regulation of the VHL gene. These findings open new avenues for diagnosis and research into the VHL-related-hypoxia-signaling pathway.
Published: 2018
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6. Integrative analysis of dysregulated microRNAs and mRNAs in multiple recurrent synchronized renal tumors from patients with von Hippel-Lindau disease

Author: Sophie Couvé, Nathalie Droin, Sophie Giraud, Virginie Verkarre, Mathieu Chiquet, Sophie Gad, Brigitte Bressac-De-Paillerets, Philippe Dessen, Betty Gardie, Viorel Vasiliu, Stéphane Richard, Bin Tean Teh, Arnaud Mejean, Sophie Ferlicot, Charles-Henry Gattolliat, Cedric Orear, Vincent Molinié, and Guillaume Meurice
Subjects: Adult, Male, 0301 basic medicine, Cancer Research, von Hippel-Lindau Disease, Tumor suppressor gene, Biology, Kidney, urologic and male genital diseases, Neoplasms, Multiple Primary, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Cell Line, Tumor, microRNA, medicine, Humans, miRNA and mRNA profiling, RNA, Messenger, Von Hippel–Lindau disease, Carcinoma, Renal Cell, Aged, Oligonucleotide Array Sequence Analysis, Aged, 80 and over, Regulation of gene expression, Gene Expression Profiling, Cancer, Articles, Middle Aged, medicine.disease, Molecular medicine, Kidney Neoplasms, clear-cell renal cell carcinoma, Gene Expression Regulation, Neoplastic, Gene expression profiling, MicroRNAs, 030104 developmental biology, Oncology, Von Hippel-Lindau Tumor Suppressor Protein, Case-Control Studies, 030220 oncology & carcinogenesis, Cancer research, Female, Neoplasm Recurrence, Local, integrative analyses
Abstract: Von Hippel-Lindau (VHL) disease is a rare auto-somal dominant syndrome that is the main cause of inherited clear-cell renal cell carcinoma (ccRCC), which generally occurs in the form of multiple recurrent synchronized tumors. Affected patients are carriers of a germline mutation in the VHL tumor suppressor gene. Somatic mutations of this gene are also found in sporadic ccRCC and numerous pan-genomic studies have reported a dysregulation of microRNA (miRNA) expression in these sporadic tumors. In order to investigate the molecular mechanisms underlying the pathogenesis of VHL-associated ccRCC, particularly in the context of multiple tumors, the present study characterized the mRNA and miRNA transcriptome through an integrative analysis compared with sporadic renal tumors. In the present study, two series of ccRCC samples were used. The first set consisted of several samples from different tumors occurring in the same patient, for two independent patients affected with VHL disease. The second set consisted of 12 VHL-associated tumors and 22 sporadic ccRCC tumors compared with a pool of normal renal tissue. For each sample series, an expression analysis of miRNAs and mRNAs was conducted using microarrays. The results indicated that multiple tumors within the kidney of a patient with VHL disease featured a similar pattern of miRNA and gene expression. In addition, the expression levels of miRNA were able to distinguish VHL-associated tumors from sporadic ccRCC, and it was identified that 103 miRNAs and 2,474 genes were differentially expressed in the ccRCC series compared with in normal renal tissue. The majority of dysregulated genes were implicated in 'immunity' and 'metabolism' pathways. Taken together, these results allow a better understanding of the occurrence of ccRCC in patients with VHL disease, by providing insights into dysregulated miRNA and mRNA. In the set of patients with VHL disease, there were few differences in miRNA and mRNA expression, thus indicating a similar molecular evolution of these synchronous tumors and suggesting that the same molecular mechanisms underlie the pathogenesis of these hereditary tumors.
Published: 2018
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7. Update on hypoxia-inducible factors and hydroxylases in oxygen regulatory pathways: from physiology to therapeutics

Author: Lisa Oliver, Peter J. Ratcliffe, Betty Gardie, Jiannis Ragoussis, Peppi Koivunen, Valérie Trichet, Claire Vinatier, Ines Batinic-Haberle, Judith V.M.G. Bovée, Johanna Myllyharju, Florence Robriquet, The Francis Crick Institute, Target Discovery Institute [Oxford, UK], University of Oxford [U.K.], Oulu Center for Cell-Matrix Research [Oulu, Finland], Biocenter Oulu and Faculty of Biochemistry & Molecular Medicine [Oulu, Finland]-University of Oulu [Finland], McGill University, Montréal (McGill University) ( McGill ), Department of Pathology [Leiden, The Netherlands], Leiden University Medical Center (LUMC), Duke university [Durham], Regenerative Medicine and Skeleton research lab ( RMeS ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os, Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), École pratique des hautes études ( EPHE ), The meeting 'Hypoxia Nantes 2106' (https://hypoxia.univ-nantes.fr) was financially supported by Alliance Bio Expertise, Baker Ruskinn, the Région Pays de la Loire, project 'ERRATA' and 'EryCan', Laboratory of Excellence GR-Ex, reference ANR-11-LABX-0051, Nantes University, and Dove Press., ANR-11-IDEX-0005-02/11-LABX-0051,GR-Ex,Biogenèse et pathologies du globule rouge ( 2011 ), Target Discovery Institute [Oxford, UK] (TDI), University of Oxford [Oxford], The Francis Crick Institute [London], Genome Quebec Innovation Centre [Montréal, Canada], McGill University = Université McGill [Montréal, Canada], Department of Radiation Oncology [Durham, NC, USA], Duke University Medical Center, Université de Nantes - UFR Odontologie, Université de Nantes (UN), Team STEP 'Skeletal physiopathology and joint regenerative medicine' (Inserm U1229 - RMeS), Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), University of Oxford, RMeS - Skeletal Physiopathology and Joint Regenerative Medicine (RMeS-REJOINT), Regenerative Medicine and Skeleton (RMeS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Jehan, Frederic, and Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID
Subjects: 0301 basic medicine, Physiology, Review, Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, lipid metabolism, medicine, genomics, cancer, oxidative stress, lcsh:R5-920, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, musculoskeletal, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, hypoxia, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Hypoxia (medical), 3. Good health, Oxidative stress, 030104 developmental biology, Hypoxia-inducible factors, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, medicine.symptom, Large group, lcsh:Medicine (General)
Abstract: Peter Ratcliffe,1,2 Peppi Koivunen,3 Johanna Myllyharju,3 Jiannis Ragoussis,4 Judith VMG Bovée,5 Ines Batinic-Haberle,6 Claire Vinatier,7 Valérie Trichet,8 Florence Robriquet,9 Lisa Oliver,9 Betty Gardie9,10 1Target Discovery Institute, University of Oxford, 2The Francis Crick Institute, London, UK; 3Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; 4McGill University and Genome Quebec Innovation Centre, McGill University, Montreal, Canada; 5Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands; 6Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, USA; 7INSERM UMR 1229, Regenerative Medicine and Skeleton-RMeS, Team STEP, University of Nantes, UFR Odontology, 8UMR 1238 INSERM, Université de Nantes, Faculté de Médecine, 9CRCINA, INSERM, Université de Nantes, Nantes, 10Ecole Pratique des Hautes Etudes, PSL Research University, Paris, France Abstract: The “Hypoxia Nantes 2016” organized its second conference dedicated to the field of hypoxia research. This conference focused on “the role of hypoxia under physiological conditions as well as in cancer” and took place in Nantes, France, in October 6–7, 2016. The main objective of this conference was to bring together a large group of scientists from different spheres of hypoxia. Recent advances were presented and discussed around different topics: genomics, physiology, musculoskeletal, stem cells, microenvironment and cancer, and oxidative stress. This review summarizes the major highlights of the meeting. Keywords: hypoxia, genomics, lipid metabolism, musculoskeletal, cancer, oxidative stress&nbsp
Published: 2017
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8. Gene panel sequencing in idiopathic erythrocytosis

Author: Betty Gardie, Céline Garrec, François Girodon, Fabrice Airaud, Stéphane Bézieau, Lipides - Nutrition - Cancer (U866) ( 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-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université Paris-Dauphine, PSL Research University, Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-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 ), Lipides - Nutrition - Cancer (U866) (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-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL), 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), université de Bourgogne, LNC, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement
Subjects: 0301 basic medicine, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Letter, Genetic testing, MEDLINE, Polycythemia, Biology, Idiopathic erythrocytosis, 03 medical and health sciences, 0302 clinical medicine, Polycythemia vera, Gene panel, medicine, Humans, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, Online Only Articles, Exome sequencing, Genetics, Genetic syndromes, Genetic Variation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Sequence Analysis, DNA, Hematology, Gene panel sequencing, medicine.disease, 030104 developmental biology, Molecular Diagnostic Techniques, Mutation, 030215 immunology
Abstract: Erythrocytosis is a rare disorder characterized by increased red cell mass and elevated hemoglobin concentration and hematocrit. Several genetic variants have been identified as causes for erythrocytosis in genes belonging to different pathways including oxygen sensing, erythropoiesis and oxygen transport. However, despite clinical investigation and screening for these mutations, the cause of disease cannot be found in a considerable number of patients, who are classified as having idiopathic erythrocytosis. In this study, we developed a targeted next-generation sequencing panel encompassing the exonic regions of 21 genes from relevant pathways (~79 Kb) and sequenced 125 patients with idiopathic erythrocytosis. The panel effectively screened 97% of coding regions of these genes, with an average coverage of 450×. It identified 51 different rare variants, all leading to alterations of protein sequence, with 57 out of 125 cases (45.6%) having at least one of these variants. Ten of these were known erythrocytosis-causing variants, which had been missed following existing diagnostic algorithms. Twenty-two were novel variants in erythrocytosis-associated genes (EGLN1, EPAS1, VHL, BPGM, JAK2, SH2B3) and in novel genes included in the panel (e.g. EPO, EGLN2, HIF3A, OS9), some with a high likelihood of functionality, for which future segregation, functional and replication studies will be useful to provide further evidence for causality. The rest were classified as polymorphisms. Overall, these results demonstrate the benefits of using a gene panel rather than existing methods in which focused genetic screening is performed depending on biochemical measurements: the gene panel improves diagnostic accuracy and provides the opportunity for discovery of novel variants.
Published: 2017
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9. The role of PHD2 mutations in the pathogenesis of erythrocytosis

Author: Joanne Ewing, Stéphane Richard, Frank S. Lee, Rasheduzzaman Chowdhury, Celeste Bento, Frédéric Lambert, Patrick R. Arsenault, Mary Frances McMullin, Melanie J. Percy, Helena Almeida, Betty Gardie, David Hoogewijs, Christopher J. Schofield, and University of Zurich
Subjects: Genetics, biology, hypoxia, Nonsense mutation, 610 Medicine & health, Review, 10052 Institute of Physiology, Frameshift mutation, Germline mutation, 10076 Center for Integrative Human Physiology, Oxygen homeostasis, biology.protein, erythrocytosis, 570 Life sciences, Missense mutation, PHD2, HIF, erythropoietin, Hypoxia, Haploinsufficiency, Transcription factor, EGLN1
Abstract: The transcription of the erythropoietin (EPO) gene is tightly regulated by the hypoxia response pathway to maintain oxygen homeostasis. Elevations in serum EPO level may be reflected in an augmentation in the red cell mass, thereby causing erythrocytosis. Studies on erythrocytosis have provided insights into the function of the oxygen-sensing pathway and the critical proteins involved in the regulation of EPO transcription. The α subunits of the hypoxia-inducible transcription factor are hydroxylated by three prolyl hydroxylase domain (PHD) enzymes, which belong to the iron and 2-oxoglutarate-dependent oxygenase superfamily. Sequence analysis of the genes encoding the PHDs in patients with erythrocytosis has revealed heterozygous germline mutations only occurring in Egl nine homolog 1 (EGLN1, also known as PHD2), the gene that encodes PHD2. To date, 24 different EGLN1 mutations comprising missense, frameshift, and nonsense mutations have been described. The phenotypes associated with the patients carrying these mutations are fairly homogeneous and typically limited to erythrocytosis with normal to elevated EPO. However, exceptions exist; for example, there is one case with development of concurrent paraganglioma (PHD2-H374R). Analysis of the erythrocytosis-associated PHD2 missense mutations has shown heterogeneous results. Structural studies reveal that mutations can affect different domains of PHD2. Some are close to the hypoxia-inducible transcription factor α/2-oxoglutarate or the iron binding sites for PHD2. In silico studies demonstrate that the mutations do not always affect fully conserved residues. In vitro and in cellulo studies showed varying effects of the mutations, ranging from mild effects to severe loss of function. The exact mechanism of a potential tumor-suppressor role for PHD2 still needs to be elucidated. A knockin mouse model expressing the first reported PHD2-P317R mutation recapitulates the phenotype observed in humans (erythrocytosis with inappropriately normal serum EPO levels) and demonstrates that haploinsufficiency and partial deregulation of PHD2 is sufficient to cause erythrocytosis., Video abstract
Published: 2014

10. Von Hippel–Lindau: How a rare disease illuminates cancer biology

Author: Sophie Couvé, Betty Gardie, Stéphane Richard, Sophie Gad, Institut National du Cancer [Boulogne Billancourt] (INC), Laboratoire de Génétique Oncologique [Villejuif], École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), and Bernardo, Elizabeth
Subjects: Cancer Research, Pathology, medicine.medical_specialty, von Hippel-Lindau Disease, endocrine system diseases, Angiogenesis, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Neuroendocrine tumors, Biology, urologic and male genital diseases, Targeted therapy, 03 medical and health sciences, Rare Diseases, Targeted therapies, 0302 clinical medicine, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Renal cell carcinoma, Neoplasms, medicine, Animals, Humans, HIF, neoplasms, Genetic Association Studies, Germ-Line Mutation, 030304 developmental biology, 0303 health sciences, Cilium, medicine.disease, Penetrance, female genital diseases and pregnancy complications, 3. Good health, Disease Models, Animal, Von Hippel–Lindau, Von Hippel-Lindau Tumor Suppressor Protein, 030220 oncology & carcinogenesis, Rare disease
Abstract: International audience; Von Hippel–Lindau (VHL) disease is a rare autosomal dominant syndrome (1/36,000 live births) with highly penetrance that predispose to the development of a panel of highly vascularized tumors (model of tumoral angiogenesis). Main manifestations include central nervous system (CNS) and retinal haeman-gioblastomas, endolymphatic sac tumors, clear-cell renal cell carcinomas (RCC), phaeochromocytomas and pancreatic neuroendocrine tumors. RCC has become the first potential cause of mortality and VHL disease is the main cause of inherited RCC. The disease is caused by germline mutations in the VHL tumor-suppressor gene that plays a major role in regulation of the oxygen-sensing pathway by targeting the hypoxia-inducible factor HIF for degradation in proteasome. VHL has also major HIF-independent functions , specially in regulation of primary cilium, extracellular matrix and apoptosis. Somatic inactivation of the VHL gene is the main molecular event in most sporadic RCC and the treatment of advanced RCC has been revolutionized by targeted therapy with drugs that block angiogenesis. These drugs are now in first line in metastatic sporadic RCC and have shown promising results for RCC, pancreatic neuroendocrine tumors and malignant pheochromocytomas in VHL patients.
Published: 2013
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11. Corrigendum: A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma

Author: Olivier Caron, Etienne Rouleau, Hamida Mohamdi, F. Boitier, Jean-Luc Perrot, Eve Maubec, Arnaud de la Fouchardière, Stéphane Richard, Pierre Vabres, Luc Thomas, Rosette Lidereau, Simon Saule, Diana Zelenika, Pilar Galan, Tanguy Martin-Denavit, Lorenza Pastorino, N. Poulalhon, Jérôme Couturier, Bruno Labeille, Eve Corda, Caroline Robert, Philippe Dessen, Marie-Françoise Avril, Bernard Escudier, Christian Ingvar, Sandy Giuliano, Celia Badenas, Robert Ballotti, Benoit d’Hayer, Gilbert M. Lenoir, Betty Gardie, Stéphane Dalle, Laurence Brugières, Brigitte Bressac-de Paillerets, Audrey Remenieras, Valérie Chaudru, Paola Ghiorzo, Hélène Blanché, Philippe Bahadoran, Fabienne Lesueur, Håkan Olsson, Bin Tean Teh, Philippe Vielh, Corine Bertolotto, Pascale Andry-Benzaquen, Thomas Strub, Florence Demenais, Vincent Molinié, Mahaut de Lichy, Susana Puig, Karine Bille, Sophie Gad, Annick Rossi, Mark Lathrop, Nicolas Dupin, Irwin Davidson, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Mutation, Multidisciplinary, Melanoma, Carcinoma, SUMO protein, Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease_cause, medicine.disease, Microphthalmia-associated transcription factor, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Germline mutation, medicine, Cancer research, Epigenetics, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS
Abstract: Nature 480, 94–98 (2011); doi:10.1038/nature10539 In this Letter, one image was mistakenly duplicated during preparation of the artwork. In the original Fig. 3d, the left image illustrating migration of RCC4 cells transduced with empty adenovirus (EV) at 24 h is a duplicate of the middle image showing migration of RCC4 cells transduced with an adenovirus encoding Mi-WT.
Published: 2016
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12. Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia

Author: Romain Carcenac, Michel Leporrier, Stéphane Richard, Michel Barrois, Jean-Jacques Kiladjian, Jacques Pouysségur, André Baruchel, Nathalie M. Mazure, David Hoogewijs, Roland H. Wenger, Anne-Paule Gimenez-Roqueplo, Charline Ladroue, Brigitte Bressac-de Paillerets, Nicole Casadevall, Jean Feunteun, Betty Gardie, Sophie Gad, Fadi Fakhoury, Olivier Hermine, Federica Storti, Bernardo, Elizabeth, 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), Zürich Center for Integrative Human Physiology (ZIHP), Universität Zürich [Zürich] = University of Zurich (UZH)-Institute of Physiology, Service de Génétique [Villejuif], Institut Gustave Roussy (IGR), Laboratoire de Recherche en Imagerie : Méthodes d'imagerie des Échanges transcapillaires (LRI - EA4062), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique [CHU HEGP], 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), Laboratoire d'Hématologie Biologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Hematopoïese et cellules souches normales et pathologiques (U790), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Investigations Cliniques, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie greffe [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Département de Néphrologie [CHU Necker], Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Institut de signalisation, biologie du développement et cancer (ISBDC), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Expert National Cancers Rares INCa 'PREDIR' and Réseau National INCa [AP-HP Hôpital Bicêtre, Paris], Service d'urologie, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, This work was supported by grants from the 'Association pour la Recherche sur le Cancer' (ARC), the French National Cancer Institute ('INCa', PNES Rein, and Réseau National Prédispositions héréditaires au cancer du rein) and the French Ligue Nationale contre le Cancer (Comités du Cher et de l’Indre) as well as by the HypoxiaNet COST Action TD0901. DH is supported by a postdoctoral Marie Curie IEF Fellowship from the European Commission and the Sassella Stiftung. DH and RHW are supported by grants from the State Secretariat of Education and Research (C10.0106) and from the NCCR Kidney.CH, funded by the SNF., 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 ), Zürich Center for Integrative Human Physiology ( ZIHP ), University of Zürich [Zürich] ( UZH ) -Institute of Physiology, Institut Gustave Roussy ( IGR ), Laboratoire de Recherche en Imagerie : Méthodes d'imagerie des Échanges transcapillaires ( LRI - EA4062 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Génétique [AP-HP Hôpital Européen Georges Pompidou, Paris], Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Service d'Hématologie Clinique, CHU Caen-Hôpital Clémenceau, Hematopoïese et cellules souches normales et pathologiques ( U790 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CHU Saint Louis [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Stabilité Génétique et Oncogenèse ( UMR 8200 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de signalisation, biologie du développement et cancer ( ISBDC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre-Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)
Subjects: Adult, Male, hypoxia inducible factor, Adolescent, Tumor suppressor gene, Mutant, Procollagen-Proline Dioxygenase, [SDV.CAN]Life Sciences [q-bio]/Cancer, Polycythemia, Biology, medicine.disease_cause, Germline, Hypoxia-Inducible Factor-Proline Dioxygenases, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Hydroxylation, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, erythrocytosis, medicine, Humans, PHD2, Cells, Cultured, Germ-Line Mutation, hypoxia-inducible transcription factor, 030304 developmental biology, 0303 health sciences, Base Sequence, Hydrolysis, Original Articles, Hematology, Middle Aged, Hypoxia (medical), Hypoxia-Inducible Factor 1, alpha Subunit, Molecular biology, 3. Good health, HEK293 Cells, chemistry, Hypoxia-inducible factors, 030220 oncology & carcinogenesis, Female, Mutant Proteins, medicine.symptom, Carcinogenesis
Abstract: International audience; BACKGROUND: Congenital secondary erythrocytoses are due to deregulation of hypoxia inducible factor resulting in overproduction of erythropoietin. The most common germline mutation identified in the hypoxia signaling pathway is the Arginine 200-Tryptophan mutant of the von Hippel-Lindau tumor suppressor gene, resulting in Chuvash polycythemia. This mutant displays a weak deficiency in hypoxia inducible factor α regulation and does not promote tumorigenesis. Other von Hippel-Lindau mutants with more deleterious effects are responsible for von Hippel-Lindau disease, which is characterized by the development of multiple tumors. Recently, a few mutations in gene for the prolyl hydroxylase domain 2 protein (PHD2) have been reported in cases of congenital erythrocytosis not associated with tumor formation with the exception of one patient with a recurrent extra-adrenal paraganglioma.DESIGN AND METHODS: Five PHD2 variants, four of which were novel, were identified in patients with erythrocytosis. These PHD2 variants were functionally analyzed and compared with the PHD2 mutant previously identified in a patient with polycythemia and paraganglioma. The capacity of PHD2 to regulate the activity, stability and hydroxylation of hypoxia inducible factor α was assessed using hypoxia-inducible reporter gene, one-hybrid and in vitro hydroxylation assays, respectively.RESULTS: This functional comparative study showed that two categories of PHD2 mutants could be distinguished: one category with a weak deficiency in hypoxia inducible factor α regulation and a second one with a deleterious effect; the mutant implicated in tumor occurrence belongs to the second category.CONCLUSIONS: As observed with germline von Hippel-Lindau mutations, there are functional differences between the PHD2 mutants with regards to hypoxia inducible factor regulation. PHD2 mutation carriers do, therefore, need careful medical follow-up, since some mutations must be considered as potential candidates for tumor predisposition.
Published: 2011
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13. A study of 36 unrelated cases with pure erythrocytosis revealed three new mutations in the erythropoietin receptor gene

Author: Frédéric Galactéros, Betty Gardie, Valérie Ugo, Nicole Casadevall, Michel Goossens, Elodie Mazurier, Henri Wajcman, Maha Al-Sheikh, and Claude Préhu
Subjects: Adult, Male, Adolescent, Procollagen-Proline Dioxygenase, Polycythemia, Biology, medicine.disease_cause, Hypoxia-Inducible Factor-Proline Dioxygenases, Frameshift mutation, Exon, Receptors, Erythropoietin, medicine, Humans, Child, Gene, Aged, Genetics, Mutation, Janus kinase 2, Hematology, Middle Aged, Molecular biology, Stop codon, Erythropoietin receptor, Gene Expression Regulation, Von Hippel-Lindau Tumor Suppressor Protein, biology.protein, Female, Variants of PCR
Abstract: Thirty-six unrelated cases with erythrocytosis of unknown origin were investigated. Exons 5-8 of the erythropoietin receptor gene (EPOR), the von Hippel-Lindau gene, and the prolyl hydroxylase domain protein 2 gene (PHD2) were screened by direct DNA sequencing. The Janus kinase 2 mutation, JAK2 (Val617Phe), was screened by allele specific PCR. In this study, three new mutations of EPOR causing deletions in exon 8 were found: the first led directly to a stop codon [g.5957_5958delTT (p.Phe424X)], the second to a stop codon after one residue [g.5828_5829delCC (p.Pro381GlnfsX1)] and the third to a stop codon following a frameshift sequence of 23 residues [g.5971delC (p.Leu429TrpfsX23)]. One patient had a previously reported EPOR mutation [g.6146A>G (p.Asn487Ser)] and another, a silent one (g.5799G>A). All were heterozygotes. In addition, 2 patients were positive for JAK2 (Val617Phe), and 2 reported elsewhere, were mutated in the PHD2 gene [c.606delG (p.Met202IlefsX71).
Published: 2008
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14. Pathogenesis of Myeloproliferative Neoplasms: Role and Mechanisms of Chronic Inflammation

Author: Sylvie Hermouet, Betty Gardie, Edith Bigot-Corbel, Service d'Hématologie [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), 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), Laboratoire de Biochimie [Nantes], École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), and Bernardo, Elizabeth
Subjects: Myeloid, Disease, Review Article, medicine.disease_cause, Pathogenesis, 0302 clinical medicine, Neoplasms, Hypereosinophilic Syndrome, Polycythemia Vera, 0303 health sciences, Mutation, Leukemia, biology, food and beverages, 3. Good health, medicine.anatomical_structure, Phenotype, 030220 oncology & carcinogenesis, Cytokines, medicine.symptom, Receptors, Thrombopoietin, Mastocytosis, Thrombocythemia, Essential, lcsh:RB1-214, Article Subject, Immunology, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Myeloproliferative Disorders, [SDV.CAN] Life Sciences [q-bio]/Cancer, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, medicine, lcsh:Pathology, Humans, Genetic Predisposition to Disease, 030304 developmental biology, Cell Biology, Janus Kinase 2, medicine.disease, Primary Myelofibrosis, biology.protein, Cancer research, Calreticulin
Abstract: Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal diseases characterized by the excessive and chronic production of mature cells from one or several of the myeloid lineages. Recent advances in the biology of MPNs have greatly facilitated their molecular diagnosis since most patients present with mutation(s) in theJAK2, MPL,orCALRgenes. Yet the roles played by these mutations in the pathogenesis and main complications of the different subtypes of MPNs are not fully elucidated. Importantly, chronic inflammation has long been associated with MPN disease and some of the symptoms and complications can be linked to inflammation. Moreover, the JAK inhibitor clinical trials showed that the reduction of symptoms linked to inflammation was beneficial to patients even in the absence of significant decrease in theJAK2-V617F mutant load. These observations suggested that part of the inflammation observed in patients withJAK2-mutated MPNs may not be the consequence ofJAK2mutation. The aim of this paper is to review the different aspects of inflammation in MPNs, the molecular mechanisms involved, the role of specific genetic defects, and the evidence that increased production of certain cytokines depends or not on MPN-associated mutations, and to discuss possible nongenetic causes of inflammation.
Published: 2015
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15. Raf-1-induced growth arrest in human mammary epithelial cells is p16-independent and is overcome in immortal cells during conversion

Author: Betty Gardie, Catherine L Olsen, Martha R. Stampfer, and Paul Yaswen
Subjects: Senescence, Cancer Research, Telomerase, Cell type, Gene Conversion, Biology, medicine.disease_cause, Transduction (genetics), p14arf, Genetics, medicine, Telomerase reverse transcriptase, Breast, Molecular Biology, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p16, Cyclin, Cell Cycle, Epithelial Cells, Cell biology, DNA-Binding Proteins, Proto-Oncogene Proteins c-raf, body regions, Cell Transformation, Neoplastic, Carcinogenesis
Abstract: Using an estrogen-inducible retroviral system, we demonstrate that oncogenic Raf-1 induces growth arrest and morphological changes in finite lifespan human mammary epithelial cells (HMEC). This arrest does not rely on expression of the cyclin-dependent kinase inhibitor (CKI) p16(INK4a), nor on changes in expression of the CKIs p21(Cip1), p14(ARF), p27(Kip1) or p57(Kip2). The Raf-induced arrest is independent of viral oncogene mediated inactivation of p53 and pRB, or c-myc overexpression. Flow cytometric analysis demonstrates that cells arrest in both G1 and G2. The Raf-induced arrest is mitigated or eliminated in some immortally transformed HMEC. Immortal HMEC that have both overcome replicative senescence and undergone the recently described conversion process maintain growth in the presence of transduced oncogenic Raf-1; they also gain EGF-independent growth and a low frequency of anchorage-independent growth. However, HMEC that have overcome replicative senescence but have not undergone conversion and HMEC immortalized by transduction with the catalytic subunit of telomerase, hTERT, remain severely growth arrested. These results indicate that the molecular mechanisms responsible for the Raf-1-induced growth arrest may vary among different finite lifespan cell types, and that in HMEC, this mechanism is altered during the conversion process, rather than as a direct consequence of overcoming senescence or expressing hTERT.
Published: 2002
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16. Transgenic Expression of the p16INK4a Cyclin-Dependent Kinase Inhibitor Leads to Enhanced Apoptosis and Differentiation Arrest of CD4−CD8− Immature Thymocytes

Author: Stéphanie Eyquem, Betty Gardie, Chantal Lagresle, Marika Pla, Jean-Christophe Bories, Magali Fasseu, Jean-Claude Vieville, and François Sigaux
Subjects: CD4-Positive T-Lymphocytes, CD3 Complex, T-Lymphocytes, T cell, CD3, Immunology, Apoptosis, Mice, Transgenic, Thymus Gland, CD8-Positive T-Lymphocytes, Lymphocyte Activation, Antibodies, Mice, Cyclin-dependent kinase, medicine, Animals, Humans, Immunology and Allergy, IL-2 receptor, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p16, Mice, Knockout, biology, Nuclear Proteins, Cell Differentiation, Receptors, Antigen, T-Cell, gamma-delta, Cell cycle, Molecular biology, DNA-Binding Proteins, Thymocyte, medicine.anatomical_structure, T cell differentiation, biology.protein, RNA, CD8, HeLa Cells, Signal Transduction
Abstract: In the thymus, T cell development proceeds by successive steps of differentiation, expansion, and selection. Control of thymocyte proliferation is critical to insure the full function of the immune system and to prevent T cells from transformation. Deletion of the cell cycle inhibitor p16INK4a is frequently observed in human T cell neoplasias and, in mice, gene targeted inactivation of the Ink4a locus enhances thymocyte expansion and predisposes mutant animal to tumorigenesis. Here, we investigate the mechanism by which p16Ink4a controls thymocyte development by analyzing transgenic mice expressing the human p16INK4a into the T cell lineage. We show that forced expression of p16INK4a in thymocytes blocked T cell differentiation at the early CD4−CD8−CD3−CD25+ stage without significantly affecting the development of γδ T cells. Pre-TCR function was mimicked by the induction of CD3 signaling in thymocytes of recombinase activating gene (RAG)-2-deficient mice (RAG-2−/−). Upon anti-CD3ε treatment in vivo, p16INK4a-expressing RAG-2−/− thymocytes were not rescued from apoptosis, nor could they differentiate. Our data demonstrate that expression of p16INK4a prevents the pre-TCR-mediated expansion and/or survival of differentiating thymocytes.
Published: 2002
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17. 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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18. Genomic Alterations of the p19ARF Encoding Exons in T-Cell Acute Lymphoblastic Leukemia

Author: Jean-Michel Cayuela, Sophie Martini, François Sigaux, and Betty Gardie
Subjects: Adult, Male, Adolescent, Tumor suppressor gene, Immunology, Locus (genetics), Thymus Gland, Biology, Polymerase Chain Reaction, Biochemistry, Exon, Tumor Suppressor Protein p14ARF, Humans, Leukemia-Lymphoma, Adult T-Cell, RNA, Messenger, Allele, Child, Gene, Alleles, Recombination, Genetic, Genetics, Recombinase activity, Proteins, RNA-Directed DNA Polymerase, Gene rearrangement, Cell Biology, Hematology, Cell cycle, Blotting, Southern, Female, Gene Deletion
Abstract: We have previously shown that the disruption/deletion of the MTS(MTS1-MTS2) locus due to illegitimate V(D)J recombinase activity is a genetic event characteristic of T-cell acute lymphoblastic leukemia (T-ALL). Inactivation of the p16INK4a tumor suppressor protein, encoded by MTS1, is thought to be the major functional consequence of these chromosomal rearrangements. The two other cell cycle inhibitors encoded by genes identified in the locus (p19ARF by MTS1 and p15INK4b by MTS2), also represent possible candidates for inactivating events. By analyzing p16INK4aexpression in three cases in which an identical 36-kb deletion had deleted MTS2 and disrupted the p19ARF, but spared the p16INK4aMTS1 encoding exons, we have excluded p16INK4a and pinpointed p19ARF and/or p15INK4b as the functional target(s) of this rearrangement. Moreover, by the study of the MTS genomic configuration of 149 rearranged alleles from a large series of T-ALL cases, we have shown that p19ARF encoding exons were always disrupted or deleted, whereas p16INK4a and p15INK4b encoding exons were spared in four and 21 cases, respectively. These results suggest that p19ARF may be targeted by the genetic events that occur in the MTS locus in the majority of T-ALLs.
Published: 1998
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19. Identification of TET1 Partners That Control Its DNA-Demethylating Function

Author: Fiona LePape, Arulraj Nadaradjane, François M. Vallette, Lisenn Lalier, Betty Gardie, and Pierre-François Cartron
Subjects: Genetics, Cancer Research, biology, EZH2, Short Report, Methylation, MECP2, Cell biology, Proliferating cell nuclear antigen, chemistry.chemical_compound, chemistry, DNA methylation, Cancer cell, biology.protein, DNA, Demethylation
Abstract: Several recent reports have identified TET1 as the main enzyme modulating DNA methylation and gene transcription via hydroxylation of 5-methylcytosine. However, little is known about the protein network that controls TET1 activity. By using a new proximity ligation in situ assay, we identified MeCP2, HDAC1/6/7, EZH2, mSin3A, PCNA, and LSD1 as TET1-interacting proteins. We also discerned that TET1/PCNA acts as a demethylator of the cyclical methylation/demethylation process, the perturbation of which promotes the aberrant methylation hallmarks frequently observed in cancer cells.
Published: 2013

20. Genetic Basis of Congenital Erythrocytosis: Mutation Update and Online Databases

Author: Celeste, Bento, Melanie J, Percy, Betty, Gardie, Tabita Magalhães, Maia, Richard, van Wijk, Silverio, Perrotta, Fulvio, Della Ragione, Helena, Almeida, Cedric, Rossi, François, Girodon, Maria, Aström, Drorit, Neumann, Susanne, Schnittger, Britta, Landin, Milen, Minkov, Maria Luigia, Randi, Stéphane, Richard, Nicole, Casadevall, William, Vainchenker, Susana, Rives, Sylvie, Hermouet, M Leticia, Ribeiro, Mary Frances, McMullin, Holger, Cario, Aurelie, Chauveau, Anne-Paule, Gimenez-Roqueplo, Brigitte, Bressac-de-Paillerets, Didem, Altindirek, Felipe, Lorenzo, Frederic, Lambert, Harlev, Dan, Sophie, Gad-Lapiteau, Ana, Catarina Oliveira, Cédric, Rossi, Cristina, Fraga, Gennadiy, Taradin, Guillermo, Martin-Nuñez, Helena, Vitória, Herrera, Diaz Aguado, Jan, Palmblad, Julia, Vidán, Luis, Relvas, Maria Leticia, Ribeiro, Maria, Luigi Larocca, Maria, Luigia Randi, Maria, Pedro Silveira, Melanie, Percy, Mor, Gross, Ricardo, Marques da Costa, Soheir, Beshara, Tal, Ben-Ami, Valérie, Ugo, Bento, Celeste, Percy, Melanie J, Gardie, Betty, Magalhaes Maia, Tabita, van Wijk, Richard, Perrotta, Silverio, DELLA RAGIONE, Fulvio, Almeida, Helena, Rossi, Cedric, Girodon, Francoi, Astrom, Maria, Neumann, Drorit, Schnittger, Susanne, Landin, Britta, Minkov, Milen, (Randi, Maria Luigia, Richard, Stephane, Casadevall, Nicole, Vainchenker, William, Rives, Susana, Hermouet, Sylvie, Ribeiro, M. Leticia, Mcmullin, Mary France, and Cario, Holger
Subjects: medicine.medical_specialty, Polycythemia, Biology, Bioinformatics, Databases, Genetic, Genetics, medicine, Receptors, Erythropoietin, Humans, Genetic Predisposition to Disease, Erythropoietin, Genetics (clinical), Internet, Hemoglobin variants, EPAS1, Hypoxia (medical), Cell Hypoxia, Erythropoietin receptor, Mutation, biology.protein, Medical genetics, medicine.symptom, Leiden Open Variation Database, medicine.drug, EGLN1, Signal Transduction
Abstract: Congenital erythrocytosis (CE), or congenital polycythemia, represents a rare and heterogeneous clinical entity. It is caused by deregulated red blood cell production where erythrocyte overproduction results in elevated hemoglobin and hematocrit levels. Primary congenital familial erythrocytosis is associated with low erythropoietin (Epo) levels and results from mutations in the Epo receptor gene (EPOR). Secondary CE arises from conditions causing tissue hypoxia and results in increased Epo production. These include hemoglobin variants with increased affinity for oxygen (HBB, HBA mutations), decreased production of 2,3-bisphosphoglycerate due to BPGM mutations, or mutations in the genes involved in the hypoxia sensing pathway (VHL, EPAS1, and EGLN1). Depending on the affected gene, CE can be inherited either in an autosomal dominant or recessive mode, with sporadic cases arising de novo. Despite recent important discoveries in the molecular pathogenesis of CE, the molecular causes remain to be identified in about 70% of the patients. With the objective of collecting all the published and unpublished cases of CE the COST action MPN&MPNr-Euronet developed a comprehensive Internet-based database focusing on the registration of clinical history, hematological, biochemical, and molecular data (http://www.erythrocytosis.org/). In addition, unreported mutations are also curated in the corresponding Leiden Open Variation Database.
Published: 2013

21. Next Generation Sequencing Is a Useful Tool for the Diagnosis of Congenital/Idiopathic Erythrocytoses

Author: Betty Gardie, Ricordeau Ingrid, François Girodon, Garrec Céline, Bézieau Stéphane, Fabrice Airaud, Pacault Mathilde, and Dumont Solenne
Subjects: Mutation, Candidate gene, Immunology, Cell Biology, Hematology, Disease, 030204 cardiovascular system & hematology, Biology, Bioinformatics, medicine.disease, medicine.disease_cause, Biochemistry, Erythropoietin receptor, 03 medical and health sciences, 0302 clinical medicine, Polycythemia vera, medicine, Clinical significance, Exome sequencing, Myeloproliferative neoplasm, 030215 immunology
Abstract: Introduction: Erythrocytoses are characterized by an elevated red cell mass. The most widely studied disease is Polycythemia Vera (PV), a myeloproliferative neoplasm due to the acquired JAK2-V617F mutation. However, other types of erythrocytoses exist and are of major importance. They can be either inherited (Congenital Erythrocytosis-CE) or diagnosed in adult patients with no family history (Idiopathic Erythrocytosis-IE). CE/IE are not associated with myeloproliferation but they can be associated with severe thrombo-embolic or haemorrhagic events, pulmonary arterial hypertension and, rarely, tumours. The 8 genes identified so far as causing CE lie at the crossroads of major biological pathways (metabolism, inflammation, oncogenesis) and are implicated in multiple diseases. These genes are involved (i) in the regulation of the hypoxia pathway, PHD2 (also called EGLN1), HIF-2A (EPAS1), VHL, (ii) in proliferation and differentiation of erythroid progenitors (EPOR), or (iii) in mature cell function, haemoglobins (HBB, HBA1, HBA2) or bisphosphoglyceratemutase (BPGM). However, in 80% of cases the cause remains unknown meaning that no proper diagnosis can be made, no prognosis or advice can be provided to CE/IE patients and their families, and no curative treatment exists. Method: We created and developed a national network in France to (i) identify, (ii) collect and (iii) analyze the genomic abnormalities in patients suspected of CE/IE. The selection of patients was performed using a clinical and biological data sheet including mandatory further tests in order to exclude patients with PV or obvious secondary erythrocytosis related to lung, cardiac or renal disorder. Next generation sequencing (NGS) has been used to analyse the presence of mutations in 17 genes (VHL, PHD1, PHD2 and PHD3, HIF1A, HIF2A, HIF3A, FH, BPGM, and 8 other candidate genes). SureDesign software (Agilent, Santa Clara, CA) was used to design the custom HaloPlex capture assay. For sequence capture, HaloPlex Target Enrichment System Kit (AgilentR), for Illumina sequencing was used, according to the manufacturer's instructions. Results: To date, samples from 103 patients have been recorded, among whom 46 have been tested using NGS approach. Variants in 10 (21%) patients [9 males and 1 female ; median age 50 y. (12-71)] with unknown significance have been detected, including 4 in PHD genes, 5 in HIF genes, and 1 in JAK2 gene. In patients with variants, a familial history of erythrocytosis was noted in 2. No independent thrombotic complication was reported in the 10 patients. The proportion of variants detected (21%) was close to the classical rate of genomic abnormalities usually observed in CE/IE. In 2 patients (one with a PHD2 and one with a JAK2 variants), the erythropoietin was low, whereas for the others, the erythropoietin was normal. Of note, the median age of the patients was surprisingly high, suggesting that the diagnostic was not previously performed due to the absence of available tests. Indeed, the diagnostic approaches using NGS techniques led to a considerable time gain and facilitated the identification of certain molecular abnormalities associated with CE/IE Conclusion: NGS is a useful tool to explore mutations in CE/IE, but identifies genetic variants in only 20% of patients with such disorder. In vitro, in cellulo and in vivo (including zebrafish models) functional studies are currently performed to validate the clinical relevance of these variants. Further exams including whole exome sequencing are planned to achieve a right diagnosis in the 80% remaining CE/IE patients without identified genomic abnormalities. Disclosures No relevant conflicts of interest to declare.
Published: 2016
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22. Novel FH mutations in families with hereditary leiomyomatosis renal cell cancer (HLRCC) and in patients with isolated type 2 papillary renal cell carcinoma

Author: Catherine Dugast, Christelle Pruvost-Balland, Dan Lipsker, Nicolas Janin, Isabelle Coupier, Isabelle Mortemousque, Sophie Deveaux, Brigitte Gilbert-Dussardier, Laurence Faivre, Pierre Vabres, Emmanuel Van Glabeke, Hélène Dollfus, Min-Han Tan, Dominique Leroux, Pierre Rustin, Bernard Escudier, Marie-Françoise Avril, Joelle Roume, Veronica Cusin, Virginie Verkarre, Johny Bombled, Luc Thomas, Felicia Malthieu, Betty Gardie, Jean Feunteun, Darouna Kattygnarath, Jean -Baptiste Meric, Arnaud Mejean, Ghislaine Plessis, Olivier Caron, Victoria Perrier-Trudova, Stéphane Richard, Frédéric Caux, Virginie Joulin, Gilbert M. Lenoir, Abdelhamid Slama, Christine Maugard, Serena Rooker, Michel Barrois, Sandrine Lefevre, Brigitte Bressac-de Paillerets, Audrey Remenieras, Christine Theodore, Didier Bessis, Michelle Steinraths, Michel Field, Bruce Poppe, Yves Leport, Carol Cremin, Patrick Collignon, Barbara McGilliwray, Nadem Soufir, Bin Tean Teh, 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), Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hématopoïèse normale et pathologique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie, Hôpital de Bicêtre, AP-HP, Le Kremlin-Bicêtre, Service de Dermatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Dermatologie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Gustave Roussy (IGR), Service de dermatologie [Avicenne], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13), Service de Génétique Médicale, Centre Hospitalier Intercommunal, Toulon, Service d'Oncogénétique et Génétique Médicale, BC Cancer Agency, Vancouver, Service de Génétique Médicale, Hôpital Civil, Strasbourg, Consultation d'Oncogénétique, CHU, Rennes, Département d'immunothérapie, 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), Genetic Services, Royal North Shore Hospital, St Leonards, Service de Génétique, CHU, Poitiers, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Département de Génétique, CHU, Liège, Cabinet de Dermatologie, Vire, Service d'onco-hématologie et génétique, CHU Grenoble, Service de Dermatologie, Hôpital Civil, Strasbourg, Centre médico-chirurgical Atlantique, Puilboreau, Laboratoire de diagnostic génétique, Hôpital Universitaire de Strasbourg, Strasbourg, Service d'urologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Service de Génétique Médicale, Hôpital Bretonneau, Tours, Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Center for Medical Genetics, Universiteit Gent, Gand, Service de Dermatologie, Hôpital Saint Louis, AP-HP, Paris, Molecular Genetics Laboratory, Capital Coasts DHB, Wellington South, Consultation de Génétique Médicale, Hôpital Ambroise Paré, AP-HP, Boulogne, Consultation de Génétique, Hôpital Bichat-Claude Bernard, AP-HP, Paris, Division of Medical Genetics,Victoria General Hospital, Victoria, BC, Department of Medical Oncology, National Cancer Centre, Service d'Oncologie Médicale, Hôpital Foch, Suresnes, Service de Dermatologie, Centre Hospitalier Sud, Hospices Civils, Lyon, Service de Dermatologie (CHU de Dijon), Service d'Urologie, Hôpital André Grégoire, Service d'Onco-Hématologie, Centre Médical de Bligny, Briis sous Forges, CHU Necker - Enfants Malades [AP-HP], Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Centre Expert National Cancer Rares PREDIR, Service d'Urologie, CHU de Bicêtre, Le Kremlin-Bicêtre, Van Andel Research Institute, Grand Rapids, Michigan, Van Andel Institute [Grand Rapids], Génétique Oncologique EPHE, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, Peer, Hal, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], and Universiteit Gent = Ghent University (UGENT)
Subjects: Adult, Male, Proband, Skin Neoplasms, Genotype, Mutation, Missense, Biology, Bioinformatics, urologic and male genital diseases, Fumarate Hydratase, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, INDEL Mutation, Neoplastic Syndromes, Hereditary, Cell Line, Tumor, Leiomyomatosis, medicine, Genetics, Humans, Missense mutation, Molecular genetics, Frameshift Mutation, Carcinoma, Renal Cell, Germ-Line Mutation, Genetics (clinical), Aged, 030304 developmental biology, Gene Rearrangement, 0303 health sciences, Papillary renal cell carcinomas, Cancer, Middle Aged, medicine.disease, Penetrance, Kidney Neoplasms, Pedigree, 3. Good health, Codon, Nonsense, 030220 oncology & carcinogenesis, Mutation, Uterine Neoplasms, Cancer research, Cancer: urological, Female, Hereditary leiomyomatosis and renal cell carcinoma, Kidney cancer, Gene Deletion
Abstract: International audience; Background Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder predisposing humans to cutaneous and uterine leiomyomas; in 20% of affected families, type 2 papillary renal cell cancers (PRCCII) also occur with aggressive course and poor prognosis. HLRCC results from heterozygous germline mutations in the tumor suppressor fumarate hydratase (FH) gene. Methods As part of the French National Cancer Institute (INCa) "Inherited predispositions to kidney cancer" network, we performed sequence analysis and a functional study of FH in 56 families with clinically proven or suspected HLRCC and in 23 patients with isolated PRCCII (5 familial and 18 sporadic). Results We identified 32 different germline FH mutations (15 missense, six frameshifts, four nonsense, one deletion/insertion, five splice site and one complete deletion) in 40/56 (71.4%) families with proven or suspected HLRCC and in 4/23 (17.4%) probands with PRCCII alone, including 2 sporadic cases. Twenty-one of these were novel and all were demonstrated as deleterious by significant reduction of FH enzymatic activity. In addition, five asymptomatic parents in three families were confirmed as carrying disease-causing mutations. Conclusions This study identified and characterized 21 novel FH mutations and demonstrated that PRCCII can be the only one manifestation of HLRCC. Due to the incomplete penetrance of HLRCC, we propose to extend the FH mutation analysis to every patient with PRCCII occurring before 40 yrs of age or when renal tumor harbors characteristic histologic features, in order to discover previously ignored HLRCC-affected families.
Published: 2011
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23. No evidence for a genetic modifier for renal cell cancer risk in HLRCC syndrome

Author: Leigha Senter, Pia Vahteristo, Stéphane Richard, Riitta Herva, Lauri A. Aaltonen, Erik Björck, Virpi Launonen, Marja Hietala, Rainer Lehtonen, Betty Gardie, Laura Näätsaari, Kristiina Aittomäki, Maija Ht Kiuru, Taru A. Koski, Ignacio Blanco, Satu-Leena Sallinen, Didier Bessis, Richard S. Houlston, Auli Karhu, Outi Vierimaa, and Emmanuel Van Glabeke
Subjects: Adult, Male, Cancer Research, DNA Mutational Analysis, Locus (genetics), Biology, urologic and male genital diseases, Fumarate Hydratase, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Genetic linkage, Leiomyomatosis, Genotype, Genetics, medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Carcinoma, Renal Cell, Genetics (clinical), Finland, Genetic Association Studies, Germ-Line Mutation, 030304 developmental biology, Genetic testing, Aged, 80 and over, 0303 health sciences, Evidence-Based Medicine, medicine.diagnostic_test, Leiomyoma, Haplotype, Human genetics, Kidney Neoplasms, United States, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Uterine Neoplasms, Female
Abstract: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumor predisposition syndrome caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. Cutaneous and uterine leiomyomas are the most common clinical manifestations of HLRCC, whereas only approximately 20% of the families display renal cell cancer (RCC). The number of RCC cases in these families varies from one to five. Interestingly, families with multiple RCC cases are mainly found in Finland and the USA. Such aggregation of RCC in only some families and populations has led to the hypothesis that besides FH mutations also other inherited genetic and/or environmental factors may contribute to the malignant kidney tumor formation. To search for such a genetic modifier we have performed a genome-wide linkage analysis in two and an identical by descent analysis in four Finnish HLRCC families with several RCC patients. Additional Finnish and French families were used in fine-mapping and haplotype analyses. The only region compatible with linkage was the locus surrounding the FH gene itself in chromosome 1q43. The genes in the putative candidate region were screened, but no potentially pathogenic alterations were observed. Although these data do not rule out the existence of a genetic modifier, they emphasize the contribution of the FH genotype in HLRCC related RCC. Therefore, as all FH mutation carriers may have an increased risk for developing renal cancer, counseling and genetic testing should be offered for all HLRCC family members and clinical follow-up should be organized for the mutation carriers.
Published: 2010

24. PHD2 mutation and congenital erythrocytosis with paraganglioma

Author: Charline Ladroue, Romain Carcenac, Michel Leporrier, Sophie Gad, Claire Le Hello, Françoise Galateau-Salle, Jean Feunteun, Jacques Pouysségur, Stéphane Richard, and Betty Gardie
Subjects: Adult, Male, Angiogenesis, Sequence analysis, Procollagen-Proline Dioxygenase, Loss of Heterozygosity, Polycythemia, Biology, medicine.disease_cause, Mediastinal Neoplasms, Hypoxia-Inducible Factor-Proline Dioxygenases, Loss of heterozygosity, Paraganglioma, Germline mutation, medicine, Humans, Hemochromatosis Protein, Gene, Germ-Line Mutation, Mutation, Histocompatibility Antigens Class I, Homozygote, Membrane Proteins, Neoplasms, Second Primary, General Medicine, Sequence Analysis, DNA, medicine.disease, Pedigree, Cancer research, Erythropoiesis, Female
Abstract: Prolyl hydroxylase domain (PHD) proteins play a major role in regulating the hypoxia-inducible factor (HIF) that induces expression of genes involved in angiogenesis, erythropoiesis, and cell metabolism, proliferation, and survival. Germ-line mutations in the prolyl hydroxylase domain 2 gene (PHD2) have been reported in patients with familial erythrocytosis but not in association with tumors. We describe a patient with erythrocytosis and recurrent paraganglioma who carries a newly discovered PHD2 mutation. This mutation affects PHD2 function and stabilizes HIF-alpha proteins. In addition, we demonstrate loss of heterozygosity of PHD2 in the tumor, suggesting that PHD2 could be a tumor-suppressor gene.
Published: 2008

25. 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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26. Disruption of the multiple tumor suppressor gene MTS1/p16(INK4a)/CDKN2 by illegitimate V(D)J recombinase activity in T-cell acute lymphoblastic leukemias

Author: Jean-Michel Cayuela, François Sigaux, and Betty Gardie
Subjects: Genetics, Recombinase activity, Tumor suppressor gene, Base Sequence, Sequence analysis, Immunology, Breakpoint, Molecular Sequence Data, Locus (genetics), Cell Biology, Hematology, Gene rearrangement, Biology, Gene Rearrangement, T-Lymphocyte, Biochemistry, Exon, Multigene Family, DNA Nucleotidyltransferases, Humans, Leukemia-Lymphoma, Adult T-Cell, Gene, VDJ Recombinases, Cyclin-Dependent Kinase Inhibitor p16, Gene Deletion
Abstract: We have recently shown that the multiple tumor suppressor gene 1 (MTS1 ) encoding the p16INK4a and p19ARF cell-cycle inhibitors is inactivated by deletion or disruption in most human T-cell acute lymphoblastic leukemias (T-ALLs), representing the most frequent genetic event thus far described in this disease. To analyze the mechanism of these chromosomal events, we used cloning, sequencing, and/or polymerase chain reaction mapping to study 15 rearrangements occurring in the MTS1 locus. We found that these breakpoints occur in two clusters (MTS1bcrα and MTS1bcrβ ). The three rearrangements occurring in MTS1bcrα correspond to a recurrent recombination juxtaposing 5′ MTS2 exon 1 and 5′ MTS1 exon 1α sequences. Breakpoints for 10 of 12 rearrangements within MTS1bcrβ are located at a polymorphic (CA) repeat, suggesting that this sequence might play a role in the clustering. For both MTS1bcrα and MTS1bcrβ, sequence analyses and PCR mapping experiments show that the tightly clustered breakpoints are located in the vicinity of heptamers whose sequence is similar to those involved in the V(D)J recombination. Moreover, short deletions, GC-rich random nucleotide additions, and clone-specific junctional sequences are present in all cases, further suggesting that the rearrangements are due to illegitimate V(D)J recombinase activity. These data are the first demonstration that a tumor suppressor gene can be inactivated by the V(D)J recombinational mechanism. Moreover, they reinforce the view that this process, normally required for T-cell differentiation, plays a crucial role in the pathogenesis of T-ALL.
Published: 1997

27. Abstract 5011: Potential tumor suppressor role of PHD2 : functional study of mutations identified in germline DNA of patients with congenital polycythemia with or without paraganglioma

Author: Kiladjian Jean-Claude, Stéphane Richard, Sophie Giraud, Sophie Gad, Olivier Hermine, Nathalie M. Mazure, Betty Gardie, Jacques Pouysségur, Romain Carcenac, J Bombled, André Baruchel, Michel Leporrier, Michel Barrois, and Charline Ladroue
Subjects: Genetics, Cancer Research, biology, medicine.disease, Compound heterozygosity, Phenotype, Germline, Protein ubiquitination, Ubiquitin ligase, Germline mutation, Oncology, Hypoxia-inducible factors, Paraganglioma, biology.protein, Cancer research, medicine
Abstract: The Hypoxia Inducible Factor (HIF) plays a major role in tissue response to hypoxia. HIF induces expression of many genes involved in anaerobic glycolysis, angiogenesis, erythropoiesis and cell proliferation. HIF-alpha subunit is tightly regulated by a family of specific hydroxylases in normoxia. PHD (prolyl-hydroxylase domain) proteins hydroxylate HIF-alpha, thereby allowing its attachment to the VHL protein, a component of an E3 ubiquitin ligase complex involved in protein ubiquitination and degradation. Mutations in HIF regulators have been described and lead to the stabilization of HIF, activation of target genes and development of either tumors or polycythemia. Heterozygous germline mutations in the VHL gene predispose to the von Hippel-Lindau disease characterized by a panel of highly vascularized tumors (central nervous system and retinal hemangioblastomas, pheochromocytomas, renal cell carcinoma, pancreatic endocrine tumors) whereas homozygous or compound heterozygous VHL mutations are responsible for isolated polycythemia (”Chuvash polycythemia”) with high circulating erythropoietin levels. Recently, heterozygous germline mutations in the PHD2 gene have been described in few patients with such congenital polycythemia and a particular mutation (H374R) has been identified in a patient with a polycythemia and a recurrent paraganglioma1. This observation raised the question of a possible role of PHD2 loss of function in the genesis of tumors usually seen in the VHL disease. We report here four new heterozygous PHD2 germline mutations in patients with familial or apparently sporadic polycythemia. We performed a functional study of these mutants compared to the H374R mutant and we showed differences in the capacity of the PHD2 mutants to downregulate HIF-alpha. These differences, tested in various conditions, are highly reproducible and suggest that there may be a genotype/phenotype correlation for the PHD2 mutants like the VHL mutants with their different ability to regulate HIF associated with different phenotypes in the VHL disease. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5011.
Published: 2010
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28. Abstract 1844: No evidence for genetic factor increasing renal cell cancer risk in Hereditary Leiomyomatosis and Renal Cell Cancer syndrome

Author: Maija Ht Kiuru, Stéphane Richard, Outi Vierimaa, Riitta Herva, Virpi Launonen, Lauri A. Aaltonen, Marja Hietala, Erik Björck, Laura Näätsaari, Satu-Leena Sallinen, Leigha Senter, Pia Vahteristo, Ignacio Blanco, Emmanuel Van Glabeke, Kristiina Aittomäki, Taru A. Koski, Auli Karhu, Betty Gardie, Rainer Lehtonen, Didier Bessis, and Richard S. Houlston
Subjects: Cancer Research, Pathology, medicine.medical_specialty, medicine.diagnostic_test, Locus (genetics), Biology, urologic and male genital diseases, medicine.disease, 01 natural sciences, Phenotype, 3. Good health, 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, Leiomyomatosis, Germline mutation, Oncology, Fumarase, Hereditary leiomyomatosis and renal cell cancer syndrome, medicine, Cancer research, 030212 general & internal medicine, 0101 mathematics, Gene, Genetic testing
Abstract: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary tumor predisposition syndrome with fumarate hydratase (FH), which encodes a tricarboxylic acid cycle enzyme fumarase, as the predisposing gene. The HLRCC family members carry heterozygous germline mutations of the FH gene and the tumors often harbor a second hit making the growth fumarase deficient. The phenotype includes benign cutaneous and uterine leiomyomas as well as renal cell cancer (RCC). The HLRCC related RCCs usually belong to histological papillary type II subtype and are solitary, unilateral and aggressive. The benign leiomyomas are the most common manifestation of the syndrome affecting almost all FH mutation carriers whereas the renal cell cancer phenotype affects only about 20% of the HLRCC families. Interestingly, majority of the families with multiple renal cell cancer cases have concentrated in Finland and the U.S. Why the malignant phenotype affects only a part of the HLRCC patients is unknown. There is no genotype-phenotype correlation and type or site of the FH mutation does not affect the phenotype. The fumarase enzyme activity levels do not correlate with the phenotype either. Thus it is possible that the appearance of RCC requires, in addition to FH mutation, another genetic factor. To search for such a factor in four Finnish HLRCC families with multiple RCC cases we performed genome wide linkage and/or identical by descent (IBD) analyses. After finemapping procedures the only region compatible with linkage was the FH locus itself in 1q43. The genes of the region were screened but no pathognomonic mutations were found. Although these results do not exclude the existence of a genetic RCC risk modifier in HLRCC, the role of FH mutations behind RCC tumors is emphasized. Counseling and genetic testing should be available for HLRCC family members and the FH mutation carriers should be carefully followed up to enable early detection and treatment of the aggressive cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1844.
Published: 2010
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29. An Antioxidant Response Phenotype Shared between Hereditary and Sporadic Type 2 Papillary Renal Cell Carcinoma

Author: David Petillo, Kyle A. Furge, Bernice Wong Hui Min, Min-Han Tan, Betty Gardie, Ming Zhou, Ximing J. Yang, Stéphane Richard, Douglas Whitten, Vincent Molinié, Jing Chii Wong, Puay Hoon Tan, Douglas Roossien, Aikseng Ooi, Victoria Perrier-Trudova, Zhongfa Zhang, and Bin Tean Teh
Subjects: Cancer Research, NF-E2-Related Factor 2, Aldo-Keto Reductases, Biology, Response Elements, medicine.disease_cause, Antioxidants, Fumarate Hydratase, Aldehyde Reductase, Cell Line, Tumor, Null cell, medicine, Humans, RNA, Messenger, Carcinoma, Renal Cell, Gene, Genetics, Gene knockdown, Mutation, Kelch-Like ECH-Associated Protein 1, Papillary renal cell carcinomas, Nuclear Respiratory Factor 1, Intracellular Signaling Peptides and Proteins, Cell Biology, Hypoxia-Inducible Factor 1, alpha Subunit, Phenotype, Kidney Neoplasms, Gene Expression Regulation, Neoplastic, Oncology, Fumarase, Cancer research, Hereditary leiomyomatosis and renal cell carcinoma
Abstract: Summary Fumarate hydratase ( FH ) mutation causes hereditary type 2 papillary renal cell carcinoma (PRCC2). The main effect of FH mutation is fumarate accumulation. The current paradigm posits that the main consequence of fumarate accumulation is HIF-α stabilization. Paradoxically, FH mutation differs from other HIF-α stabilizing mutations, such as VHL and SDH mutations, in its associated tumor types. We identified that fumarate can directly up-regulate antioxidant response element (ARE)–controlled genes. We demonstrated that aldo-keto reductase family 1 member B10 ( AKR1B10 ) is an ARE-controlled gene and is up-regulated upon FH knockdown as well as in FH null cell lines. AKR1B10 overexpression is also a prominent feature in both hereditary and sporadic PRCC2. This phenotype better explains the similarities between hereditary and sporadic PRCC2.
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29 results on '"Betty Gardie"'

1. Involvement of PBRM1 in VHL disease‑associated clear cell renal cell carcinoma and its putative relationship with the HIF pathway

2. Germline mutation in the NBR1 gene involved in autophagy detected in a family with renal tumors

3. Absence of CALR Mutations in Idiopathic Erythrocytosis Patients with Low Serum Erythropoietin Levels

4. Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome

5. Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease

6. Integrative analysis of dysregulated microRNAs and mRNAs in multiple recurrent synchronized renal tumors from patients with von Hippel-Lindau disease

7. Update on hypoxia-inducible factors and hydroxylases in oxygen regulatory pathways: from physiology to therapeutics

8. Gene panel sequencing in idiopathic erythrocytosis

9. The role of PHD2 mutations in the pathogenesis of erythrocytosis

10. Von Hippel–Lindau: How a rare disease illuminates cancer biology

11. Corrigendum: A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma

12. Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia

13. A study of 36 unrelated cases with pure erythrocytosis revealed three new mutations in the erythropoietin receptor gene

14. Pathogenesis of Myeloproliferative Neoplasms: Role and Mechanisms of Chronic Inflammation

15. Raf-1-induced growth arrest in human mammary epithelial cells is p16-independent and is overcome in immortal cells during conversion

16. Transgenic Expression of the p16INK4a Cyclin-Dependent Kinase Inhibitor Leads to Enhanced Apoptosis and Differentiation Arrest of CD4−CD8− Immature Thymocytes

17. Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during oncogenesis

18. Genomic Alterations of the p19ARF Encoding Exons in T-Cell Acute Lymphoblastic Leukemia

19. Identification of TET1 Partners That Control Its DNA-Demethylating Function

20. Genetic Basis of Congenital Erythrocytosis: Mutation Update and Online Databases

21. Next Generation Sequencing Is a Useful Tool for the Diagnosis of Congenital/Idiopathic Erythrocytoses

22. Novel FH mutations in families with hereditary leiomyomatosis renal cell cancer (HLRCC) and in patients with isolated type 2 papillary renal cell carcinoma

23. No evidence for a genetic modifier for renal cell cancer risk in HLRCC syndrome

24. PHD2 mutation and congenital erythrocytosis with paraganglioma

25. A Comprehensive Study of the VHL-R200W Chuvash Polycythemia Mutation Reveals a Gradual Dysregulation of the Hypoxia Pathway in Oncogenesis

26. Disruption of the multiple tumor suppressor gene MTS1/p16(INK4a)/CDKN2 by illegitimate V(D)J recombinase activity in T-cell acute lymphoblastic leukemias

27. Abstract 5011: Potential tumor suppressor role of PHD2 : functional study of mutations identified in germline DNA of patients with congenital polycythemia with or without paraganglioma

28. Abstract 1844: No evidence for genetic factor increasing renal cell cancer risk in Hereditary Leiomyomatosis and Renal Cell Cancer syndrome

29. An Antioxidant Response Phenotype Shared between Hereditary and Sporadic Type 2 Papillary Renal Cell Carcinoma

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