title: Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during oncogenesis.
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.
authors.affiliation: Laboratoire de Génétique Oncologique de l'Ecole Pratique des Hautes Etudes (EPHE), Villejuif, France. Institut National de la Santé et de la Recherche Medicale (INSERM) U753, Gustave Roussy Cancer Campus, Villejuif, France. Centre Expert National Cancers Rares INCa "PREDIR" and Réseau National INCa "Maladie de VHL et prédispositions au cancer du rein," Service d'Urologie, Assistance publique, Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Couvé
authors.affiliation: Laboratoire de Génétique Oncologique de l'Ecole Pratique des Hautes Etudes (EPHE), Villejuif, France. Institut National de la Santé et de la Recherche Medicale (INSERM) U753, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Charline
authors.initials: C
authors.lastname: Ladroue
authors.affiliation: Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), CNRS-ENS de Cachan, LabEx LERMIT, Cachan, France. Equipe de Génomique Analytique, Laboratoire de Biologie Computationnelle et Quantitative, CNRS-UPMC, UMR 7238, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Laine
authors.affiliation: Laboratoire de Génétique Oncologique de l'Ecole Pratique des Hautes Etudes (EPHE), Villejuif, France. Institut National de la Santé et de la Recherche Medicale (INSERM) U753, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Karène
authors.initials: K
authors.lastname: Mahtouk
authors.affiliation: Plate-forme de Génomique, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Justine
authors.initials: J
authors.lastname: Guégan
authors.affiliation: Laboratoire de Génétique Oncologique de l'Ecole Pratique des Hautes Etudes (EPHE), Villejuif, France. Institut National de la Santé et de la Recherche Medicale (INSERM) U753, Gustave Roussy Cancer Campus, Villejuif, France. Centre Expert National Cancers Rares INCa "PREDIR" and Réseau National INCa "Maladie de VHL et prédispositions au cancer du rein," Service d'Urologie, Assistance publique, Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Gad
authors.affiliation: Laboratoire de Génétique Oncologique de l'Ecole Pratique des Hautes Etudes (EPHE), Villejuif, France. Institut National de la Santé et de la Recherche Medicale (INSERM) U753, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Le Jeune
authors.affiliation: Plate-forme de Génomique, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Le Gentil
authors.affiliation: Mathématiques Appliquées à Paris 5 (MAP5), UMR CNRS 8145, Université Paris Descartes, Paris, France.
authors.forename: Gregory
authors.initials: G
authors.lastname: Nuel
authors.affiliation: Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: William Y
authors.initials: WY
authors.lastname: Kim
authors.affiliation: Médecine Générale, Couvin, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Lecomte
authors.affiliation: INSERM U966, Université François Rabelais de Tours, Faculté de Médecine, Tours, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Pagès
authors.affiliation: INSERM U966, Université François Rabelais de Tours, Faculté de Médecine, Tours, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Collin
authors.affiliation: Département des analyses, Agence Française de Lutte contre le Dopage (AFLD), Chatenay-Malabry, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Lasne
authors.affiliation: Département de Médecine Oncologique, Gustave Roussy Cancer Campus, Villejuif, France. Centre Expert National Cancers Rares INCa "PREDIR" and Réseau National INCa "Maladie de VHL et prédispositions au cancer du rein," Service d'Urologie, Assistance publique, Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Benusiglio
authors.affiliation: Centre Expert National Cancers Rares INCa "PREDIR" and Réseau National INCa "Maladie de VHL et prédispositions au cancer du rein," Service d'Urologie, Assistance publique, Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, France. Service de Génétique, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bressac-de Paillerets
authors.affiliation: Laboratoire Stabilité génétique et Oncogénèse, UMR CNRS 8200, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Feunteun
authors.affiliation: Plate-forme de Génomique, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Lazar
authors.affiliation: Centre Expert National Cancers Rares INCa "PREDIR" and Réseau National INCa "Maladie de VHL et prédispositions au cancer du rein," Service d'Urologie, Assistance publique, Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, France. Assistance Publique, Hôpitaux de Paris, Hôpital européen Georges Pompidou, Service de Génétique, Paris, France. INSERM UMR970, Paris-Cardiovascular Research Center at HEGP, Paris, France. Université Paris Descartes, Faculté de Médecine, Paris, France.
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
authors.affiliation: Institute for Research on Cancer and Ageing of Nice (IRCAN), UMR CNRS 7284, INSERM U1081, UNS, Nice, France.
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Mazure
authors.affiliation: Plate-forme de Génomique, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Dessen
authors.affiliation: Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), CNRS-ENS de Cachan, LabEx LERMIT, Cachan, France.
authors.forename: Luba
authors.initials: L
authors.lastname: Tchertanov
authors.affiliation: Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, United Kingdom.
authors.forename: David R
authors.initials: DR
authors.lastname: Mole
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: William
authors.initials: W
authors.lastname: Kaelin
authors.affiliation: Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Ratcliffe
authors.affiliation: Laboratoire de Génétique Oncologique de l'Ecole Pratique des Hautes Etudes (EPHE), Villejuif, France. Institut National de la Santé et de la Recherche Medicale (INSERM) U753, Gustave Roussy Cancer Campus, Villejuif, France. Centre Expert National Cancers Rares INCa "PREDIR" and Réseau National INCa "Maladie de VHL et prédispositions au cancer du rein," Service d'Urologie, Assistance publique, Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, France. Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, Paris, France. betty.gardie@inserm.fr stephane.richard@u-psud.fr.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Richard
authors.affiliation: Laboratoire de Génétique Oncologique de l'Ecole Pratique des Hautes Etudes (EPHE), Villejuif, France. Unité Mixte de Recherche (UMR) INSERM U892, CNRS 6299, Centre de Recherche en Cancérologie Nantes/Angers (CRCNA), Université de Nantes, Nantes, France. betty.gardie@inserm.fr stephane.richard@u-psud.fr.
authors.forename: Betty
authors.initials: B
authors.lastname: Gardie
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D063646:Carcinogenesis / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010673:Pheochromocytoma / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000502:physiology*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497446:VHL protein, human