Format

Send to

Choose Destination
Cancer Res. 2014 Nov 15;74(22):6554-64. doi: 10.1158/0008-5472.CAN-14-1161. Epub 2014 Nov 4.

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

Author information

1
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.
2
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.
3
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.
4
Plate-forme de Génomique, Gustave Roussy Cancer Campus, Villejuif, France.
5
Mathématiques Appliquées à Paris 5 (MAP5), UMR CNRS 8145, Université Paris Descartes, Paris, France.
6
Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
7
Médecine Générale, Couvin, Belgium.
8
INSERM U966, Université François Rabelais de Tours, Faculté de Médecine, Tours, France.
9
Département des analyses, Agence Française de Lutte contre le Dopage (AFLD), Chatenay-Malabry, France.
10
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.
11
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.
12
Laboratoire Stabilité génétique et Oncogénèse, UMR CNRS 8200, Gustave Roussy Cancer Campus, Villejuif, France.
13
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.
14
Institute for Research on Cancer and Ageing of Nice (IRCAN), UMR CNRS 7284, INSERM U1081, UNS, Nice, France.
15
Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), CNRS-ENS de Cachan, LabEx LERMIT, Cachan, France.
16
Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, United Kingdom.
17
Howard Hughes Medical Institute, Chevy Chase, Maryland.
18
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.
19
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.

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.

PMID:
25371412
PMCID:
PMC5555745
DOI:
10.1158/0008-5472.CAN-14-1161
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center