Genetic Evidence of a Precisely Tuned Dysregulation in the Hypoxia Signaling Pathway during Oncogenesis

Sophie Couvé; Charline Ladroue; Elodie Laine; Karène Mahtouk; Justine Guégan; Sophie Gad; Hélène Le Jeune; Marion Le Gentil; Grégory Nuel; William Kim; Bernard Lecomte; Jean-Christophe Pagès; Christine Collin; Françoise Lasne; Patrick Benusiglio; Brigitte Bressac-de Paillerets; Jean Feunteun; Vladimir Lazar; Anne-Paule Gimenez-Roqueplo; Nathalie Mazure; Philippe Dessen; Luba Tchertanov; David Mole; William Kaelin; Peter Ratcliffe; Stéphane Richard; Betty Gardie

doi:10.1158/0008-5472.CAN-14-1161

Journal articles

Genetic Evidence of a Precisely Tuned Dysregulation in the Hypoxia Signaling Pathway during Oncogenesis

Sophie Couvé ^{1, 2, 3} Charline Ladroue ^{2, 3} Elodie Laine ^{4, 1} Karène Mahtouk ^{2, 3} Justine Guégan ⁵ Sophie Gad ^{2, 3, 1} Hélène Le Jeune ^{2, 3} Marion Le Gentil ⁵ Grégory Nuel ⁶ William Kim ⁷ Bernard Lecomte ⁸ Jean-Christophe Pagès ⁹ Christine Collin ⁹ Françoise Lasne ¹⁰ Patrick Benusiglio ^{1, 11} Brigitte Bressac-de Paillerets ^{12, 1} Jean Feunteun ¹³ Vladimir Lazar ⁵ Anne-Paule Gimenez-Roqueplo ^{1, 14} Nathalie Mazure ¹⁵ Philippe Dessen ¹¹ Luba Tchertanov ¹ David Mole ¹⁶ William Kaelin ¹⁷ Peter Ratcliffe ¹⁶ Stéphane Richard ¹⁸ Betty Gardie ^{2, 19, *}

* Corresponding author

1 INC - Institut National du Cancer [Boulogne Billancourt]

2 EPHE - École pratique des hautes études

3 U753 - Cytokines et Immunologie des Tumeurs Humaines

4 LCQB - Biologie Computationnelle et Quantitative = Laboratory of Computational and Quantitative Biology

5 Plateforme de Génomique [Gustave Roussy]

AMMICa - Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse

6 MAP5 - UMR 8145 - Mathématiques Appliquées Paris 5

7 UNC Lineberger - Lineberger Comprehensive Cancer Center

8 Médecine générale

9 Virus, pseudo-virus: Morphogénèse et Antigénicité

10 AFLD - Agence Française de Lutte contre le Dopage

11 IGR - Institut Gustave Roussy

12 Onco-génétique

Département de médecine oncologique [Gustave Roussy]

13 UMR 8200 - Stabilité Génétique et Oncogenèse

14 Angiogenesis Imaging UMR970

15 IRCAN - Institut de Recherche sur le Cancer et le Vieillissement

16 Henry Wellcome Building for Molecular Physiology

17 Howard Hugues Medical Institute

18 Génétique Oncologique EPHE, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre

19 CRCNA - Centre de Recherche en Cancérologie Nantes-Angers

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.

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Journal articles

Domain :

Life Sciences [q-bio] / Cancer

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Genetic Evidence of a Precisely Tuned Dysregulation in the Hypoxia Signaling Pathway during Oncogenesis

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Genetic Evidence of a Precisely Tuned Dysregulation in the Hypoxia Signaling Pathway during Oncogenesis

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