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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 y. Kim 7 Bernard Lecomte 8 Jean-Christophe Pagès 9 Christine Collin 9 Françoise Lasne 10 Patrick R Benusiglio 1, 11 Brigitte Bressac-de Paillerets 12, 1 Jean Feunteun 13 Vladimir Lazar 5 Anne-Paule Gimenez-Roqueplo 1, 14 Nathalie M Mazure 15 Philippe Dessen 11 Luba Tchertanov 1 David R. Mole 16 William Kaelin 17 Peter J Ratcliffe 16 Stéphane Richard 18 Betty Gardie 2, 19, * 
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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Sophie Couvé, Charline Ladroue, Elodie Laine, Karène Mahtouk, Justine Guégan, et al.. Genetic Evidence of a Precisely Tuned Dysregulation in the Hypoxia Signaling Pathway during Oncogenesis. Cancer Research, American Association for Cancer Research, 2014, 74 ((22)), pp.6554-64. ⟨10.1158/0008-5472.CAN-14-1161⟩. ⟨inserm-01401701⟩



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