Genetic Evidence of a Precisely Tuned Dysregulation in the Hypoxia Signaling Pathway during Oncogenesis - Inserm - Institut national de la santé et de la recherche médicale Accéder directement au contenu
Article Dans Une Revue Cancer Research Année : 2014

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

Grégory Nuel
Jean Feunteun
  • Fonction : Auteur
  • PersonId : 907567
Philippe Dessen
  • Fonction : Auteur
  • PersonId : 940894
Luba Tchertanov

Résumé

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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Cancer
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Dates et versions

inserm-01401701 , version 1 (23-11-2016)

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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, 2014, 74 ((22)), pp.6554-64. ⟨10.1158/0008-5472.CAN-14-1161⟩. ⟨inserm-01401701⟩
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