Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during oncogenesis
Authors list
Sophie Couvé Charline Ladroue Elodie Laine Karène Mahtouk Justine Guégan Sophie Gad Hélène Le Jeune Marion Le Gentil Gregory Nuel William Y Kim Bernard Lecomte Jean-Christophe Pagès Christine Collin Françoise Lasne Patrick R Benusiglio Brigitte Bressac-de Paillerets Jean Feunteun Vladimir Lazar Anne-Paule Gimenez-Roqueplo Nathalie M Mazure Philippe Dessen Luba Tchertanov David R Mole William Kaelin Peter Ratcliffe Stéphane Richard Betty Gardie Toggle all authors (27)
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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Publisher website (DOI) 10.1158/0008-5472.can-14-1161
Europe PubMed Central 25371412
Pubmed 25371412
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