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

TitleGenetic Evidence of a Precisely Tuned Dysregulation in the Hypoxia Signaling Pathway during Oncogenesis.
Publication TypeJournal Article
Year of Publication2014
AuthorsCouvé, S, Ladroue, C, Laine, E, Mahtouk, K, Guégan, J, Gad, S, Le Jeune, H, Le Gentil, M, Nuel, G, Kim, WY, Lecomte, B, Pagès, J-C, Collin, C, Lasne, F, Benusiglio, PR, de Paillerets, BBressac-, Feunteun, J, Lazar, V, Gimenez-Roqueplo, A-P, Mazure, NM, Dessen, P, Tchertanov, L, Mole, DR, Kaelin, W, Ratcliffe, P, Richard, S, Gardie, B
JournalCancer Res
Volume74
Issue22
Pagination6554-64
Date Published2014 Nov 15
ISSN1538-7445
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. Cancer Res; 74(22); 6554-64. ©2014 AACR.

DOI10.1158/0008-5472.CAN-14-1161
Alternate JournalCancer Res.
PubMed ID25371412