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    Publication Date: 2011-10-21
    Description: So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes; risk factors associated with RCC include smoking, obesity and hypertension. A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers. The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene; it also stimulates the transcription of hypoxia inducible factor (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes. We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (PsiKXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K-occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bertolotto, Corine -- Lesueur, Fabienne -- Giuliano, Sandy -- Strub, Thomas -- de Lichy, Mahaut -- Bille, Karine -- Dessen, Philippe -- d'Hayer, Benoit -- Mohamdi, Hamida -- Remenieras, Audrey -- Maubec, Eve -- de la Fouchardiere, Arnaud -- Molinie, Vincent -- Vabres, Pierre -- Dalle, Stephane -- Poulalhon, Nicolas -- Martin-Denavit, Tanguy -- Thomas, Luc -- Andry-Benzaquen, Pascale -- Dupin, Nicolas -- Boitier, Francoise -- Rossi, Annick -- Perrot, Jean-Luc -- Labeille, Bruno -- Robert, Caroline -- Escudier, Bernard -- Caron, Olivier -- Brugieres, Laurence -- Saule, Simon -- Gardie, Betty -- Gad, Sophie -- Richard, Stephane -- Couturier, Jerome -- Teh, Bin Tean -- Ghiorzo, Paola -- Pastorino, Lorenza -- Puig, Susana -- Badenas, Celia -- Olsson, Hakan -- Ingvar, Christian -- Rouleau, Etienne -- Lidereau, Rosette -- Bahadoran, Philippe -- Vielh, Philippe -- Corda, Eve -- Blanche, Helene -- Zelenika, Diana -- Galan, Pilar -- French Familial Melanoma Study Group -- Aubin, Francois -- Bachollet, Bertrand -- Becuwe, Celine -- Berthet, Pascaline -- Bignon, Yves Jean -- Bonadona, Valerie -- Bonafe, Jean-Louis -- Bonnet-Dupeyron, Marie-Noelle -- Cambazard, Frederic -- Chevrant-Breton, Jacqueline -- Coupier, Isabelle -- Dalac, Sophie -- Demange, Liliane -- d'Incan, Michel -- Dugast, Catherine -- Faivre, Laurence -- Vincent-Fetita, Lynda -- Gauthier-Villars, Marion -- Gilbert, Brigitte -- Grange, Florent -- Grob, Jean-Jacques -- Humbert, Philippe -- Janin, Nicolas -- Joly, Pascal -- Kerob, Delphine -- Lasset, Christine -- Leroux, Dominique -- Levang, Julien -- Limacher, Jean-Marc -- Livideanu, Cristina -- Longy, Michel -- Lortholary, Alain -- Stoppa-Lyonnet, Dominique -- Mansard, Sandrine -- Mansuy, Ludovic -- Marrou, Karine -- Mateus, Christine -- Maugard, Christine -- Meyer, Nicolas -- Nogues, Catherine -- Souteyrand, Pierre -- Venat-Bouvet, Laurence -- Zattara, Helene -- Chaudru, Valerie -- Lenoir, Gilbert M -- Lathrop, Mark -- Davidson, Irwin -- Avril, Marie-Francoise -- Demenais, Florence -- Ballotti, Robert -- Bressac-de Paillerets, Brigitte -- England -- Nature. 2011 Oct 19;480(7375):94-8. doi: 10.1038/nature10539.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] INSERM, U895 (equipe 1), Equipe labelisee Ligue Contre le Cancer, C3M, 06204 Nice, France [2] Universite of Nice Sophia-Antipolis, UFR Medecine, 06204 Nice, France [3] Centre Hospitalier Universitaire de Nice, Service de Dermatologie, 06204 Nice, France [4].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: Carcinoma, Renal Cell/*genetics ; Cell Movement/genetics ; Gene Frequency ; *Genetic Predisposition to Disease ; *Germ-Line Mutation ; Humans ; Melanoma/*genetics ; Microphthalmia-Associated Transcription Factor/*genetics ; Neoplasm Invasiveness/genetics ; Sumoylation
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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