[en] 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.
Disciplines :
Genetics & genetic processes
Author, co-author :
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
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
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