A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.

Abstract

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 (ΨKXE) 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.

• Authors: Corine Bertolotto, Fabienne Lesueur, Sandy Giuliano, Thomas Strub, Mahaut de Lichy, Karine Bille, Philippe Dessen, Benoit d'Hayer, Hamida Mohamdi, Audrey Remenieras, Eve Maubec, Arnaud de la Fouchardière, Vincent Molinié, Pierre Vabres, Stéphane Dalle, Nicolas Poulalhon, Tanguy Martin-Denavit, Luc Thomas, Pascale Andry-Benzaquen, Nicolas Dupin, Françoise Boitier, Annick Rossi, Jean-Luc Perrot, Bruno Labeille, Caroline Robert, Bernard Escudier, Olivier Caron, Laurence Brugières, Simon Saule, Betty Gardie, Sophie Gad, Stéphane Richard, Jérôme Couturier, Bin Tean Teh, Paola Ghiorzo, Lorenza Pastorino, Susana Puig, Celia Badenas, Hakan Olsson, Christian Ingvar, Etienne Rouleau, Rosette Lidereau, Philippe Bahadoran, Philippe Vielh, Eve Corda, Hélène Blanché, Diana Zelenika, Pilar Galan, French Familial Melanoma Study Group, François Aubin, Bertrand Bachollet, Céline Becuwe, Pascaline Berthet, Yves Jean Bignon, Valérie Bonadona, Jean-Louis Bonafe, Marie-Noëlle Bonnet-Dupeyron, Fréderic Cambazard, Jacqueline Chevrant-Breton, Isabelle Coupier, Sophie Dalac, Liliane Demange, Michel d'Incan, Catherine Dugast, Laurence Faivre, Lynda Vincent-Fétita, Marion Gauthier-Villars, Brigitte Gilbert, Florent Grange, Jean-Jacques Grob, Philippe Humbert, Nicolas Janin, Pascal Joly, Delphine Kerob, Christine Lasset, Dominique Leroux, Julien Levang, Jean-Marc Limacher, Cristina Livideanu, Michel Longy, Alain Lortholary, Dominique Stoppa-Lyonnet, Sandrine Mansard, Ludovic Mansuy, Karine Marrou, Christine Matéus, Christine Maugard, Nicolas Meyer, Catherine Nogues, Pierre Souteyrand, Laurence Venat-Bouvet, Hélène Zattara, Valérie Chaudru, Gilbert M Lenoir, Mark Lathrop, Irwin Davidson, Marie-Françoise Avril, Florence Demenais, Robert Ballotti, Brigitte Bressac-de Paillerets
• Journal: Nature (Nature) Vol. 480 Issue 7375 Pg. 94-8 (Oct 19 2011) ISSN: 1476-4687 [Electronic] England
• PMID: 22012259 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MITF protein, human
• Microphthalmia-Associated Transcription Factor

Topics

• 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