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

Corine Bertolotto-Ballotti 1 Fabienne Lesueur 2 Sandy Giuliano Thomas Strub Mahaut de Lichy Karine Bille 1 Philippe Dessen 3 Benoit d'Hayer Hamida Mohamdi Audrey Remenieras 4 Eve Maubec 5 Arnaud de la Fouchardière Vincent Molinié 6 Pierre Vabres 7, 8 Stéphane Dalle 9 Nicolas Poulalhon 10 Tanguy Martin-Denavit Luc Thomas 11 Pascale Andry-Benzaquen Nicolas Dupin 12 Françoise Boitier Annick Rossi 13 Jean-Luc Perrot Bruno Labeille Caroline Robert 14 Bernard Escudier 15 Olivier Caron 16 Laurence Brugières 17 Simon Saule Betty Gardie 18 Sophie Gad 18 Stéphane Richard 19 Jérôme Couturier 20 Bin Tean Teh 21 Paola Ghiorzo Lorenza Pastorino Susana Puig Celia Badenas Hakan Olsson 22, 23 Christian Ingvar 24 Etienne Rouleau 25 Rosette Lidereau 26, 27 Philippe Bahadoran Philippe Vielh 28 Eve Corda 29 Hélène Blanché Diana Zelenika 30 Pilar Galan 31 Non Renseigné François Aubin 32 Bertrand Bachollet Céline Becuwe Pascaline Berthet 33 Yves Jean Bignon Valérie Bonadona 34 Jean-Louis Bonafe Marie-Noëlle Bonnet-Dupeyron Fréderic Cambazard 35 Jacqueline Chevrant-Breton Isabelle Coupier 36 Sophie Dalac Liliane Demange 37 Michel d'Incan 38 Catherine Dugast 39 Laurence Faivre 40 Lynda Vincent-Fétita Marion Gauthier-Villars 41 Brigitte Gilbert 42 Florent Grange Jean-Jacques Grob 43 Philippe Humbert 5 Nicolas Janin 44 Pascal Joly 45 Delphine Kerob 46 Christine Lasset 47 Dominique Leroux 48 Julien Levang Jean-Marc Limacher Cristina Livideanu Michel Longy 49 Alain Lortholary Dominique Stoppa-Lyonnet 41, 50 Sandrine Mansard Ludovic Mansuy 51 Karine Marrou Christine Matéus Christine Maugard 52 Nicolas Meyer 53 Catherine Nogues 26 Pierre Souteyrand Laurence Venat-Bouvet 54 Hélène Zattara 55 Valérie Chaudru Gilbert M Lenoir Mark Lathrop 29, 56, 57 Irwin Davidson 58 Marie-Françoise Avril 59 Florence Demenais 29, 60, 61 Robert Ballotti Brigitte Bressac-de Paillerets 62
4 Onco-génétique
Département de médecine oncologique [Gustave Roussy]
14 Service de dermatologie
Département de médecine oncologique [Gustave Roussy]
28 Pathologie morphologique
Département de biologie et pathologie médicales [Gustave Roussy]
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.
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Submitted on : Friday, July 20, 2012 - 9:49:24 AM
Last modification on : Monday, December 21, 2020 - 3:36:05 PM

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Corine Bertolotto-Ballotti, Fabienne Lesueur, Sandy Giuliano, Thomas Strub, Mahaut de Lichy, et al.. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.. Nature, Nature Publishing Group, 2011, 480 (7375), pp.94-98. ⟨10.1038/nature10539⟩. ⟨hal-00719536⟩



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