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

Bertolotto, Corine; Lesueur, Fabienne; Giuliano, Sandy; Strub, Thomas; de Lichy, Mahaut; Bille, Karine; Dessen, Philippe; d'Hayer, Benoit; Mohamdi, Hamida and Remenieras, Audrey, et al. (2011) In Nature 480(7375). p.94-259
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(1); risk factors associated with RCC include smoking, obesity and hypertension(2). A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers(3). The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene(4); it also stimulates the transcription of hypoxia inducible factor(5) (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes(6). We therefore proposed that MITF... (More)
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(1); risk factors associated with RCC include smoking, obesity and hypertension(2). A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers(3). The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene(4); it also stimulates the transcription of hypoxia inducible factor(5) (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes(6). 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 (Psi KXE) 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. (Less)
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Nature
volume
480
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7375
pages
94 - 259
publisher
Nature Publishing Group
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  • wos:000298031900041
  • scopus:82555205202
ISSN
0028-0836
DOI
10.1038/nature10539
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English
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yes
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674fff73-37a1-4a8f-8da9-d943a8599e9a (old id 2291617)
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2012-01-11 13:22:18
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@article{674fff73-37a1-4a8f-8da9-d943a8599e9a,
  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(1); risk factors associated with RCC include smoking, obesity and hypertension(2). A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers(3). The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene(4); it also stimulates the transcription of hypoxia inducible factor(5) (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes(6). 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 (Psi KXE) 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.},
  author       = {Bertolotto, Corine and Lesueur, Fabienne and Giuliano, Sandy and Strub, Thomas and de Lichy, Mahaut and Bille, Karine and Dessen, Philippe and d'Hayer, Benoit and Mohamdi, Hamida and Remenieras, Audrey and Maubec, Eve and de la Fouchardiere, Arnaud and Molinie, Vincent and Vabres, Pierre and Dalle, Stephane and Poulalhon, Nicolas and Martin-Denavit, Tanguy and Thomas, Luc and Andry-Benzaquen, Pascale and Dupin, Nicolas and Boitier, Francoise and Rossi, Annick and Perrot, Jean-Luc and Labeille, Bruno and Robert, Caroline and Escudier, Bernard and Caron, Olivier and Brugieres, Laurence and Saule, Simon and Gardie, Betty and Gad, Sophie and Richard, Stephane and Couturier, Jerome and Teh, Bin Tean and Ghiorzo, Paola and Pastorino, Lorenza and Puig, Susana and Badenas, Celia and Olsson, Håkan and Ingvar, Christian and Rouleau, Etienne and Lidereau, Rosette and Bahadoran, Philippe and Vielh, Philippe and Corda, Eve and Blanche, Helene and Zelenika, Diana and Galan, Pilar and Chaudru, Valerie and Lenoir, Gilbert M. and Lathrop, Mark and Davidson, Irwin and Avril, Marie-Francoise and Demenais, Florence and Ballotti, Robert and Bressac-de Paillerets, Brigitte},
  issn         = {0028-0836},
  language     = {eng},
  number       = {7375},
  pages        = {94--259},
  publisher    = {Nature Publishing Group},
  series       = {Nature},
  title        = {A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma},
  url          = {http://dx.doi.org/10.1038/nature10539},
  volume       = {480},
  year         = {2011},
}