Résumé
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 (Î̈ 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.
| langue originale | Anglais |
|---|---|
| Pages (de - à) | 94-98 |
| Nombre de pages | 5 |
| journal | Nature |
| Volume | 480 |
| Numéro de publication | 7375 |
| Les DOIs | |
| état | Publié - 1 déc. 2011 |
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Dans: Nature, Vol 480, Numéro 7375, 01.12.2011, p. 94-98.
Résultats de recherche: Contribution à un journal › Article › Revue par des pairs
TY - JOUR
T1 - A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma
AU - Bertolotto, Corine
AU - Lesueur, Fabienne
AU - Giuliano, Sandy
AU - Strub, Thomas
AU - De Lichy, Mahaut
AU - Bille, Karine
AU - Dessen, Philippe
AU - D'Hayer, Benoit
AU - Mohamdi, Hamida
AU - Remenieras, Audrey
AU - Maubec, Eve
AU - De La Fouchardière, Arnaud
AU - Molinié, Vincent
AU - Vabres, Pierre
AU - Dalle, Stéphane
AU - Poulalhon, Nicolas
AU - Martin-Denavit, Tanguy
AU - Thomas, Luc
AU - Andry-Benzaquen, Pascale
AU - Dupin, Nicolas
AU - Boitier, Fraņoise
AU - Rossi, Annick
AU - Perrot, Jean Luc
AU - Labeille, Bruno
AU - Robert, Caroline
AU - Escudier, Bernard
AU - Caron, Olivier
AU - Brugières, Laurence
AU - Saule, Simon
AU - Gardie, Betty
AU - Gad, Sophie
AU - Richard, Stéphane
AU - Couturier, Jérôme
AU - Teh, Bin Tean
AU - Ghiorzo, Paola
AU - Pastorino, Lorenza
AU - Puig, Susana
AU - Badenas, Celia
AU - Olsson, Hakan
AU - Ingvar, Christian
AU - Rouleau, Etienne
AU - Lidereau, Rosette
AU - Bahadoran, Philippe
AU - Vielh, Philippe
AU - Corda, Eve
AU - Blanché, Hélène
AU - Zelenika, Diana
AU - Galan, Pilar
AU - Aubin, Fraņois
AU - Bachollet, Bertrand
AU - Becuwe, Céline
AU - Berthet, Pascaline
AU - Jean Bignon, Yves
AU - Bonadona, Valérie
AU - Bonafe, Jean Louis
AU - Bonnet-Dupeyron, Marie Noëlle
AU - Cambazard, Fréderic
AU - Chevrant-Breton, Jacqueline
AU - Coupier, Isabelle
AU - Dalac, Sophie
AU - Demange, Liliane
AU - D'Incan, Michel
AU - Dugast, Catherine
AU - Faivre, Laurence
AU - Vincent-Fétita, Lynda
AU - Gauthier-Villars, Marion
AU - Gilbert, Brigitte
AU - Grange, Florent
AU - Grob, Jean Jacques
AU - Humbert, Philippe
AU - Janin, Nicolas
AU - Joly, Pascal
AU - Kerob, Delphine
AU - Lasset, Christine
AU - Leroux, Dominique
AU - Levang, Julien
AU - Limacher, Jean Marc
AU - Livideanu, Cristina
AU - Longy, Michel
AU - Lortholary, Alain
AU - Stoppa-Lyonnet, Dominique
AU - Mansard, Sandrine
AU - Mansuy, Ludovic
AU - Marrou, Karine
AU - Matéus, Christine
AU - Maugard, Christine
AU - Meyer, Nicolas
AU - Nogues, Catherine
AU - Souteyrand, Pierre
AU - Venat-Bouvet, Laurence
AU - Zattara, Hélène
AU - Chaudru, Valérie
AU - Lenoir, Gilbert M.
AU - Lathrop, Mark
AU - Davidson, Irwin
AU - Avril, Marie Fraņoise
AU - Demenais, Florence
AU - Ballotti, Robert
AU - Bressac-De Paillerets, Brigitte
N1 - Funding Information: Acknowledgements We thank the patients and family members who participated in this study and the clinicians who identified these families, the French Familial MelanomaStudy Group andthe InheritedPredispositiontoKidneyCancernetwork.We acknowledge thecontribution of the IGR Biobankfor providingMELARISK samples and the CEPH Biobank for processing DNA samples. We thank L. Larue, J, Feunteun, A. Sarasin and E. Solary for critical reviews of the manuscript. We thank V. Lazar and S. Forget for coordination of the IGR’s genomics and genetic platforms, N. Pata-Merci, V. Marty, S. Le Gras and A. Chabrier for their technical expertise, and M. Barrois for technical counselling. We also thank A. Boland for DNA extraction and quality control for genome-wide genotyping. This work was supported by grants from INSERM, Ligue Nationale Contre Le Cancer (PRE05/FD and PRE 09/FD) to F.D.; Programme Hospitalier de Recherche Clinique (PHRC 2007/AOM-07-195) to M.-F.A. and F.D.; ARC NuA09/5/5003 to B.B.-d.P.; ARC 4985 to C.B.; Institut National du Cancer (INCa)-Cancéropole Ile deFrance(melanomanetwork RS#13) toB.B.-deP.;INCa-PNESreinto B.G., S.Ga. and S.R., INCa grant R08009AP to C.B.; Fondation de France 2010 to R.B.; INCa and Ligue National Contre le Cancer to I.D., Fond de maturation IGR and Fondation Gustave Roussy to B.B.-d.P.; Société Française de Dermatologie SDF2004 to R.B. and P.B., SFD2009 to B.B.-d.P.; 2009 SGR 1337 from AGAUR, Generalitat de Catalunya, and FIS PS09/01393 from the Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain to S.P. and C.B.; and personal donations from C. and N. de Paillerets and M.-H.Wagner. to B.B.-d.P. B.B-d.P. holds an INSERM Research Fellowship for hospital-based scientists. Work at the Centre National de Génotypage (CNG) and Centre d’Etude du Polymorphisme Humain (CEPH) was supported in part by INCa.
PY - 2011/12/1
Y1 - 2011/12/1
N2 - 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 (Î̈ 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.
AB - 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 (Î̈ 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.
UR - http://www.scopus.com/inward/record.url?scp=82555205202&partnerID=8YFLogxK
U2 - 10.1038/nature10539
DO - 10.1038/nature10539
M3 - Article
C2 - 22012259
AN - SCOPUS:82555205202
SN - 0028-0836
VL - 480
SP - 94
EP - 98
JO - Nature
JF - Nature
IS - 7375
ER -