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 phenotypes1; risk factors associated with RCC include smoking, obesity and hypertension2. A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers3. The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene4; it also stimulates the transcription of hypoxia inducible factor5 (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes6. 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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ArrayExpress
Data deposits
Genome data has been deposited at the European Genome-Phenome Archive (EGA; http://www.ebi.ac.uk/ega), which is hosted at the EBI, under accession number EGAS00000000048. Gene expression data related to this paper have been submitted to the Array Express repository at the European Bioinformatics Institute (http://www.ebi.ac.uk/arrayexpress/) under the accession number E-TABM-1198.
Change history
02 December 2015
Nature 480, 94–98 (2011); doi:10.1038/nature10539 In this Letter, one image was mistakenly duplicated during preparation of the artwork. In the original Fig. 3d, the left image illustrating migration of RCC4 cells transduced with empty adenovirus (EV) at 24 h is a duplicate of the middle image showing migration of RCC4 cells transduced with an adenovirus encoding Mi-WT.
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Acknowledgements
We thank the patients and family members who participated in this study and the clinicians who identified these families, the French Familial Melanoma Study Group and the Inherited Predisposition to Kidney Cancer network. We acknowledge the contribution of the IGR Biobank for providing MELARISK 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 N°A09/5/5003 to B.B.-d.P.; ARC 4985 to C.B.; Institut National du Cancer (INCa)- Cancéropole Ile de France (melanoma network RS#13) to B.B.-deP.; INCa- PNES rein to 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.
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C.B., F.L., M.L., F.D., R.B. and B.B.-d.P. designed the experiments and wrote the manuscript. A.Re., B.G., S.S. and G.M.L. participated in the scientific discussions. E.M., P.Va., S.D., N.P., T.M.-D., L.T., P.A.-B., N.D., F.B., A.Ro., J.-L.P., B.L., C.R., B.E., O.C., L.B., S.R., J.C., B.T., P.Gh., L.P., S.P., C.B., H.O., C.I., E.R., R.L. and P.B. collected biological samples. P.Ga. collected the control samples. F.L., M.d.L. and B.d’H. performed sequencing and genotyping of patients. H.B. supervised DNA extraction and quality control for genome-wide genotyping. D.Z. and M.L. were responsible for the genome-wide genotyping of cases and controls and genotyping of MITF variant in controls. E.C. carried out the analysis of SNP genotype data. F.D. supervised the statistical analysis of all genotyped data. K.B. and S.Gi. performed the functional analysis. A.d.l.F., V.M. and P.Vi. performed MITF immunostaining. T.S. and I.D. designed and performed the ChIP-seq experiments. P.D. performed the gene expression profiling analysis. M.-F.A. initiated the collection of melanoma and RCC cases. S.R. initiated the collection of RCC families. M.-F.A and F.D. initiated the MELARISK collection. H.M. and V.C. contributed to the management of the MELARISK database.
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Bertolotto, C., Lesueur, F., Giuliano, S. et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 480, 94–98 (2011). https://doi.org/10.1038/nature10539
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DOI: https://doi.org/10.1038/nature10539
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