• A Corrigendum to this article was published on 02 December 2015

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.

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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.

Author information

Author notes

    • Fabienne Lesueur
    •  & Audrey Remenieras

    Present addresses: Genetic Cancer Susceptibility group, International Agency for Research on Cancer, 69372 Lyon, France (F.L.); Genetic Department, Institut Paoli Calmettes, 13273 Marseille, France (A.R.).

    • Corine Bertolotto
    • , Fabienne Lesueur
    • , Sandy Giuliano
    • , Robert Ballotti
    •  & Brigitte Bressac-de Paillerets

    These authors contributed equally to this work.

Affiliations

  1. INSERM, U895 (équipe 1), Equipe labélisée Ligue Contre le Cancer, C3M, 06204 Nice, France

    • Corine Bertolotto
    • , Sandy Giuliano
    • , Karine Bille
    •  & Robert Ballotti
  2. Université of Nice Sophia-Antipolis, UFR Médecine, 06204 Nice, France

    • Corine Bertolotto
    • , Sandy Giuliano
    •  & Robert Ballotti
  3. Centre Hospitalier Universitaire de Nice, Service de Dermatologie, 06204 Nice, France

    • Corine Bertolotto
    • , Philippe Bahadoran
    •  & Robert Ballotti
  4. Service de Génétique, Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France

    • Fabienne Lesueur
    • , Mahaut de Lichy
    • , Benoit d’Hayer
    • , Audrey Remenieras
    • , Gilbert M. Lenoir
    •  & Brigitte Bressac-de Paillerets
  5. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université de Strasbourg, 67404 Illkirch, France

    • Thomas Strub
    •  & Irwin Davidson
  6. INSERM, UMR985, Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France and Université Paris-Sud 11, 91405 Orsay

    • Philippe Dessen
  7. INSERM, U946, Genetic Variation and Human Diseases Unit, 75010 Paris, France

    • Hamida Mohamdi
    • , Eve Maubec
    • , Eve Corda
    • , Valérie Chaudru
    • , Florence Demenais
    •  & Brigitte Bressac-de Paillerets
  8. Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d’Hématologie, 75010 Paris, France

    • Hamida Mohamdi
    •  & Florence Demenais
  9. Fondation Jean Dausset-Centre d’Etude du Polymorphisme Humain (CEPH), 75010 Paris, France

    • Hamida Mohamdi
    • , Eve Corda
    • , Hélène Blanché
    • , Valérie Chaudru
    • , Mark Lathrop
    •  & Florence Demenais
  10. AP-HP, Hôpital Bichat, Service de Dermatologie, Faculté Paris Diderot, 75018 Paris, France

    • Eve Maubec
  11. Département de Pathologie, Centre Léon Bérard, 69008 Lyon, France

    • Arnaud de la Fouchardière
  12. Department of Pathology, Hôpital Saint-Joseph, 75014 Paris, France

    • Vincent Molinié
  13. Department of Dermatology, Centre Hospitalier Universitaire, 21079 Dijon, France

    • Pierre Vabres
  14. Lyon 1 University and Centre Hospitalier Lyon Sud, Department of Dermatology, 69495 Pierre Bénite, France

    • Stéphane Dalle
    • , Nicolas Poulalhon
    • , Tanguy Martin-Denavit
    •  & Luc Thomas
  15. AP-HP, Hôpital Cochin -Tarnier, Service de Dermatologie and Université Paris Descartes, 75006 Paris, France

    • Pascale Andry-Benzaquen
    • , Nicolas Dupin
    • , Françoise Boitier
    •  & Marie-Françoise Avril
  16. Unité de Génétique Clinique, Hôpital Charles Nicolle, CHU Rouen, 76038 Rouen, France

    • Annick Rossi
  17. Department of Dermatology, CHU Hôpital Nord, 42055 Saint-Etienne, France

    • Jean-Luc Perrot
    •  & Bruno Labeille
  18. Department of Medicine, Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France

    • Caroline Robert
    • , Bernard Escudier
    •  & Olivier Caron
  19. Department of Pediatry, Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France

    • Laurence Brugières
  20. Institut Curie, CNRS UMR33 and INSERM U1021, Université Paris-Sud 11, 91405 Orsay, France

    • Simon Saule
  21. Génétique Oncologique EPHE-INSERM U753, Faculté de Médecine, Université Paris-Sud 11 and Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France

    • Betty Gardie
    • , Sophie Gad
    •  & Stéphane Richard
  22. Centre Expert National Cancers Rares PREDIR, INCa/AP-HP, Service d’Urologie, Hôpital de Bicêtre, 94275 Le Kremlin-Bicêtre, France

    • Stéphane Richard
  23. Service de Génétique, Institut Curie, 75005 Paris, France

    • Jérôme Couturier
  24. Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, 49503 Michigan, USA

    • Bin Tean Teh
  25. NCCS-VARI Translational Research Laboratory, National Cancer Center Singapore, 16910 Singapore

    • Bin Tean Teh
  26. Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy

    • Paola Ghiorzo
    •  & Lorenza Pastorino
  27. Dermatology Department and Biochemistry and Molecular Genetics, Melanoma Unit, Hospital Clinic, IDIBAPS, and CIBER de Enfermedades Raras, Instituto de Salud Carlos III, 08036 Barcelona, Spain

    • Susana Puig
    •  & Celia Badenas
  28. Department of Oncology, Lund University and Hospital, Lund, 22185 Sweden

    • Hakan Olsson
  29. Department of Surgery, Lund University and Hospital, Lund, 22185 Sweden

    • Christian Ingvar
  30. Service d’Oncogénétique, Hôpital René Huguenin- Institut Curie, 92210 Saint-Cloud, France

    • Etienne Rouleau
    •  & Rosette Lidereau
  31. Department of Pathology, Translational Research Laboratory and Biobank, Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France

    • Philippe Vielh
  32. Commissariat à l’Energie Atomique, Centre National de Génotypage, 91057 Evry, France

    • Diana Zelenika
    •  & Mark Lathrop
  33. INSERM, UMR557, INRA U1125, CNAM, Paris 13, CRNH Idf, 93000 Bobigny, France

    • Pilar Galan
  34. Université d’Evry Val d’Essonne, 91025 Evry, France

    • Valérie Chaudru
  35. Université Paris-Sud 11, Faculté de Médecine, 94275 Le Kremlin-Bicêtre, France

    • Gilbert M. Lenoir
  36. Centre Hospitalier Universitaire St Jacques, Dermatologie et Vénéréologie, 2 Place St Jacques, 25030 Besançon, France.

    • François Aubin
    • , Philippe Humbert
    •  & Julien Levang
  37. Institut de Cancérologie Gustave Roussy, Service de Dermatologie, 114 Rue Edouard Vaillant, 94805 Villejuif, France.

    • Bertrand Bachollet
    •  & Christine Matéus
  38. Hôpital de l’Hôtel-Dieu, Service de Dermatologie, 1 place de l'Hôpital, 69288 Lyon Cedex 2, France.

    • Céline Becuwe
    •  & Karine Marrou
  39. Service d’Oncologie Génétique, Centre François Baclesse, 3 Avenue du Général Harris, 14076 Caen Cedex 5, France.

    • Pascaline Berthet
  40. Centre Hospitalier Jean Perrin, 58 rue Montalembert, BP 392, 63011 Clermont-Ferrand Cedex 1, France.

    • Yves Jean Bignon
  41. Centre Léon Bérard, Unité Clinique d’Oncologie Génétique, 28 Rue Laënnec, 69373 Lyon Cedex 8, France.

    • Valérie Bonadona
    •  & Christine Lasset
  42. Unité de Dermatologie, Centre Hospitalier Universitaire de Rangueil, 1 avenue Jean Poulhès, TSA 50032, 31059 Toulouse, France.

    • Jean-Louis Bonafe
  43. Centre Hospitalier, Service de Génétique, 179 Boulevard Maréchal Juin, 26953 Valence Cedex 9, France

    • Marie-Noëlle Bonnet-Dupeyron
  44. Centre Hospitalier Universitaire de St Etienne, Hôpital Nord, Service de Dermatologie, Vénéréologie, 42055 St Etienne Cedex 2, France.

    • Fréderic Cambazard
  45. Chru Pontchaillou, Service de Dermatologie, 35 Rue André Le Guillloux, 35033 Rennes, France.

    • Jacqueline Chevrant-Breton
  46. Centre Hospitalier Universitaire Hôpital Arnaud de Villeneuve, Unité d’Oncogénétique, 371 Avenue Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France.

    • Isabelle Coupier
  47. Centre Hospitalier Universitaire Hôpital du Bocage, Service de Dermatologie, 2 boulevard Maréchal de Lattre de Tassigny, BP 77908, 21079 Dijon, France.

    • Sophie Dalac
  48. Polyclinique Courlancy, Service de Radiothérapie et Oncologie Médicale, 38 rue de Courlancy, 51000 Reims, France.

    • Liliane Demange
  49. Centre Hospitalier Universitaire Estaing, Service de Dermatologie, 1 Place Lucie Aubrac, 63003 Clermont Ferrand Cedex 1, France.

    • Michel d’Incan
    • , Sandrine Mansard
    •  & Pierre Souteyrand
  50. Centre Eugene Marquis, Oncologie Génétique, Rue de la Bataille de Flandres Dunkerque, CS 44229, 35042 Rennes, France.

    • Catherine Dugast
  51. Centre Hospitalier Universitaire Hôpital du Bocage, Centre de Génétique, 2 Boulevard Maréchal de Lattre de Tassigny, BP77908, 21079 Dijon, France.

    • Laurence Faivre
  52. Hopital Cochin, Service de Dermatologie, Pavillon Tarnier, 89 rue d’Assas, 75006 Paris, France.

    • Lynda Vincent-Fétita
  53. Institut Curie, Génétique Oncologique, 26 rue d’Ulm, 75248 Paris Cedex 5, France.

    • Marion Gauthier-Villars
    •  & Dominique Stoppa-Lyonnet
  54. Centre Hospitalier Universitaire La Milétrie, Service de Génétique Médicale, 2 rue de la Milétrie, BP 577, 86021 Poitiers, France.

    • Brigitte Gilbert
  55. Hôpital Robert Debré, Service de Dermatologie U42, Avenue du Général Koenig, 51092 Reims, France.

    • Florent Grange
  56. Hôpital Sainte-Marguerite, Service de Dermatologie, 270 Boulevard Sainte-Marguerite, 13274 Marseille Cedex 9, France.

    • Jean-Jacques Grob
  57. Centre Hospitalier Universitaire Sart Tilman, Département de Génétique Humaine, Centre Hospitalier Universitaire de Liege, 4000 Liege, Belgium.

    • Nicolas Janin
  58. Centre Hospitalier Universitaire de Rouen, Hôpitaux de Rouen, Clinique Dermatologique, Hôpital Charles Nicolle, 1 rue de Germont, 76031 Rouen, France.

    • Pascal Joly
  59. Hopital Saint-Louis, Service de Dermatologie, 1 Avenue Claude Vellefaux, 75475 Paris Cedex 10, France.

    • Delphine Kerob
  60. Centre Hospitalier Universitaire de Grenoble, Hôpital Couple Enfant, Département de Génétique et Procréation, Génétique Clinique, Consultations d’Oncogénétique, BP 217-F, 38043 Grenoble Cedex 9, France.

    • Dominique Leroux
  61. Hôpital Pasteur, Hôpitaux civils de Colmar, Service d’Oncologie, 39 Avenue Liberté, 68024 Colmar, France.

    • Jean-Marc Limacher
  62. Centre Hospitalier Universitaire Toulouse, Hopital Purpan, Service de Dermatologie, Place du Docteur Baylac TSA 40031, 31059 Toulouse Cedex 9, France.

    • Cristina Livideanu
  63. Institut Bergonié, Laboratoire de Génétique Moléculaire, 229 cours de l’Argonne, 33076 Bordeaux, France.

    • Michel Longy
  64. Centre Catherine de Sienne, Oncologie Médicale, 2 rue Eric Tabarly, BP 20215, 44202 Nantes Cedex 2, France.

    • Alain Lortholary
  65. Centre Alexis Vautrin, Consultation Oncogénétique, UF Nancy 9901, 6 avenue de Bourgogne, 54511 Vandoeuvre Les Nancy, France.

    • Ludovic Mansuy
  66. Centre Hospitalier Universitaire de Strasbourg, Consultations d’Oncogénétique, Service d’Hématologie et d’Oncologie, 1 place de l’Hôpital, 67091 Strasbourg, France.

    • Christine Maugard
  67. Centre Hospitalier Universitaire de Toulouse, Hôpital Larrey, Service de Dermatologie, Vénéréologie, 24 Chemin de Pouvourville, TSA 30030, 31059 Toulouse Cedex 9, France.

    • Nicolas Meyer
  68. Centre René Huguenin, Service d'Oncogénétique, 35 rue Dailly, 92210 St Cloud, France.

    • Catherine Nogues
  69. Oncogénétique, Centre Hospitalier Universitaire de Limoges, Hôpital Universitaire de Dupuytren, 2 Avenue Martin Luther King, 87042 Limoges, France.

    • Laurence Venat-Bouvet
  70. Département de Génétique Médicale, Hôpital de la Timone, Unité de Génétique Clinique, 264, rue St Pierre, 13005 Marseille, France.

    • Hélène Zattara

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Brigitte Bressac-de Paillerets.

Supplementary information

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https://doi.org/10.1038/nature10539

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