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

Corine Bertolotto-Ballotti; Fabienne Lesueur; Sandy Giuliano; Thomas Strub; Mahaut de Lichy; Karine Bille; Philippe Dessen; Benoit d'Hayer; Hamida Mohamdi; Audrey Remenieras; Eve Maubec; Arnaud de La Fouchardière; Vincent Molinié; Pierre Vabres; Stéphane Dalle; Nicolas Poulalhon; Tanguy Martin-Denavit; Luc Thomas; Pascale Andry-Benzaquen; Nicolas Dupin; Françoise Boitier; Annick Rossi; Jean-Luc Perrot; Bruno Labeille; Caroline Robert; Bernard Escudier; Olivier Caron; Laurence Brugières; Simon Saule; Betty Gardie; Sophie Gad; Stéphane Richard; Jérôme Couturier; Bin Tean Teh; Paola Ghiorzo; Lorenza Pastorino; Susana Puig; Celia Badenas; Hakan Olsson; Christian Ingvar; Etienne Rouleau; Rosette Lidereau; Philippe Bahadoran; Philippe Vielh; Eve Corda; Hélène Blanché; Diana Zelenika; Pilar Galan; Non Renseigné; François Aubin; Bertrand Bachollet; Céline Becuwe; Pascaline Berthet; Yves Jean Bignon; Valérie Bonadona; Jean-Louis Bonafe; Marie-Noëlle Bonnet-Dupeyron; Fréderic Cambazard; Jacqueline Chevrant-Breton; Isabelle Coupier; Sophie Dalac; Liliane Demange; Michel d'Incan; Catherine Dugast; Laurence Faivre; Lynda Vincent-Fétita; Marion Gauthier-Villars; Brigitte Gilbert; Florent Grange; Jean-Jacques Grob; Philippe Humbert; Nicolas Janin; Pascal Joly; Delphine Kerob; Christine Lasset; Dominique Leroux; Julien Levang; Jean-Marc Limacher; Cristina Livideanu; Michel Longy; Alain Lortholary; Dominique Stoppa-Lyonnet; Sandrine Mansard; Ludovic Mansuy; Karine Marrou; Christine Matéus; Christine Maugard; Nicolas Meyer; Catherine Nogues; Pierre Souteyrand; Laurence Venat-Bouvet; Hélène Zattara; Valérie Chaudru; Gilbert M Lenoir; Mark Lathrop; Irwin Davidson; Marie-Françoise Avril; Florence Demenais; Robert Ballotti; Brigitte Bressac-de Paillerets

doi:10.1038/nature10539

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

Journal article

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

Corine Bertolotto-Ballotti, Fabienne Lesueur, Sandy Giuliano, Thomas Strub, Mahaut de Lichy, Karine Bille, Philippe Dessen, Benoit d'Hayer, Hamida Mohamdi, Audrey Remenieras, …

Nature, Vol.480(7375), pp.94-98

01/12/2011

DOI: https://doi.org/10.1038/nature10539

PMID: 22012259

Abstract

sumo

germline mutation

renal carcinoma

multidisciplinary sciences

science and technology

melanoma

cancer cells

Carcinoma, Renal Cell

Cell Movement

Gene Frequency

Genetic Predisposition to Disease

Germ-Line Mutation

Humans

Melanoma

Microphthalmia-Associated Transcription Factor

Neoplasm Invasiveness

Sumoylation

rein

carcinome

oncologie

germine

mélanome

mutation

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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Title: A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.
Creators - without role: Corine Bertolotto-Ballotti - Biologie et pathologies des cellules mélanocytaires : de la pigmentation cutanée aux mélanomes
Fabienne Lesueur - Institut Gustave Roussy
Sandy Giuliano - La Ligue Contre le Cancer
Thomas Strub - Inserm
Mahaut de Lichy - Institut Gustave Roussy
Karine Bille - Inserm
Philippe Dessen - Institut Gustave Roussy
Benoit d'Hayer
Hamida Mohamdi - Inserm
Audrey Remenieras - Institut Gustave Roussy
Eve Maubec - Human Genetic of Infectious Diseases
Arnaud de La Fouchardière - Centre Léon Bérard
Vincent Molinié - Hôpital Saint Joseph
Pierre Vabres - Centre Hospitalier Universitaire Dijon Bourgogne
Stéphane Dalle - Hôpital Lyon Sud
Nicolas Poulalhon - Hôpital Lyon Sud
Tanguy Martin-Denavit - Hôpital Lyon Sud
Luc Thomas - Hôpital Lyon Sud
Pascale Andry-Benzaquen - Université Paris Cité
Nicolas Dupin - Hôpital Cochin
Françoise Boitier - Université Paris Cité
Annick Rossi - Hôpital Charles-Nicolle
Jean-Luc Perrot
Bruno Labeille - Hôpital Nord
Caroline Robert - Institut Gustave Roussy
Bernard Escudier - Institut Gustave Roussy
Olivier Caron - Institut Gustave Roussy
Laurence Brugières - Institut Gustave Roussy
Simon Saule - Inserm
Betty Gardie - Université Paris-Sud
Sophie Gad - Inserm
Stéphane Richard - Génétique Oncologique EPHE, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre
Jérôme Couturier - Institut Curie
Bin Tean Teh - Cancer Genetics
Paola Ghiorzo - University of Genoa
Lorenza Pastorino - University of Genoa
Susana Puig - Instituto de Investigación de Enfermedades Raras
Celia Badenas - Instituto de Investigación de Enfermedades Raras
Hakan Olsson - Lund University
Christian Ingvar - Lund University
Etienne Rouleau - Institut Curie
Rosette Lidereau - Hôpital René Huguenin
Philippe Bahadoran - Centre Hospitalier Universitaire de Nice
Philippe Vielh - Institut Gustave Roussy
Eve Corda - Fondation Jean Dausset-CEPH
Hélène Blanché - Fondation Jean Dausset-CEPH
Diana Zelenika - Université de Montpellier, Institut des Neurosciences de Montpellier - INM
Pilar Galan - Inserm
Non Renseigné
François Aubin - Hôpital Saint-Jacques
Bertrand Bachollet - Institut Gustave Roussy
Céline Becuwe - Hôtel-Dieu de Lyon
Pascaline Berthet - Centre François Baclesse
Yves Jean Bignon - Centre Jean Perrin
Valérie Bonadona - Centre Léon Bérard
Jean-Louis Bonafe
Marie-Noëlle Bonnet-Dupeyron
Fréderic Cambazard - Centre Hospitalier Universitaire de Saint-Étienne
Jacqueline Chevrant-Breton - Hôpital Pontchaillou
Isabelle Coupier - Hôpital Arnaud de Villeneuve
Sophie Dalac
Liliane Demange - L’Institut du Cancer Courlancy Reims
Michel d'Incan - Service de Dermatologie
Catherine Dugast - Centre Eugène Marquis
Laurence Faivre - Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
Lynda Vincent-Fétita - Hôpital Cochin
Marion Gauthier-Villars - Institut Curie
Brigitte Gilbert - Centre Hospitalier Universitaire de Poitiers
Florent Grange - Hôpital Robert-Debré
Jean-Jacques Grob - Service de dermatologie
Philippe Humbert - Hôpital Saint-Jacques
Nicolas Janin - Centre Hospitalier Universitaire de Liège
Pascal Joly - Université de Rouen Normandie
Delphine Kerob - Hôpital Saint-Louis
Christine Lasset - Centre Léon Bérard
Dominique Leroux - Hôpital Couple Enfant
Julien Levang - Hôpital Saint-Jacques
Jean-Marc Limacher
Cristina Livideanu
Michel Longy - Institut Bergonié
Alain Lortholary
Dominique Stoppa-Lyonnet - Institut Curie
Sandrine Mansard - Centre Hospitalier Universitaire de Clermont-Ferrand
Ludovic Mansuy - Délégation Centre-Est
Karine Marrou - Hôtel-Dieu de Lyon
Christine Matéus - Institut Gustave Roussy
Christine Maugard - Laboratoire de Diagnostic Génétique [CHU Strasbourg]
Nicolas Meyer - Hôpital Larrey
Catherine Nogues - Hôpital René Huguenin
Pierre Souteyrand - Centre Hospitalier Universitaire de Clermont-Ferrand
Laurence Venat-Bouvet - Hôpital Universitaire Dupuytren
Hélène Zattara - Hôpital de la Timone
Valérie Chaudru - Université d'Évry Val-d'Essonne
Gilbert M Lenoir - Université Paris-Sud
Mark Lathrop - Commissariat à l'Énergie Atomique et aux Énergies Alternatives
Irwin Davidson - Centre National de la Recherche Scientifique
Marie-Françoise Avril - Hôpital Cochin
Florence Demenais - Fondation Jean Dausset-CEPH
Robert Ballotti - Centre Hospitalier Universitaire de Nice
Brigitte Bressac-de Paillerets - Contrôle transcriptionnel et épigénétique de l’hématopoïèse maligne
Publication Details: Nature, Vol.480(7375), pp.94-98
Grant note: 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^oA09/5/5003 to B.B.-d.P.; ARC 4985 to C. B.; Institut National du Cancer (INCa)-Canceropole 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.; Societe Francaise 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 Genotypage (CNG) and Centre d'Etude du Polymorphisme Humain (CEPH) was supported in part by INCa.
Identifiers: 9934143709311
Academic Unit: Institut des Neurosciences de Montpellier - INM
Language: English
Resource Type: Journal article
Local Fields: hal-00719536