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

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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.

Details

Authors
  • Corine Bertolotto
  • 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 Fouchardiere
  • Vincent Molinie
  • Pierre Vabres
  • Stephane Dalle
  • Nicolas Poulalhon
  • Tanguy Martin-Denavit
  • Luc Thomas
  • Pascale Andry-Benzaquen
  • Nicolas Dupin
  • Francoise Boitier
  • Annick Rossi
  • Jean-Luc Perrot
  • Bruno Labeille
  • Caroline Robert
  • Bernard Escudier
  • Olivier Caron
  • Laurence Brugieres
  • Simon Saule
  • Betty Gardie
  • Sophie Gad
  • Stephane Richard
  • Jerome Couturier
  • Bin Tean Teh
  • Paola Ghiorzo
  • Lorenza Pastorino
  • Susana Puig
  • Celia Badenas
  • Etienne Rouleau
  • Rosette Lidereau
  • Philippe Bahadoran
  • Philippe Vielh
  • Eve Corda
  • Helene Blanche
  • Diana Zelenika
  • Pilar Galan
  • Valerie Chaudru
  • Gilbert M. Lenoir
  • Mark Lathrop
  • Irwin Davidson
  • Marie-Francoise Avril
  • Florence Demenais
  • Robert Ballotti
  • Brigitte Bressac-de Paillerets
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
  • Surgery
Original languageEnglish
Pages (from-to)94-98
JournalNature
Volume480
Issue number7375
Publication statusPublished - 2011
Publication categoryResearch
Peer-reviewedYes