6533b850fe1ef96bd12a83f5
RESEARCH PRODUCT
A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma
Corine Bertolotto-ballottiFabienne LesueurSandy GiulianoThomas StrubMahaut De LichyKarine BillePhilippe DessenBenoit D'hayerHamida MohamdiAudrey RemenierasEve MaubecArnaud De La FouchardièreVincent MoliniéPierre VabresStéphane DalleNicolas PoulalhonTanguy Martin-denavitLuc ThomasPascale Andry-benzaquenNicolas DupinFrançoise BoitierAnnick RossiJean-luc PerrotBruno LabeilleCaroline RobertBernard EscudierOlivier CaronLaurence BrugièresSimon SauleBetty GardieSophie GadStéphane RichardJérôme CouturierBin Tean TehPaola GhiorzoLorenza PastorinoSusana PuigCelia BadenasHakan OlssonChristian IngvarEtienne RouleauRosette LidereauPhilippe BahadoranPhilippe VielhEve CordaHélène BlanchéDiana ZelenikaPilar GalanNon RenseignéFrançois AubinBertrand BacholletCéline BecuwePascaline BerthetYves Jean BignonValérie BonadonaJean-louis BonafeMarie-noëlle Bonnet-dupeyronFréderic CambazardJacqueline Chevrant-bretonIsabelle CoupierSophie DalacLiliane DemangeMichel D'incanCatherine DugastLaurence FaivreLynda Vincent-fétitaMarion Gauthier-villarsBrigitte GilbertFlorent GrangeJean-jacques GrobPhilippe HumbertNicolas JaninPascal JolyDelphine KerobChristine LassetDominique LerouxJulien LevangJean-marc LimacherCristina LivideanuMichel LongyAlain LortholaryDominique Stoppa-lyonnetSandrine MansardLudovic MansuyKarine MarrouChristine MatéusChristine MaugardNicolas MeyerCatherine NoguesPierre SouteyrandLaurence Venat-bouvetHélène ZattaraValérie ChaudruGilbert M LenoirMark LathropIrwin DavidsonMarie-françoise AvrilFlorence DemenaisRobert BallottiBrigitte Bressac-de Pailleretssubject
multidisciplinary sciencesMESH : Germ-Line MutationSUMO proteinurologic and male genital diseasesmedicine.disease_causeMESH : Neoplasm Invasiveness[ SDV.CAN ] Life Sciences [q-bio]/CancerMESH : Carcinoma Renal Cell0302 clinical medicineGene FrequencyCell MovementMESH: Germ-Line MutationMESH : Cell MovementMESH : Gene FrequencyMESH: Cell MovementComputingMilieux_MISCELLANEOUSGenetics0303 health sciencesMultidisciplinaryMESH: SumoylationMelanomaMESH : SumoylationMESH: Genetic Predisposition to Diseaserenal carcinomaMESH: Carcinoma Renal CellMicrophthalmia-associated transcription factorMESH : Microphthalmia-Associated Transcription Factor3. Good healthgermline mutation030220 oncology & carcinogenesisMESH: Microphthalmia-Associated Transcription Factorscience and technologyMESH: MelanomasumoMESH : Melanoma[SDV.CAN]Life Sciences [q-bio]/CancerBiology03 medical and health sciencesGermline mutationmelanomaMESH: Gene FrequencyGenetic predispositionmedicineHumansGenetic Predisposition to DiseaseNeoplasm InvasivenessCarcinoma Renal CellneoplasmsTranscription factorGerm-Line Mutation030304 developmental biologyMicrophthalmia-Associated Transcription FactorMESH: HumansMESH : HumansSumoylationMESH: Neoplasm Invasivenessmedicine.diseaseHIF1Acancer cellsCancer researchMESH : Genetic Predisposition to DiseaseCarcinogenesisdescription
International audience; 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2011-12-01 |