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

被引：388

作者：

Bertolotto, Corine ^{[1
,2
,3
]}

Lesueur, Fabienne ^{[40
]}

Giuliano, Sandy ^{[1
,2
]}

Strub, Thomas ^{[4
]}

de Lichy, Mahaut ^{[40
]}

Bille, Karine ^{[1
]}

Dessen, Philippe ^{[5
]}

d'Hayer, Benoit ^{[40
]}

Mohamdi, Hamida ^{[6
,7
,8
]}

Remenieras, Audrey ^{[40
]}

Maubec, Eve ^{[6
,9
]}

de la Fouchardiere, Arnaud ^{[10
]}

Molinie, Vincent ^{[11
]}

Vabres, Pierre ^{[12
]}

Dalle, Stephane ^{[13
,14
]}

Poulalhon, Nicolas ^{[13
,14
]}

Martin-Denavit, Tanguy ^{[13
,14
]}

Thomas, Luc ^{[13
,14
]}

Andry-Benzaquen, Pascale ^{[15
,16
]}

Dupin, Nicolas ^{[15
,16
]}

Boitier, Francoise ^{[15
,16
]}

Rossi, Annick ^{[17
]}

Perrot, Jean-Luc ^{[18
]}

Labeille, Bruno ^{[18
]}

Robert, Caroline ^{[19
]}

Escudier, Bernard ^{[19
]}

Caron, Olivier ^{[19
]}

Brugieres, Laurence ^{[20
]}

Saule, Simon ^{[21
,22
]}

Gardie, Betty ^{[23
]}

Gad, Sophie ^{[23
]}

Richard, Stephane ^{[23
,24
]}

Couturier, Jerome ^{[25
]}

Teh, Bin Tean ^{[26
,27
]}

Ghiorzo, Paola ^{[28
]}

Pastorino, Lorenza ^{[28
]}

Puig, Susana ^{[29
,30
,31
]}

Badenas, Celia ^{[29
,30
,31
]}

Olsson, Hakan ^{[32
]}

Ingvar, Christian ^{[33
]}

Rouleau, Etienne ^{[34
]}

Lidereau, Rosette ^{[34
]}

Bahadoran, Philippe ^{[3
]}

Vielh, Philippe ^{[35
]}

Corda, Eve ^{[6
,8
]}

Blanche, Helene ^{[8
]}

Zelenika, Diana ^{[38
]}

Galan, Pilar ^{[36
]}

Chaudru, Valerie ^{[6
,8
,37
]}

Lenoir, Gilbert M. ^{[39
,40
]}

机构：

[1] C3M, Equipe Labelisee Ligue Canc, INSERM, U895,Equipe 1, F-06204 Nice, France

[2] Univ Nice Sophia Antipolis, UFR Med, F-06204 Nice, France

[3] Ctr Hosp Univ Nice, Serv Dermatol, F-06204 Nice, France

[4] Univ Strasbourg, INSERM, CNRS, Inst Genet & Biol Mol & Cellulaire, F-67404 Illkirch Graffenstaden, France

[5] Inst Cancerol Gustave Roussy, INSERM, UMR985, F-94805 Villejuif, France

[6] INSERM, U946, Genet Variat & Human Dis Unit, F-75010 Paris, France

[7] Univ Paris Diderot, Inst Univ Hematol, F-75010 Paris, France

[8] Fdn Jean Dausset, CEPH, F-75010 Paris, France

[9] Hop Bichat Claude Bernard, AP HP, Serv Dermatol, Fac Paris Diderot, F-75018 Paris, France

[10] Ctr Leon Berard, Dept Pathol, F-69008 Lyon, France

[11] Hop St Joseph, Dept Pathol, F-75014 Paris, France

[12] Ctr Hosp Univ, Dept Dermatol, F-21079 Dijon, France

[13] Univ Lyon 1, F-69495 Pierre Benite, France

[14] Ctr Hosp Lyon Sud, Dept Dermatol, F-69495 Pierre Benite, France

[15] Hop Cochin Tarnier, AP HP, Serv Dermatol, F-75006 Paris, France

[16] Univ Paris 05, F-75006 Paris, France

[17] CHU Rouen, Hop Charles Nicolle, Unite Genet Clin, F-76038 Rouen, France

[18] CHU Hop Nord, Dept Dermatol, F-42055 St Etienne, France

[19] Inst Cancerol Gustave Roussy, Dept Med, F-94805 Villejuif, France

[20] Inst Cancerol Gustave Roussy, Dept Pediatry, F-94805 Villejuif, France

[21] Univ Paris 11, INSERM, U1021, F-91405 Orsay, France

[22] Univ Paris 11, Inst Curie, CNRS, UMR33, F-91405 Orsay, France

[23] Univ Paris 11, Genet Oncol EPHE INSERM U753, Fac Med, F-94805 Villejuif, France

[24] Hop Bicetre, Ctr Expert Natl Canc Rares PREDIR, INCa AP HP, Serv Urol, F-94275 Le Kremlin Bicetre, France

[25] Inst Curie, Serv Genet, F-75005 Paris, France

[26] Van Andel Res Inst, Canc Genet Lab, Grand Rapids, MI 49503 USA

[27] Natl Canc Ctr Singapore, NCCS VARI Translat Res Lab, Singapore 16910, Singapore

[28] Univ Genoa, Dept Internal Med, I-16132 Genoa, Italy

[29] Hosp Clin Barcelona, Dept Dermatol, IDIBAPS, E-08036 Barcelona, Spain

[30] Hosp Clin Barcelona, Melanoma Unit, IDIBAPS, E-08036 Barcelona, Spain

[31] Inst Salud Carlos III, CIBER Enfermedades Raras, Barcelona 08036, Spain

[32] Lund Univ & Hosp, Dept Oncol, S-22185 Lund, Sweden

[33] Lund Univ & Hosp, Dept Surg, S-22185 Lund, Sweden

[34] Hop Rene Huguenin, Serv Oncogenet, F-92210 St Cloud, France

[35] Inst Cancerol Gustave Roussy, Dept Pathol, Translat Res Lab & Biobank, F-94805 Villejuif, France

[36] CRNH Idf, INSERM, UMR557, INRA U1125,CNAM, F-93000 Bobigny, France

[37] Univ Evry Val Essonne, F-91025 Evry, France

[38] CEA, Ctr Natl Genotypage, F-91057 Evry, France

[39] Univ Paris 11, Fac Med, F-94275 Le Kremlin Bicetre, France

[40] Inst Cancerol Gustave Roussy, Serv Genet, F-94805 Villejuif, France

来源：

NATURE | 2011年 / 480卷 / 7375期

关键词：

NF-KAPPA-B; GENE-EXPRESSION; CANCER; CELLS; HYPOXIA; SURVIVAL; SUMO; IDENTIFICATION; RECEPTOR;

D O I：

10.1038/nature10539

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：94 / U259

页数：7

共 37 条

[31] A Region within the 5′-Untranslated Region of Hypoxia-inducible Factor-1α mRNA Mediates Its Turnover in Lung Adenocarcinoma Cells [J].