A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.
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.
1] INSERM, U895 (équipe 1), Equipe labélisée Ligue Contre le Cancer, C3M, 06204 Nice, France [2] Université of Nice Sophia-Antipolis, UFR Médecine, 06204 Nice, France [3] Centre Hospitalier Universitaire de Nice, Service de Dermatologie, 06204 Nice, France [4].
Corine
C
Bertolotto
Fabienne
F
Lesueur
Sandy
S
Giuliano
Thomas
T
Strub
Mahaut
M
de Lichy
Karine
K
Bille
Philippe
P
Dessen
Benoit
B
d'Hayer
Hamida
H
Mohamdi
Audrey
A
Remenieras
Eve
E
Maubec
Arnaud
A
de la Fouchardière
Vincent
V
Molinié
Pierre
P
Vabres
Stéphane
S
Dalle
Nicolas
N
Poulalhon
Tanguy
T
Martin-Denavit
Luc
L
Thomas
Pascale
P
Andry-Benzaquen
Nicolas
N
Dupin
Françoise
F
Boitier
Annick
A
Rossi
Jean-Luc
JL
Perrot
Bruno
B
Labeille
Caroline
C
Robert
Bernard
B
Escudier
Olivier
O
Caron
Laurence
L
Brugières
Simon
S
Saule
Betty
B
Gardie
Sophie
S
Gad
Stéphane
S
Richard
Jérôme
J
Couturier
Bin Tean
BT
Teh
Paola
P
Ghiorzo
Lorenza
L
Pastorino
Susana
S
Puig
Celia
C
Badenas
Hakan
H
Olsson
Christian
C
Ingvar
Etienne
E
Rouleau
Rosette
R
Lidereau
Philippe
P
Bahadoran
Philippe
P
Vielh
Eve
E
Corda
Hélène
H
Blanché
Diana
D
Zelenika
Pilar
P
Galan
François
F
Aubin
Bertrand
B
Bachollet
Céline
C
Becuwe
Pascaline
P
Berthet
Yves Jean
YJ
Bignon
Valérie
V
Bonadona
Jean-Louis
JL
Bonafe
Marie-Noëlle
MN
Bonnet-Dupeyron
Fréderic
F
Cambazard
Jacqueline
J
Chevrant-Breton
Isabelle
I
Coupier
Sophie
S
Dalac
Liliane
L
Demange
Michel
M
d'Incan
Catherine
C
Dugast
Laurence
L
Faivre
Lynda
L
Vincent-Fétita
Marion
M
Gauthier-Villars
Brigitte
B
Gilbert
Florent
F
Grange
Jean-Jacques
JJ
Grob
Philippe
P
Humbert
Nicolas
N
Janin
Pascal
P
Joly
Delphine
D
Kerob
Christine
C
Lasset
Dominique
D
Leroux
Julien
J
Levang
Jean-Marc
JM
Limacher
Cristina
C
Livideanu
Michel
M
Longy
Alain
A
Lortholary
Dominique
D
Stoppa-Lyonnet
Sandrine
S
Mansard
Ludovic
L
Mansuy
Karine
K
Marrou
Christine
C
Matéus
Christine
C
Maugard
Nicolas
N
Meyer
Catherine
C
Nogues
Pierre
P
Souteyrand
Laurence
L
Venat-Bouvet
Hélène
H
Zattara
Valérie
V
Chaudru
Gilbert M
GM
Lenoir
Mark
M
Lathrop
Irwin
I
Davidson
Marie-Françoise
MF
Avril
Florence
F
Demenais
Robert
R
Ballotti
Brigitte
B
Bressac-de Paillerets
D002292:Carcinoma, Renal Cell / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics; D058207:Sumoylation
C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor