Discovery of a gene that predisposes to both melanoma and renal carcinoma

October 20 2011

Carried out by Inserm and the Institut de cancérologie Gustave Roussy (IGR) in Villejuif and coordinated by Dr Brigitte Bressac-de Paillerets, Head of IGR Genetics Department, a study has identified a germline mutation that is responsible for a common predisposition to melanoma (skin cancer) and renal carcinoma (kidney cancer). This mutation is called Mi-E318K and appears on the gene encoding a protein called MITF (microphthalmia-associated transcription factor). It makes this mutated gene over-active which leads to an increased risk of melanoma and renal cancer in individuals carrying this mutation. The results of this research (1) are published as a letter online in the scientific journal, Nature.

A recent study has identified the main features of the co-existence of melanoma and renal carcinoma in the same patients. Renal cancer is most often discovered once a melanoma is diagnosed through an extensive examination. Until now no environmental risk factor common to melanoma and renal carcinoma had yet been found. This study suggested the existence of a common genetic predisposition to these two cancer types.

A multi-centre group (2) of clinicians, geneticists, biologists, pathologists and biostatisticians hypothesized that the MITF gene might be implicated in this phenomenon as it was described as oncogenic (a cancer accelerator) in melanoma and that it is also known for intervening in a cell signalling pathway involved in the development of renal cancer.

The team succeeded in identifying an alteration in the DNA sequence at codon 318 of the MITF gene. This alteration was found in 8% of the patients with both a melanoma and renal cancer. "The alteration, called Mi-E318K, when it is present in patients, increases by five-fold the risk of developing a melanoma, a renal cancer or both”, says Dr Brigitte Bressac-de Paillerets of the Institut Gustave Roussy. This inherited genetic alteration impairs a modification of the MITF protein, called “SUMOylation”, in response to stress, which makes it oncogenic."

"The hypothesis resulting from our work," further explain Dr Corine Bertolotto and Dr Robert Ballotti, scientists in the Inserm Unit 895 in Nice, "is that a cell signalling pathway involving MITF would normally be activated in response to oxidative stress of the cell caused by ultraviolet radiations (UV) or by a lack of oxygen. When MITF is normal, this pathway would enable the cell to either be repaired or killed if repair is not possible. The mutation of the MITF gene, when it is present, would dysregulate this pathway and lead to a higher risk of developing melanoma and/or renal cancer."

These findings open new routes in both clinical practice and research. "A screening test could be developed to detect this mutation in people affected with either melanoma or renal cancer," says Professor Marie-Françoise Avril (Cochin-Tarnier Hospital, AP-HP, Paris). "The mutation would become a biomarker of disease risk which, if present, would point to the need for special monitoring of the kidney and the skin. Advice about protection from the sun could also be given to renal carcinoma patients with fair skin and/or a high mole count." Regarding research, this work sheds new light on the pathways involved in oxidative stress (UVs and/or hypoxia) and cancer development and stimulates further investigation. "Our work shows the power of the approach used," explains Dr Florence Demenais, director of the Inserm Unit 946 - University Paris Diderot, "that has made it possible to identify a rare genetic variant conferring a moderate risk of cancer, which is currently one of the major challenges in the genetics of multifactorial diseases as cancer. Now, we nee to identify the other genetic and/or environmental factors involved in the coexistence of melanoma and renal carcinoma and, possibly, other cancers."

This work is a good example of translational research with the starting point being a clinical observation, which raises a question solved by research teams, and which leads to a more or less long-term return to a better care of patients. This laboratory-based discovery can be used in clinic through the development of a genetic test in order to offer a personalised follow-up to a well characterized group of patients. In addition, this finding may lead to the identification of new therapeutic targets against cancer. This discovery can also be exploited in research since it highlights new cellular mechanisms and contributes to a better understanding of carcinogenesis.


(1) "A sumoylation defective MITF germline mutation predisposes to melanoma and renal carcinoma" - Bertolotto C. et al, Nature
Published online 19 October 2011

(2) Institut de cancérologie Gustave Roussy ; Inserm ; Université de Nice Sophia-Antipolis ; Centre Hospitalier Universitaire de Nice ; Institut de Génétique et de Biologie Moléculaire et Cellulaire ; CNRS ; Université Paris Diderot, Sorbonne Paris Cité ; Institut Universitaire d’Hématologie ; Fondation Jean Dausset ; Centre d’Etude du Polymorphisme Humain ; AP-HP ; Centre Léon Bérard ; Hôpital Saint-Joseph ; Centre Hospitalier Universitaire de Dijon ; Centre Hospitalier Universitaire Lyon Sud ; Hôpital Charles Nicolle ; CHU Rouen ; CHU Hôpital Nord de Saint-Etienne ; Faculté de Médecine, Université Paris-Sud 11 ; Centre Expert National Cancers Rares ; INCa ; Van Andel Research Institute ; National Cancer Center Singapore ; University of Genoa ; Hospital Clinic, IDIBAPS, and CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona ; University Hospital Lund ; Hôpital René Huguenin - Institut Curie ; Commissariat à l’Energie Atomique, Centre National de Génotypage ; Université d’Evry Val d’Essonne ; Institut Paoli Calmettes.

Back to release list of thematic

Know more

Press Office
Chloé Louys
Tel.: 01 42 11 50 59 / 06 17 66 00 26)

^ Top of page
View Edit Create here