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Uveal melanoma: discovery of a new genetic predisposition


A team from Institut Curie reveals that the MBD4 gene is a major gene for predisposition to uveal melanoma, the most common form of eye cancer in adults. Until now only one genetic predisposition was known for this cancer.


A team from Institut Curie reveals that the MBD4 gene is a major gene for predisposition to uveal melanoma, the most common form of eye cancer in adults. Until now only one genetic predisposition was known for this cancer. Published in the Journal of National Cancer Institute, these results shed new light on this disease which we still don’t know enough about, and for which there is no effective chemotherapy. This research also offers new therapeutic options for some types of these ocular tumors, particularly in terms of immunotherapy.

Uveal melanoma is the most common malignant tumor of the eye in adults. It is a rare tumor with an occurrence rate of around 500 new cases a year in France. It can cause serious vision problems and, in 30 to 50% of cases, metastases (most often in the liver) can develop and compromise the patient’s survival. Since its occurrence is rare, eye cancer remains very little known to the general public, and even to health professionals. Institut Curie is the leading national center for this disease.

There are reliable arguments for the fact that hereditary factors are involved in the occurrence of uveal melanoma. Hereditary forms of uveal melanoma are extremely rare (around 1% of uveal melanomas, or around 5 hereditary cases in France each year). Until now, the only known predisposition for uveal melanoma was a hereditary alteration of the BAP1 gene - a tumor-suppressor gene - which causes some of these hereditary cases of uveal melanoma.

Uveal melanomas are most often characterized by a low level of mutation of tumors that do not respond to immunotherapy. However, the DNA repair and uveal melanoma team at Institut Curie recently reported a few cases associated with high levels of mutations of tumors related to inactivation of the MBD4 gene, and which could benefit from immunotherapy. The MBD4 (Methyl-CpG Binding Domain 4, DNA Glycosylase) gene codes for an enzyme involved in DNA repair and appears to act as a tumor-suppressor gene. Its inactivation leads to accumulation of a very specific type of mutation, the same that are produced when an individual or a cell ages.

Marc-Henri Stern, head of the DNA repair and uveal melanoma team in the Cancer, Heterogeneity, Instability and Plasticity unit (Institut Curie, Inserm U830) explains: “Our work began with the observation of a patient presenting with metastasized uveal melanoma and which, against all expectations, responded exceptionally to the immune checkpoint inhibitors, whereas these cancers do not generally respond to immunotherapy. We revealed a mutation in this patient on the MBD4 gene in the germ cells, which is thus hereditary.”

Researchers and doctors at Institut Curie have analyzed more than 1,000 cases of patients suffering from uveal melanoma diagnosed at Institut Curie. For each of them, they systematically searched for the presence or absence of MBD4 mutations in the blood cells, thus in the patient’s genetic patrimony. They identified 8 harmful MBD4 mutations and showed that inactivation of this gene was associated with a high rate of mutations in these patients’ tumors, demonstrating that this is a new genetic predisposition to uveal melanoma. Germ mutations of MBD4 give a relative risk: an individual carrying this mutation has a 10 times higher risk of developing uveal melanoma than a person without the mutation. By comparison, even harmful BRCA1 mutations in breast cancer do not give this type of relative risk. “This being said, uveal melanoma is a very rare disease. They do have a 10 times greater risk of developing it but it remains a very rare probability in a person’s life,” explains Marc-Henri Stern.

These results open up a whole field of investigation in medical genetics. The work currently being done aims to determine whether these MBD4 mutations predispose to other types of cancers, and to understand the characteristics of these tumors inactivated for the MBD4 gene. “Furthermore, we know that these tumors that occur in the MBD4 context are hypermutated and thus likely to react favorably to immunotherapy. These results support the need to carry out systematic screening to search for these mutations since there is a real hope for the treatment of these patients,” continues Marc-Henri Stern.

Thus, the aim of the Institut Curie teams is to develop reagents to be able to carry out diagnoses in the hospital. On the longer term, they plan to explore and develop new therapeutic strategies for treating uveal melanoma.



  • Germline MBD4 mutations and predisposition to uveal melanoma. Derrien AC, Rodrigues M, Eeckhoutte A, Dayot S, Houy A, Mobuchon L, Gardrat S, Lequin D, Ballet S, Pierron G, Alsafadi S, Mariani O, El-Marjou A, Matet A, Colas C, Cassoux N, Stern MH. Journal of National Cancer Institute. April 2020.
  • Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors. Rodrigues M, Mobuchon L, Houy A, Fiévet A, Gardrat S, Barnhill RL, Popova T, Servois V, Rampanou A, Mouton A, Dayot S, Raynal V, Galut M, Putterman M, Tick S, Cassoux N, Roman-Roman S, Bidard FC, Lantz O, Mariani P, Piperno-Neumann S, Stern MH. Nature Communications. 2018.

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