Uveal melanoma (UM) is a rare, aggressive ocular cancer occurring in adults, with an incidence of 1 to 9 cases per million people per year (1). It arises from melanocytes in the uveal tract, which includes the choroid, the ciliary body, and the iris. The most common symptoms are blurred or distorted vision, visual field loss or photopsia (2, 3). The 5-year survival rates are quite encouraging for localized and regional stages, standing at 85% and 67% respectively. However, the most significant challenge in managing this disease occurs in the metastatic stage, where the survival rate drops to 16% (4). With more than 30% of these patients developing metastases, almost invariably in the liver, UM is therefore known for its poor prognosis as a result of the absence of efficacious treatments, with a median survival of only 10 months (5–7).

Most patients are diagnosed with UM between the ages of 50 and 70 (2). The main risk factors — such as skin phototype, geographic gradient from south to north (linked to the phototype), congenital ocular melanocytes, family history, and hereditary cancer predisposition — are non-modifiable. Focusing on the decreasing north-south gradient, Virgili et al., supported the protective role of skin pigmentation between the population of northern and southern Algeria (8). However, even if UM incidence increase with latitude, there is no evidence for a link between ultraviolet radiation and UM occurrence (8, 9). These factors suggest the important role that genetic predisposition plays in the development of UM (2). Approximately 1 to 2% of UM and 22% of familial cases have been linked to hereditary cancer predisposition and result from pathogenic genetic variations, primarily in the BAP1 gene, and more recently in MBD4. These genes are associated with syndromic hereditary cancer predisposition. Pathogenic variants in BAP1 confer a high risk of various cancers, including UM (16-36% risk), with a median onset age of 53 years compared to 62 years for sporadic forms. This risk extends to other tumors such as cutaneous melanoma, pleural melanoma (20-25%), and renal cancer (10%). MBD4 for its part has been associated with an increased risk of colorectal cancer and acute myeloid leukemia (10). The transmission risk for the BAP1 and MBD4 genes is estimated at 50% per conception, owing to their autosomal dominant inheritance pattern, affecting both males and females. Identifying a pathogenic variant in the BAP1 or MBD4 genes enables tailored medical management for affected individuals and their relatives, including international screening recommendations for BAP1, which involve clinical skin examinations, eye fundus examinations, and imagery for pulmonary and renal assessments (11). Additionally, constitutional genetic anomalies in genes such as BRCA1, BRCA2, CHEK2, PALB2, SMARCE1, POT1, TP53AIP1, MSH6, MLH1, MLH2 and PMS2 have been described in UM patients, although their involvement remains unclear (12). Epidemiological studies have also shown an increased risk of prostate cancer, thyroid cancer, and leukemia among UM patients, which is not currently associated with BAP1 or MBD4 (13, 14).

The identification of candidate genes for hereditary predisposition to uveal melanoma is of great interest, as it holds the potential to revolutionize patient care. Indeed, validation of these potential genes could enable their integration into a diagnostic approach. Patients could then be offered screening and preventive measures tailored to their tumor spectrum, as well as appropriate familial genetic counselling. Following this line of research, our study, IGCMU (Identification de nouveaux Gènes Candidats à la predisposition héréditaire au Mélanome de l’Uvée) aims to identify new candidate genes for hereditary predisposition to UM, particularly in cases not linked to BAP1 or MBD4. We will also explore the role of genes associated with other hereditary cancer syndromes and examine their potential involvement in UM, contributing to a broader understanding of the genetic landscape of this rare cancer.

This study aims to explore the hereditary aspects of UM by identifying new candidate genes involved in cancer predisposition. While the roles of BAP1 and MBD4 are already known in family clusters, around 78% of UMs are not linked to them (10). This highlights the need to know what other genes could have an impact on the occurrence of this disease. In order to better understand the mechanisms behind UM and improve patient outcomes, it is essential to continue research in this area. Many research teams are or have been working on this topic. In France, we can cite the Curie Institute and the Melanoma Patient Network Europe, which focus on understanding why some European individuals are at a significantly higher risk and why some patients develop aggressive forms of the disease with a high likelihood of metastasis. This project has obtained American funding under the “Rare Melanomas Focused Program Award” call for proposals with the aim of developing three themes: 1- identifying UM predisposition factors, 2- establishing and identifying isogenic cell lines from the original uveal melanocyte, and 3- identifying recurrent, immunogenic neoantigens specific to UM (15).

One study (NCT05179174) is currently recruiting UM patients in order to identify genetic and epigenetic biomarkers in UM using miRNA analysis, while also focusing on the GNA11 and GNAQ genes. These genes are located on chromosomes 9q21.2 and 19p13.3 and encode for proteins vital for signaling pathways in uveal melanoma (UM). Mutations in these genes have already been studied, and have been identified in approximately 80-90% of UM cases (3, 16). However, they have not been associated with patient outcomes or disease-free survival (17, 18).

One of the limits of our study is the small sample size. We have defined our recruitment capacity according to the number of cases identified in the French national association of patients with eye cancers (A.N.P.A.C.O.), which supports this research. In order to expand the cohort and thank to the Plan France Médecine Génomique 2025, we plan to request access to the national sequencing platform data, so that we can add data from other UM patients. Indeed, on a national scale in France, all cases of uveal melanoma occurring before the age of 40 are addressed to, sequenced and stored on this platform.

The possible involvement of genes like BRCA1, BRCA2, CHEK2, and POT1, which are known to play a role in other hereditary cancers, could lead to new knowledge of UM, especially in family cases (12). By conducting exome sequencing and focusing on genes associated with various hereditary cancer syndromes, this research could expand the current understanding of the genetics of UM because of similar biological mechanisms and signaling pathways that could affect its progression. For example, a recent study found that certain mutations in genes involved in the PI3K/AKT/mTOR pathway could have a prognostic value in UM. CHEK2 and PDK1, for instance, have been shown to be associated with the development of metastases, as well as DHX9. This retrospective analysis involved 69 UM cases with a median age of 59 years, and 39% presented metastatic disease at inclusion (19). Given the small size of this cohort, a larger, prospective study could be valuable to validate these findings.

Previous studies have also explored the involvement of BRCA1 (12, 20), BRCA2 (21, 22) and CHEK2 (12). The study examining the relationship between BRCA1 and UM was retrospective. Researchers also analyzed a substantial cohort of BRCA mutation carriers and explored whether any of the 469 cases developed UM. They identified two cases of UM, a frequency higher than the typical incidence in the general population, which is about five to six cases per million inhabitants (20). These findings suggest that pursuing research in this direction could be worthwhile.

One of the studies investigating the involvement of BRCA2 was prospective, conducted in Israel, and included 30% of UM cases in the country in the 1990s. In brief, 149 patients were included, but only 4 out of the 143 assessable patients were found to carry BRCA2 mutations. This limited number of mutations reduced the study’s ability to establish a strong association between this gene and UM (21). The other study exploring the involvement of BRCA2 in UM was also prospective and conducted in the 1990s. It reached a similar conclusion; however, the screening of patients could have been biased, as genomic analyses were preferentially performed on UM cases with a family history of breast or ovarian cancer — cancers that are known to be associated with BRCA mutations (22).

Other genomic analyses found only sporadic associations with UM (2, 21, 22). Some of these studies are 20 years old and current analysis techniques could provide new insights. This is why we have initiated the IGCMU study, in an attempt to find answers to these questions and expand research by including other targets such as PALB2, POT1, MSH6, MLH1, SMARCE1, TP53AIP1, MLH2 and PMS2.

The single-center design of our study enables a close coordination between oncologists, geneticists, bioinformaticians, and clinical staff, ensuring the quality in the process of genetic analysis. This approach is important given the complexity of analyzing genetic data for such a rare condition.

Finally, the identification of new candidate genes could not only improve our understanding of the genetic origins of UM, but also lead to better clinical management for patients and their families.

In conclusion, this study aims to fill a gap in the current knowledge on hereditary predisposition to uveal melanoma. By identifying new candidate genes associated with the disease, this research has the potential to enhance patient care and ultimately improve outcomes for patients with uveal melanoma.