Abstract 4906: A prospective analysis identified mismatch repair genes as predisposing for uveal melanoma
Authors: Marc-Henri Stern, Anaïs Le Ven, Marie-Charlotte Villy, André B. Silveira, Alexandre Houy, Mathilde Warcoin, Marine Le Mentec, Fatoumata Simaga, Antoine De Pauw, Bruno Buecher, Marion Gauthier-Villars, Thibault Verrier, Kevin Merchadou, Victor Renault, Anne Vincent-Salomon, Juliette Sauge, Sophie El Zein, Catherine Dubois d’Enghien, Sophie Piperno-Neumann, Alexandre Matet, Denis Malaise, Nathalie Cassoux, Livia Lumbroso-Le Rouic, Dominique Stoppa-Lyonnet, Manuel R. Rodrigues, Lisa Golmard, Chrystelle Colas
Journal: Cancer Research (2025)

Background and Aim: Uveal melanoma (UM) is the most common intraocular malignancy in adults. Thus far, germline mutations of two genes have been identified to be predisposing to UM with a high penetrance: BAP1, responsible for the BAP1 tumor predisposition syndrome (BAP1-TPDS), and MBD4, which germline alterations are associated with tumor predisposition, specific tumor mutational signature and response to immunotherapy. However, only a fraction of familial and bilateral/multifocal forms of UM can be explained by these germline alterations, suggesting the existence of other predisposing factors. Methods: We analyzed a panel of 122 candidate cancer predisposing genes by target sequencing on germline DNA from a prospective unbiased cohort of 381 patients diagnosed with UM at Institut Curie between July 2021 and February 2023. Results: We identified 29 pathogenic variants (PVs) in genes that are relevant for patient monitoring and genetic counselling (6 in MBD4, 3 in BAP1, 3 in BRCA2, 1 in ATM, 3 in FAN1, 2 in FANCL, 3 in FANCM, 1 in MLH1, 1 in MSH2, 2 in MSH6 and 4 in PMS2). Two patients had PVs in MSH6, 4 in PMS2, 1 in MLH1 and 1 in MSH2. The frequencies of the 3 MisMatch Repair (MMR) genes MLH1, MSH2 and MSH6 were significantly higher than in the gnomAD (v2.1.1) non-Finnish European database as a matched control sub-cohort (p=0.00073, OR: 10.4 [2.8-27.5]). PMS2 was excluded from this statistical analysis because its pseudogene prevents the interpretation of public data. One UM tumor sample was further characterized from the patient carrying the germline MLH1 PV. This UM displayed biallelic inactivation of MLH1, loss of MLH1 and PMS2 expression by immuno-histochemistry, a prominent Substitution Mutational Signature 6 (SBS6) associated with MMR deficiency from whole Genome Sequencing (WGS) and an MSI-H phenotype. Conclusions: This study confirms MMR genes as predisposing factors in UM, as suggested by two previous case reports identifying MLH1 germline PVs and biallelic inactivation in UM cases (Lobo et al. Virchows Arch 2017;470:347; Abdel-Rahman et al. Ophthalmology 2020;127:668). Further analyses will be needed to define the risk of developing UM for patients with a Lynch syndrome. Citation Format: Marc-Henri Stern, Anaïs Le Ven, Marie-Charlotte Villy, André B. Silveira, Alexandre Houy, Mathilde Warcoin, Marine Le Mentec, Fatoumata Simaga, Antoine De Pauw, Bruno Buecher, Marion Gauthier-Villars, Thibault Verrier, Kevin Merchadou, Victor Renault, Anne Vincent-Salomon, Juliette Sauge, Sophie El Zein, Catherine Dubois d’Enghien, Sophie Piperno-Neumann, Alexandre Matet, Denis Malaise, Nathalie Cassoux, Livia Lumbroso-Le Rouic, Dominique Stoppa-Lyonnet, Manuel R. Rodrigues, Lisa Golmard, Chrystelle Colas. A prospective analysis identified mismatch repair genes as predisposing for uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4906.