Familial uveal melanoma and other tumours in 25 families with monoallelic germline MBD4 variants
Marie-Charlotte Villy, Anaïs Le Ven, Marine Le Mentec, Julien Masliah-Planchon, Alexandre Houy, Ivan Bièche, Sophie Vacher, Anne Vincent-Salomon, Catherine Dubois d’Enghien, Mathias Schwartz, Sophie Piperno-Neumann, Alexandre Matet, Denis Malaise, Virginie Bubien, Alain Lortholary, Amal Ait Omar, Mathias Cavaillé, Dominique Stoppa-Lyonnet, Nathalie Cassoux, Marc-Henri Stern, Manuel Rodrigues, Lisa Golmard, Chrystelle Colas- Cancer Research
- Oncology
Abstract
Background
Monoallelic germline MBD4 pathogenic variants (PVs) were recently reported to cause a predisposition to uveal melanoma (UM), associated with a specific tumour mutational signature and good response to immunotherapy. Monoallelic tumour PVs have also been described in brain tumours, breast cancers and myxofibrosarcomas, whereas biallelic germline MBD4 PVs have been involved in a recessive hereditary adenomatous polyposis and a specific type of acute myeloid leukaemia.
Methods
We analysed MBD4 for all patients diagnosed with UM at Institut Curie since July 2021 and in the 3,240 consecutive female probands explored at the Institut Curie for suspicion of predisposition to breast cancer between July 2021 and February 2023.
Results
We here describe 25 families whose probands carry a monoallelic germline PV in MBD4. Eighteen of them presented with UM (including a case of multiple UM), and 7 with breast cancer. Family histories showed the first familial case of UM in monoallelic MBD4 PV carriers and other various types of cancers in relatives, especially breast, renal and colorectal tumours.
Conclusions
Monoallelic MBD4 PV may thus explain some familial and multiple UM, as well as various cancer types, expanding the tumour spectrum of this predisposition. Further genetic testing in relatives combined with molecular tumour analyses will help define the tumour spectrum and estimate each tumour risk.