Familial uveal melanoma and other tumours in 25 families with monoallelic germline MBD4 variants
Menée en France entre 2021 et 2023 par la recherche systématique de mutations du gène MBD4 chez 289 patients atteints d'un mélanome de l'uvée et 3 240 femmes présentant des antécédents familiaux de cancer du sein, cette étude analyse l'association entre une mutation mono-allélique du gène MBD4 et le risque de développer un mélanome de l'uvée ou d'autres tumeurs
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.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.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.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.