Uveal melanoma patient with germline MBD4 nonsense mutation

There is currently no effective treatment for metastasised uveal melanoma (UM). Recently, it was reported that a UM patient was responsive to checkpoint inhibitor (CI) treatment, due to a high tumour mutation burden correlated with a germline loss-of-function MBD4 mutation. Here, we report on another UM patient who carried an MBD4 germline nonsense variant (p.Leu563Ter) and her tumour showed a 5-fold higher than average mutation burden. We confirmed the association between germline loss-of-function variant in MBD4 and CI response. The patient experienced stable disease (10 months) and survived two years with metastatic disease, which is twice as long as median survival. Additionally, the frequency of MBD4 loss-of-function variants in reported UM cohorts was >20 times higher than in an aggregated population genome database (P < 5x10-5), implying a potential role as UM predisposition gene. These findings provide a strong basis for the inclusion of MBD4 in screening of potential UM-prone families as well as stratification of immunotherapy.

• Type: Other
• Archiver: EGA European Genome-Phenome Archive