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 fivefold 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 2 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 < 5 × 10-5), implying a potential role as UM predisposition gene. These findings provide a strong basis for the inclusion of MBD4 in the screening of potential UM-prone families as well as stratification of immunotherapy.

中文翻译：

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pembrolizumab和ipilimumab治疗的具有种系MBD4无意义突变的葡萄膜黑色素瘤患者的长期稳定疾病。

目前尚无转移性葡萄膜黑色素瘤（UM）的有效治疗方法。最近，有报道说，由于高的肿瘤突变负担与种系功能丧失MBD4突变相关，因此UM患者对检查点抑制剂（CI）治疗有反应。在这里，我们报道了另一位携带MBD4种系无义变异（p.Leu563Ter）的UM患者，她的肿瘤显示出比平均突变负担高出五倍。我们证实了MBD4中种系功能丧失变异与CI反应之间的关联。患者经历了稳定的疾病（10个月），并以转移性疾病生存了2年，是中位生存期的两倍。此外，报告的UM队列中MBD4功能丧失变异的频率比聚集的人口基因组数据库高20倍以上（P <5×10-5），暗示其可能是UM易感基因。这些发现为将MBD4包括在潜在的易UM家族筛查以及免疫治疗分层中提供了坚实的基础。