Uveal melanoma (UM) is a rare intraocular cancer with the highest incidence in northern latitudes. Metastases develop in approximately 50% of patients, whereafter the median survival is 13 months. Generally, the mutation burden of these tumors is low. Germline variants predisposing to UM have been previously described in BRCA1‐associated protein 1 (BAP1 ). Recently, germline and somatic loss‐of‐function (LOF) variants in the methyl‐CpG‐binding domain 4 (MBD4 ) gene have been found to cause a hypermutated UM, and MBD4 also has been put forward as a gene predisposing to UM. We sequenced for MBD4 germline variants in 440 Finnish patients with UM and identified seven rare exonic missense variants in 16 (3.6%) patients, of which one likely alters MBD4 function. The frequency of likely pathogenic variants in our cohort is 0.23% (1/432; 95% CI, 0.01–1.28). We identified no LOF variants though their frequency in the Finnish population is 0.052%. Thus, our data do not support the suggestion that MBD4 germline variants predispose to UM. Somatic loss of MBD4 might modify the mutational burden in UM and change its response to immune checkpoint inhibitors.

中文翻译：

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在芬兰葡萄膜黑色素瘤患者中，MBD4中的种系功能丧失变体很少见。

葡萄膜黑色素瘤（UM）是一种罕见的眼内癌，在北纬地区发病率最高。大约50％的患者发生转移，此后中位生存期为13个月。通常，这些肿瘤的突变负担很低。先前在BRCA1相关蛋白1（BAP1）中描述了诱发UM的种系变异。最近，已发现甲基CpG结合域4（MBD4）基因中的种系和体细胞功能丧失（LOF）变异体导致UM超突变，并且MBD4也已被提出为UM易感基因。我们为MBD4排序440例UM芬兰患者的生殖系变体，并在16例（3.6％）患者中鉴定出7种罕见的外显子错义变体，其中一个可能改变了MBD4的功能。在我们队列中，可能的病原体变异的频率为0.23％（1/432; 95％CI，0.01-1.28）。我们没有发现LOF变异，尽管它们在芬兰人群中的发生率为0.052％。因此，我们的数据不支持MBD4种系变体易患UM的建议。MBD4的体细胞丢失可能会改变UM中的突变负担，并改变其对免疫检查点抑制剂的反应。