Repo Pauliina E, Jakkula Eveliina, Hiltunen Juho, Putkuri Heidi, Staskiewicz-Tuikkanen Aleksandra, Järvinen Reetta-Stiina, Täll Martin, Raivio Virpi, Al-Jamal Rana'a T, Kivelä Tero T, Turunen Joni A
Eye Genetics Group, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.
Ocular Oncology Service, Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Pigment Cell Melanoma Res. 2025 Jan;38(1):e13198. doi: 10.1111/pcmr.13198. Epub 2024 Sep 30.
Uveal melanoma (UM) is a rare yet aggressive eye cancer causing over 50% mortality from metastasis. Familial UM, amounting to 1%-6% of patients in Finland and the United States, mostly lack identified genetic cause, while 8% show associations with other cancer syndromes. We searched novel genetic associations for predisposition to UM, additional to already studied BAP1 and MBD4, by using targeted amplicon sequencing of 19 genes associated with UM, BAP1, or renal cell carcinoma in 270 consecutively enrolled Finnish patients with UM. Key UM drivers GNAQ, GNA11, CYSLTR2, PLCB4, EIF1AX, and SF3B1 lacked pathogenic germline variants. One patient carried the pathogenic BRCA1 variant c.3626del p.(Leu1209*), and one harbored a novel truncating MET variant c.252C > G p.(Tyr84*), classified as likely pathogenic. FLCN and BRCA2, previously identified with pathogenic variants in patients with UM, did not have such variants in our cohort. Two patients were heterozygous for a pathogenic recessive BLM variant c.2824-2A > T. None of the carriers of identified variants had familial UM. We identified BRCA1 and MET as genes with pathogenic germline variants in Finnish UM patients, each with a frequency of 0.4% (95% confidence interval, 0-2).
葡萄膜黑色素瘤（UM）是一种罕见但侵袭性强的眼癌，转移导致的死亡率超过50%。在芬兰和美国，家族性UM占患者的1%-6%，大多未发现明确的遗传病因，而8%与其他癌症综合征有关联。我们通过对270例连续入组的芬兰UM患者中与UM、BAP1或肾细胞癌相关的19个基因进行靶向扩增子测序，寻找除已研究的BAP1和MBD4之外的UM易感性新遗传关联。UM关键驱动基因GNAQ、GNA11、CYSLTR2、PLCB4、EIF1AX和SF3B1缺乏致病性种系变异。一名患者携带致病性BRCA1变异c.3626del p.(Leu1209*)，一名患者携带一种新的MET截短变异c.252C＞G p.(Tyr84*)，分类为可能致病。先前在UM患者中鉴定出致病性变异的FLCN和BRCA2在我们的队列中没有此类变异。两名患者为致病性隐性BLM变异c.2824-2A＞T的杂合子。已鉴定变异的携带者均无家族性UM。我们在芬兰UM患者中鉴定出BRCA1和MET为具有致病性种系变异的基因，每个基因的频率均为0.4%（95%置信区间，0-2）。
