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, Helsinki, Finland.
Ocular Oncology Service, Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Pigment Cell Melanoma Res. 2025 Sep;38(5):e70041. doi: 10.1111/pcmr.70041.
Some patients with uveal melanoma (UM) show genetic cancer predisposition: ~2% harbor a pathogenic or likely pathogenic (P/LP) germline variant in BAP1 or, rarely, in 20 other cancer-associated genes. Up to 75% of patients with familial UM (FUM) lack genetic diagnosis, prompting a search beyond BAP1. We studied with exome sequencing blood samples from 106 patients with UM and higher-than-average risk of cancer (UM ≤ 45 years of age, bilateral or familial UM, or personal history of non-ocular cancer) and no P/LP variants in BAP1. Sixteen (15%; 95% confidence interval [CI] 9-23) patients carried at least one P/LP variant in dominant cancer genes (CHEK2, DDX41, FANCM, HOXB13, RAD50, SDHA, SDHB) and fifteen in recessive ones. Only CHEK2 and FANCM have previously been reported in patients with UM. Six patients (6%; 95% CI 2-12) carried multilocus P/LP variants. Their median age at diagnosis of UM was 51 (range, 22-69) years, 9 years less than the cohort median of 60 (range, 13-89). This suggests a role for co-occurring pathogenic variants and potentially multilocus inherited neoplasia allele syndrome (MINAS) in UM predisposition. None with FUM carried P/LP variants, warranting investigation of further genes, lower penetrance variants, and multi-gene heterozygosity in UM predisposition.
一些葡萄膜黑色素瘤（UM）患者表现出遗传性癌症易感性：约2%的患者在BAP1基因中携带致病性或可能致病性（P/LP）种系变异，极少数情况下，在其他20个癌症相关基因中携带此类变异。高达75%的家族性UM（FUM）患者缺乏基因诊断结果，这促使人们在BAP1基因之外进行探索。我们对106例UM患者且患癌风险高于平均水平（UM患者年龄≤45岁、双侧或家族性UM，或有非眼癌个人史）且BAP1基因中无P/LP变异的患者的血液样本进行了外显子组测序研究。16例（15%；95%置信区间[CI]为9%-23%）患者在显性癌症基因（CHEK2、DDX41、FANCM、HOXB13、RAD50、SDHA、SDHB）中携带至少一个P/LP变异，15例患者在隐性癌症基因中携带此类变异。此前仅在UM患者中报道过CHEK2和FANCM。6例（6%；95%CI为2%-12%）患者携带多位点P/LP变异。他们诊断为UM时的中位年龄为51岁（范围为22 - 69岁），比队列中位年龄60岁（范围为13 - 89岁）小9岁。这表明共发致病性变异和潜在的多位点遗传性肿瘤等位基因综合征（MINAS）在UM易感性中起作用。没有FUM患者携带P/LP变异，这就需要对UM易感性中的其他基因、低外显率变异和多基因杂合性进行研究。
