Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
Exp Eye Res. 2021 Apr;205:108456. doi: 10.1016/j.exer.2021.108456. Epub 2021 Jan 23.
Retinoblastoma (Rb) is the most common primary intraocular childhood malignancy and one of the main causes of blindness in children. In China, most tumors are diagnosed at an advanced stage and have relatively poor outcomes compared to developed countries. Here, we aimed to update the clinical manifestations and RB transcriptional corepressor 1 (RB1) mutation spectrum in Chinese Rb patients. Medical charts of 184 eyes in 145 Chinese Rb patients belonging to unrelated families were reviewed. Genomic DNA was isolated from peripheral blood of the patients and their parents. Mutation analysis of whole coding regions, promoter regions and flanking splice sites in the RB1 gene was performed. In addition, multiplex ligation-dependent probe amplification (MLPA) was done to detect gross aberrations. Germline RB1 mutations were observed in 37.2% (54/145) of Rb patients. RB1-mutated patients presented with earlier age of diagnosis (p = 0.019), with a significantly larger proportion of bilateral cases (p = <0.001) and secondary malignancies (p = 0.027) relative to those without RB1 mutations. For ocular clinical presentations, RB1-mutated retinoblastomas presented with a larger proportion of ectropion uveae (p = 0.017) and iris neovascularization (p = 0.001). These RB1 mutations comprised of 13 (24.1%) nonsense mutation, 13 (24.1%) splicing mutations, 11 (20.4%) frameshift deletions, 11 (20.4%) gross mutations, 3 (5.6%) missense mutations, 2 (3.7%) promoter mutations and 1 (1.9%) non-frameshift deletion. In addition, 8 novel RB1 mutations were identified. These germline RB1 mutations were not related to age at diagnosis or laterality. Here, we provide a comprehensive spectrum of RB1 germline mutations in Chinese Rb patients and describe correlations between RB1 mutations and clinical presentations. Our study also provides new evidence that will inform management and genetic counselling of Rb patients and families.
视网膜母细胞瘤（Rb）是最常见的儿童眼内原发性恶性肿瘤之一，也是儿童失明的主要原因之一。在中国，大多数肿瘤在晚期诊断，与发达国家相比，治疗效果较差。在这里，我们旨在更新中国 Rb 患者的临床表现和 RB 转录核心抑制因子 1（RB1）突变谱。回顾了 145 例无血缘关系的 Rb 患者的 184 只眼的病历。从患者及其父母的外周血中分离基因组 DNA。对 RB1 基因的整个编码区、启动子区和侧翼剪接位点进行突变分析。此外，还进行了多重连接依赖性探针扩增（MLPA）以检测大片段缺失。在 37.2%（54/145）的 Rb 患者中观察到 RB1 种系突变。与未发生 RB1 突变的患者相比，RB1 突变患者的诊断年龄更早（p=0.019），双侧病例的比例显著更高（p=0.001），继发性恶性肿瘤的比例更高（p=0.027）。对于眼部临床表现，RB1 突变的视网膜母细胞瘤有更大比例的葡萄膜外翻（p=0.017）和虹膜新生血管形成（p=0.001）。这些 RB1 突变包括 13 个（24.1%）无义突变、13 个（24.1%）剪接突变、11 个（20.4%）移码缺失、11 个（20.4%）大片段缺失、3 个（5.6%）错义突变、2 个（3.7%）启动子突变和 1 个（1.9%）非移码缺失。此外，还鉴定了 8 个新的 RB1 突变。这些种系 RB1 突变与诊断年龄或侧别无关。在这里，我们提供了中国 Rb 患者 RB1 种系突变的综合谱，并描述了 RB1 突变与临床表现之间的关系。我们的研究还提供了新的证据，为 Rb 患者及其家庭的管理和遗传咨询提供信息。
