Department of Surgery, King Hussein Cancer Center, Amman, Jordan.
Department of Cell Therapy and Applied Genomics, King Hussein Cancer Center, Amman, Jordan.
Hematol Oncol Stem Cell Ther. 2020 Sep;13(3):152-159. doi: 10.1016/j.hemonc.2020.02.006. Epub 2020 Mar 23.
OBJECTIVE/BACKGROUND: Retinoblastoma (RB), the most common intraocular malignancy in children, is caused by biallelic inactivation of the human retinoblastoma susceptibility gene (RB1). We are evaluating the impact of the type of RB1 gene mutation on clinical presentation and management outcome.
A retrospective case series of 50 patients with RB. Main outcomes were clinical and pathologic features and types of RB1 gene mutations detected using quantitative multiplex polymerase chain reaction (PCR), allele-specific PCR, next-generation sequencing analysis, and Sanger sequencing.
Twenty (40%) patients had unilateral RB and 30 (60%) had bilateral RB. Overall, 36 (72%) patients had germline disease, 17 (47%) of whom inherited the disease. Of these 17 inherited cases, paternal origin of the RB1 mutation was seen in 15 (88%). The overall eye salvage rate was 74% (n = 49/66; 100% for Groups A + B + C, and 79% for Group D eyes). The most frequent type of mutation was a nonsense mutation generating a stop codon (15/36, 42%). Other mutations that result in a premature stop codon due to deletions or insertions with donor splice site or receptor splice site mutations were detected in 7/36 (19%), 10/36 (28%), and 2/26 (6%) patients, respectively. The remaining two (6%) patients had frameshift mutation. Patients with deletion, acceptor splice site, and frameshift mutations presented with more advanced ICRB (International Classification of Retinoblastoma) stage (75% diagnosed with Group D or E), even though there was no significant difference in eye salvage rate or tumor invasiveness between patients with different types of mutations.
Despite the heterogeneous nature of RB1 gene mutations, tumor stage remains the most important predictive factor for clinical presentation and outcome. Furthermore, acceptor splice site and frameshift mutations are associated with more advanced tumor stage at diagnosis.
目的/背景：视网膜母细胞瘤（RB）是儿童中最常见的眼内恶性肿瘤，由人视网膜母细胞瘤易感性基因（RB1）的双等位基因失活引起。我们正在评估 RB1 基因突变类型对临床表现和治疗结果的影响。
对 50 例 RB 患者进行回顾性病例系列研究。主要结局是通过定量多重聚合酶链反应（PCR）、等位基因特异性 PCR、下一代测序分析和 Sanger 测序检测到的临床和病理特征以及 RB1 基因突变类型。
20 例（40%）患者为单侧 RB，30 例（60%）为双侧 RB。总体而言，36 例（72%）患者为种系疾病，其中 17 例（47%）为遗传性疾病。在这 17 例遗传性病例中，15 例（88%）RB1 突变来源于父系。总体保眼率为 74%（n=49/66；A+B+C 组为 100%，D 组为 79%）。最常见的突变类型是产生终止密码子的无义突变（15/36，42%）。由于缺失或插入导致供体位点或受体剪接位点突变而产生过早终止密码子的其他突变，分别在 7/36（19%）、10/36（28%）和 2/26（6%）患者中检测到。其余两例（6%）患者有移码突变。发生缺失、受体剪接位点和移码突变的患者 ICRB（国际视网膜母细胞瘤分类）分期更晚（75%诊断为 D 或 E 组），尽管不同类型突变的患者之间在保眼率或肿瘤侵袭性方面无显著差异。
尽管 RB1 基因突变具有异质性，但肿瘤分期仍是预测临床表现和结果的最重要因素。此外，受体剪接位点和移码突变与诊断时更晚期的肿瘤分期相关。
