Background We investigated the potential association between pathogenic BRCA1/2 variants and retinoblastoma pathogenicity. Methods In this single-centre, retrospective case series, we performed hereditary cancer panel tests using blood samples for patients with retinoblastoma diagnosed between March 2017 and October 2021. Bioinformatics prediction tools were then used to conduct in silico pathogenicity assessments for patients with BRCA1/2 family variants, in addition to the American College of Medical Genetics and Genomics (ACMG) variant classification. One patient with a germline BRCA1 variant was analysed with whole-genome sequencing (WGS), mutational signature analysis and methylation analysis for RB1 and BRCA using the patient’s tumour and blood samples. Results Of 30 retinoblastoma patients who underwent panel sequencing, six (20%) were found to carry germline variants in the BRCA1/2 or BRIP1 genes. Among these six patients, two had pathogenic or likely pathogenic variants as per the ACMG variant classification. Additionally, three patients showed potential pathogenic BRCA1/2 family variants through further analysis with alternative bioinformatics prediction tools. In the WGS analysis of a tumour from a patient with a germline likely pathogenic BRCA1 variant in one allele, we observed the loss of one RB1 allele due to a large deletion. No somatic non-synonymous mutations or frameshift indels were detected in the RB1 locus of the remaining allele. This sample also showed BRCA1 gene promoter hypermethylation in the tumour, indicating additional epigenetic silencing. Conclusion This study demonstrated that some retinoblastoma patients harboured germline BRCA1/2 family variants, which may be associated with the development of retinoblastoma along with RB1 mutations. All data relevant to the study are included in the article or uploaded as supplementary information.

中文翻译：

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视网膜母细胞瘤肿瘤亚群与 BRCA1/2 突变相关


背景 我们研究了致病性 BRCA1/2 变异与视网膜母细胞瘤致病性之间的潜在关联。方法 在这个单中心回顾性病例系列中，我们使用 2017 年 3 月至 2021 年 10 月期间诊断的视网膜母细胞瘤患者的血液样本进行遗传性癌症小组测试。然后使用生物信息学预测工具对 BRCA1/2 患者进行计算机致病性评估家族变异，以及美国医学遗传学和基因组学学院 (ACMG) 变异分类。使用患者的肿瘤和血液样本，对一名患有种系 BRCA1 变异的患者进行了全基因组测序 (WGS)、突变特征分析以及 RB1 和 BRCA 甲基化分析。结果 在接受组合测序的 30 名视网膜母细胞瘤患者中，发现 6 名 (20%) 患者携带 BRCA1/2 或 BRIP1 基因种系变异。根据 ACMG 变异分类，在这 6 名患者中，两名患者具有致病性或可能致病性变异。此外，通过使用替代生物信息学预测工具的进一步分析，三名患者显示出潜在的致病性 BRCA1/2 家族变异。在对一名等位基因中具有种系可能致病性 BRCA1 变异的患者的肿瘤进行全基因组测序分析时，我们观察到由于大​​的缺失而导致一个 RB1 等位基因的丢失。在剩余等位基因的 RB1 基因座中未检测到体细胞非同义突变或移码插入缺失。该样本还显示肿瘤中 BRCA1 基因启动子高度甲基化，表明存在额外的表观遗传沉默。结论本研究表明，一些视网膜母细胞瘤患者携带种系BRCA1/2家族变异，这可能与视网膜母细胞瘤的发生以及RB1突变有关。 与研究相关的所有数据都包含在文章中或作为补充信息上传。