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Association Between Genotype and Phenotype in Consecutive Unrelated Individuals With Retinoblastoma.

视网膜母细胞瘤连续无关个体的基因型和表型之间的相关性。

  • 影响因子:2.46
  • DOI:10.1001/jamaophthalmol.2020.2100
  • 作者列表:"Salviat F","Gauthier-Villars M","Carton M","Cassoux N","Lumbroso-Le Rouic L","Dehainault C","Levy C","Golmard L","Aerts I","Doz F","Bonnet-Serrano F","Hayek S","Savignoni A","Stoppa-Lyonnet D","Houdayer C
  • 发表时间:2020-06-18
Abstract

Importance:Retinoblastoma (RB) is the most common pediatric intraocular neoplasm. RB is a complex model in which atypical pathogenic variants, modifier genes, imprinting, and mosaicism are known to be associated with the phenotype. In-depth understanding of RB therefore requires large genotype-phenotype studies. Objective:To assess the association between genotype and phenotype in patients with RB. Design, Setting, and Participants:This single-center, retrospective cohort study, conducted from January 1, 2000, to September 30, 2017, enrolled 1404 consecutive ascertained patients with RB who consulted an oncogeneticist. All patients had their genotype and phenotype recorded. Statistical analysis was performed from July 1, 2018, to December 31, 2018. Main Outcomes and Measures:RB1 germline and somatic pathogenic variant types, family history, and disease presentation characteristics (ie, age at diagnosis, sex, laterality, and International Intraocular Retinoblastoma Classification group). Results:Among 1404 patients with RB (734 [52.3%] female; mean [SD] age, 20.2 [21.2] months), 866 cases (61.7%) were unilateral and 538 cases (38.3%) were bilateral. Loss of function variants were found throughout the coding sequence, with 259 of 272 (95.2%) somatic pathogenic variants and 537 of 606 (88.6%) germline pathogenic variants (difference, 6.6%; 95% CI, 4.0%-9.2%; P < .001) after excluding tumor-specific pathogenic variants (ie, promoter methylation and loss of heterozygosity); a novel low-penetrance region was identified in exon 24. Compared with germline pathogenic variants estimated to retain RB protein expression, germline pathogenic variants estimated to abrogate RB protein expression were associated with an earlier mean (SD) age at diagnosis (12.3 [11.3] months among 457 patients vs 16.3 [13.2] months among 55 patients; difference, 4 months; 95% CI, 1.9-6.1 months; P = .01), more frequent bilateral involvement (84.2% among 452 patients vs 65.2% among 45 patients; difference, 18.9%; 95% CI, 14.5%-23.3%; P < .001), and more advanced International Intraocular Retinoblastoma Classification group (85.3% among 339 patients vs 73.9% among 34 patients; difference: 11.4%; 95% CI, 6.5%-16.3%; P = .047). Among the 765 nongermline carriers of an RB1 pathogenic variant, most were female (419 females [54.8%] vs 346 males [45.2%]; P = .008), and males were more likely to have bilateral RB (23 males [71.4%] vs 12 females [34.3%]; P = .01). Conclusions and Relevance:These results suggest that RB risk is associated with the germline pathogenic variant and with maintenance of RB protein and that there is a sex-linked mechanism for nongermline carriers.

摘要

重要性: 视网膜母细胞瘤 (RB) 是最常见的儿童眼内肿瘤。RB 是一个复杂的模型,其中非典型致病变异、修饰基因、印记和嵌合体已知与表型相关。因此,深入了解 RB 需要大量的基因型-表型研究。 目的: 探讨 RB 患者基因型与表型的关系。 设计、地点和参与者: 这项单中心、回顾性队列研究,于 2000 年 1 月 1 日至 20 17 年 9 月 30 日进行,入组了 1404 例连续确定的 RB 患者,这些患者咨询了肿瘤遗传学家。所有患者都记录了其基因型和表型。统计分析时间为 2018 年 7 月 1 日至 20 18 年 12 月 31 日。 主要结局和指标: RB1 种系和体细胞致病变异类型、家族史和疾病表现特征 (即诊断年龄、性别、偏侧性和国际眼内视网膜母细胞瘤分类组)。 结果: 1404 例 RB 患者中 (女性 734 [52.3%]; 平均 [SD] 年龄,20.2 [21.2] 个月),单侧 866 例 (61.7%),538 例 (38.3%) 是双边的。在整个编码序列中发现了功能缺失变异,259 个体细胞致病变异中的 272 个 (95.2%) 和 537 个生殖系致病变异中的 606 个 (88.6%) (差异,6.6%; 95% CI, 4.0%-9.2%; P <.001) 排除肿瘤特异性致病变异 (即启动子甲基化和杂合性缺失) 后;在外显子 24 中发现了一个新的低 penetr率区域。与估计保留 RB 蛋白表达的生殖系致病变体相比,估计废除 RB 蛋白表达的生殖系致病变体与较早的平均值 (SD) 相关诊断时年龄 (12.3 例患者中 11.3 [457] 个月 vs 55 例患者中 16.3 [13.2] 个月; 差异,4 个月; 95% CI,1.9-6.1 个月; P =.01),双侧受累更频繁 (84.2% 例患者中为 452,45 例患者中为 65.2%; 差异,18.9%; 95% CI,14.5%-23.3%; P <.001) 和更先进的国际眼内视网膜母细胞瘤分类组 (85.3% 例患者中为 339,34 例患者中为 73.9%; 差异: 11.4%; 95% CI,6.5%-16.3%; P =.047)。在 765 例 RB1 致病变异的 nongermline 携带者中,大多数为女性 (女性 419 例 [54.8%] vs 男性 346 例 [45.2%]; P =.008),男性更可能患有双侧 RB (23 例男性 [71.4%] vs 12 例女性 [34.3%]; P =.01)。 结论和相关性: 这些结果表明 RB 风险与生殖系致病变异和 RB 蛋白的维持相关,并且对于 nongermline 携带者存在性别连锁机制。

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