Bilateral Wilms Tumor and Early Presentation in Pediatric Patients Is Associated with the Truncation of the Wilms Tumor 1 Protein
Bilateral Wilms Tumor and Early Presentation in Pediatric Patients Is Associated with the Truncation of the Wilms Tumor 1 Protein
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DOI：
10.1016/j.jpeds.2012.12.080
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发表时间：
2013-07-01
影响因子：
5.1
通讯作者：
Alexander, Stephen I.
中科院分区：
文献类型：
--
作者：
Hu, Min;Fletcher, Jeffery;Alexander, Stephen I.
目的 调查双侧肾母细胞瘤（WT）儿童的体质性肾母细胞瘤1基因（WT1）异常频率以及突变患者的肿瘤发病年龄。研究设计对8名双侧WT患者进行研究。采用高分辨率熔解和直接测序来筛选 WT1 基因。进行蛋白质印迹以确定所识别的突变是否与表达的截短的 WT1 蛋白相关。结果 WT1 突变患者的肿瘤发病中位年龄（10 个月）低于无突变患者（39 个月）。在 3 名个体外周血的外显子 8 中鉴定出三种新的杂合无义突变，而所有 3 种肿瘤组织均缺乏野生型等位基因。所有突变都会导致 WT1 蛋白过早终止密码子截短。在 1 名患者中，鉴定出 WT1 蛋白的截短形式，这表明 WT 的发育可能是由于异常蛋白的表达所致。检测到四种不同的沉默单核苷酸多态性（SNP）。所有 3 名携带致病性 WT1 突变的患者均具有 2 个同义 SNP，而其余 5 名患者中只有 1 名具有单个同义 SNP (P < .05)。结论 双侧 WT 与儿科患者的早期表现以及外显子 8 中 WT1 无义突变的高频率相关。沉默 SNP 也可能参与 WT 的发展。
Objectives To investigate the frequency of constitutional Wilms tumor 1 gene (WT1) abnormalities in children with bilateral Wilms tumor (WT) and the age of tumor onset in patients with a mutation.Study design Eight patients with bilateral WT were studied. High-resolution melting and direct sequencing were used to screen for the WT1 gene. Western blotting was performed to determine whether the identified mutations were associated with expressed truncated WT1 protein.Results The median age of tumor onset in patients with a mutation in the WT1 was lower (10 months) than in those without a mutation (39 months). Three novel heterozygous nonsense mutations were identified in exon 8 in peripheral blood from 3 individuals, whereas all 3 tumor tissues lacked the wild-type allele. All mutations led to a premature stop codon with truncation of the WT1 protein. In 1 patient, a truncated form of WT1 protein was identified, suggesting that development of the WT may have resulted from expression of an abnormal protein. Four distinct silent single-nucleotide polymorphisms (SNPs) were detected. All 3 patients with a pathogenic WT1 mutation had 2 synonymous SNPs, whereas only 1 of the remaining 5 patients had a single synonymous SNP (P < .05).Conclusions Bilateral WT are associated with early presentation in pediatric patients and a high frequency of WT1 nonsense mutations in exon 8. Silent SNPs may also be involved in the development of WT.