Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Division of Pediatric Surgery, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, 38105, USA.
Nat Commun. 2023 Dec 18;14(1):8006. doi: 10.1038/s41467-023-43730-0.
Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. Here, we evaluate this predisposition in 68 patients using whole exome or genome sequencing (n = 85 tumors from 61 patients with matched germline blood DNA), RNA-seq (n = 99 tumors), and DNA methylation analysis (n = 61 peripheral blood, n = 29 non-diseased kidney, n = 99 tumors). We determine the predominant events for bilateral Wilms tumor predisposition: 1)pre-zygotic germline genetic variants readily detectable in blood DNA [WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%), and BRCA-related genes (5%)] or 2)post-zygotic epigenetic hypermethylation at 11p15.5 H19/ICR1 that may require analysis of multiple tissue types for diagnosis. Of 99 total tumor specimens, 16 (16.1%) have 11p15.5 normal retention of imprinting, 25 (25.2%) have 11p15.5 copy neutral loss of heterozygosity, and 58 (58.6%) have 11p15.5 H19/ICR1 epigenetic hypermethylation (loss of imprinting). Here, we ascertain the epigenetic and genetic modes of bilateral Wilms tumor predisposition.
双侧 Wilms 肿瘤的发生提示存在潜在的（表观）遗传易感性。在这里，我们使用外显子组或全基因组测序（n=61 例患者的 85 个肿瘤与其匹配的种系血液 DNA）、RNA-seq（n=99 个肿瘤）和 DNA 甲基化分析（n=61 个外周血、n=29 个非病变肾脏、n=99 个肿瘤）评估了 68 例患者的这种易感性。我们确定了双侧 Wilms 肿瘤易感性的主要事件：1）种系血液 DNA 中易于检测到的合子前遗传变异[WT1（14.8%）、NYNRIN（6.6%）、TRIM28（5%）和 BRCA 相关基因（5%）]或 2）11p15.5 上的 H19/ICR1 后合子表观遗传超甲基化，这可能需要分析多种组织类型进行诊断。在 99 个总肿瘤标本中，有 16 个（16.1%）保留了 11p15.5 的印迹正常，有 25 个（25.2%）存在 11p15.5 的拷贝中性杂合性丢失，有 58 个（58.6%）存在 11p15.5 的 H19/ICR1 表观遗传超甲基化（印迹丢失）。在这里，我们确定了双侧 Wilms 肿瘤易感性的表观遗传和遗传模式。
