Prognostic importance of direct assignment of parent of origin via long-read genome and epigenome sequencing in retinoblastoma.

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL JCI insight Pub Date : 2024-12-26 DOI:10.1172/jci.insight.188216
Andrew W Stacey, Kenji Nakamichi, Jennifer Huey, Jeffrey Stevens, Natalie Waligorski, Erin E Crotty, Russell N Van Gelder, Debarshi Mustafi
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Abstract

BACKGROUNDCurrent clinical sequencing methods cannot effectively detect DNA methylation and allele-specific variation to provide parent-of-origin information from the proband alone. Parent-of-origin effects can lead to differential disease, and the inability to assign parent of origin in de novo cases limits prognostication in the majority of affected individuals with retinoblastoma, a hereditary cancer with suspected parent-of-origin effects.METHODSTo directly assign parent of origin in patients with retinoblastoma, we extracted genomic DNA from blood samples for sequencing using a programmable, targeted, single-molecule, long-read DNA genomic and epigenomic approach. This allowed germline variant calling and simultaneous haplotype-resolved CpG methylation in participants with familial (n = 7) and de novo (n = 9) retinoblastoma.RESULTSTargeted long-read sequencing allowed phasing genomic variation with a differentially methylated region in intron 2 of the retinoblastoma gene to confirm parent of origin in known familial samples. This approach allowed us to directly assign parent of origin in simple and complex de novo cases from the proband alone. The ability to assign parent of origin in all retinoblastoma cases showed that harboring disease-causing variants on the paternally inherited allele, whether arising familially or de novo, was associated with more advanced cancer staging at presentation and significantly greater risk of chemotherapy failure (P = 0.002).CONCLUSIONThis study demonstrates the diagnostic potential of multiomic long-read profiling to unveil the parent-of-origin effect in hereditary cancer. The approach in this work will be instrumental in assigning parent of origin to other genetic diseases using local and distant imprinting signals in the genome.FUNDINGNational Eye Institute, NIH; Gerber Foundation; Research to Prevent Blindness; Angie Karalis Johnson Fund; Dawn's Light Foundation; and Mark J. Daily, MD Research Fund.

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通过长读基因组和表观基因组测序对视网膜母细胞瘤中亲本来源直接分配的预后重要性。
背景:目前的临床测序方法不能有效地检测DNA甲基化和等位基因特异性变异,以提供来自先证者的父母来源信息。原生父母效应可导致不同的疾病,在新生病例中无法确定这一点,限制了大多数视网膜母细胞瘤患者的预后,这是一种疑似原生父母效应的遗传性癌症。方法:为了直接确定视网膜母细胞瘤患者的亲本来源,从血液样本中提取基因组DNA,使用可编程的靶向单分子长读DNA基因组和表观基因组方法进行测序。这使得家族性视网膜母细胞瘤患者(n=7)和新生视网膜母细胞瘤患者(n=9)的种系变异呼叫和单倍型解决的CpG甲基化同时发生。结果:靶向长读测序允许RB1基因内含子2差异甲基化区域的基因组变异,以确认已知家族样本中的父母起源。利用这种方法,我们可以在简单和复杂的从头案例中,仅从先证者就可以直接确定父母的起源。在所有视网膜母细胞瘤病例中,确定父母起源的能力表明,在父系遗传等位基因上携带致病变异,无论是家族性的还是新生的,都与出现时更晚期的癌症分期和更大的化疗失败风险相关(P=0.002)。结论:本研究证明了多组学长读谱分析在揭示遗传性癌症中父母起源效应方面的诊断潜力。这项工作中的方法将有助于利用基因组中的本地和远程印记信号来确定其他遗传疾病的父母起源。资助:美国国立卫生研究院国家眼科研究所(K08EY033789);戈贝尔的基础;预防失明的研究。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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