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来自生殖系TP53突变载体的无细胞DNA反映了类似癌症的碎片化模式

Derek Wong¹, Maha Tageldein^1,2, Ping Luo¹

¹Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.

Nature communications

|August 27, 2024

概括

患有TP53变异的Li-Fraumeni综合征 (LFS) 患者表现出明显的无细胞DNA (cfDNA) 碎片化模式. 这种碎片分析揭示了cfDNA分析作为LFS和早期癌症检测的诊断工具的潜力.

科学领域:

基因组学和分子生物学
癌症研究癌症研究
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.

背景情况:

生殖系致病TP53变体定义了Li-Fraumeni综合征 (LFS),增加了终身癌症风险.
之前的研究表明,无论癌症状况如何,LFS患者的血细胞自由DNA (cfDNA) 碎片化更短.

研究的目的:

在LFS中调查cfDNA碎片化特征的功能基础.
探索cfDNA碎片组学在LFS早期癌症检测中的实用性.

主要方法:

从82个TP53突变载体和30个健康对照对199个cfDNA样本进行碎片分析.
评估碎片末端的核酸患病率,p53结合点的核细胞定位,以及染色质的可访问性.
机器学习的应用用于对TP53突变者与野生型cfDNA的分类.

主要成果:

LFS个体在cfDNA片段末端显示出增加的A/T核酸.
观察到p53结合点的核细胞位的调节失调,以及在特定的调节区域的染色质可访问性变化.
机器学习模型在TP53突变型和野生型cfDNA (AUC-ROC 0.710-1.000) 之间实现了强大的差异化.

结论:

在LFS中cfDNA碎片化模式与潜在的遗传变异和表观遗传变化有关.
cfDNA碎片组学显示为LFS的诊断生物标志物具有前途.
纵向ctDNA碎片化分析可以促进LFS患者的早期癌症检测.

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