Inference of transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection
Inference of transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection
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DOI：
10.1038/s41467-019-12714-4
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发表时间：
2019-10-11
影响因子：
16.6
通讯作者：
Speicher, Michael R.
中科院分区：
文献类型：
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作者：
Ulz, Peter;Perakis, Samantha;Speicher, Michael R.
转录因子（TF）的失调是肿瘤发生的重要驱动因素，但缺乏用于评估转录因子活性的非侵入性测定。在这里，我们开发并验证了一种基于无细胞DNA测序和核小体足迹分析的评估TF活性的微创方法。我们使用我们开发的生物信息学管道分析了来自癌症患者和健康对照的> 1，000个无细胞DNA样本的全基因组测序数据，该管道从无细胞DNA片段化模式推断TF结合位点的可及性。我们观察患者特异性以及肿瘤特异性模式，包括前列腺癌中肿瘤亚型的准确预测，对患者的管理具有重要的临床意义。此外，我们表明，无细胞DNA TF分析是能够检测早期结直肠癌。我们的方法映射肿瘤特异性转录因子结合在体内血液样本的基础上，使非编码基因组的一个关键部分，适合临床分析。
Deregulation of transcription factors (TFs) is an important driver of tumorigenesis, but noninvasive assays for assessing transcription factor activity are lacking. Here we develop and validate a minimally invasive method for assessing TF activity based on cell-free DNA sequencing and nucleosome footprint analysis. We analyze whole genome sequencing data for >1,000 cell-free DNA samples from cancer patients and healthy controls using a bioinformatics pipeline developed by us that infers accessibility of TF binding sites from cell-free DNA fragmentation patterns. We observe patient-specific as well as tumor-specific patterns, including accurate prediction of tumor subtypes in prostate cancer, with important clinical implications for the management of patients. Furthermore, we show that cell-free DNA TF profiling is capable of detection of early-stage colorectal carcinomas. Our approach for mapping tumor-specific transcription factor binding in vivo based on blood samples makes a key part of the noncoding genome amenable to clinical analysis.