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化学进展 2019, Vol. 31 Issue (10): 1384-1395 DOI: 10.7536/PC190320 前一篇   后一篇

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循环肿瘤DNA的检测:从数字化到测序

范昭璇1,2,3,4, 赵亮1,2,3,4,**(), 张学记1,2,3,4,**()   

  1. 1. 北京科技大学精准医疗与健康研究院 北京 100083
    2. 北京科技大学生物工程与传感技术研究中心 北京 100083
    3. 北京科技大学化学与生物工程学院 北京 100083
    4. 北京科技大学北京市生物工程与传感技术重点实验室 北京 100083
  • 收稿日期:2019-03-18 出版日期:2019-10-15 发布日期:2019-08-05
  • 通讯作者: 赵亮, 张学记
  • 基金资助:
    国家自然科学基金项目(21675011); 国家自然科学基金项目(21727815); 中央高校基本科研业务费(FRF-TP-17-001A2)

The Detection of Circulating Tumor DNA: From Digitalization to Sequencing

Zhaoxuan Fan1,2,3,4, Liang Zhao1,2,3,4,**(), Xueji Zhang1,2,3,4,**()   

  1. 1. The Institute of Precision Medicine and Health, University of Science and Technology Beijing, Beijing 100083, China
    2. Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing 100083, China
    3. School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
    4. Beijing Key Laboratory for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing 100083, China
  • Received:2019-03-18 Online:2019-10-15 Published:2019-08-05
  • Contact: Liang Zhao, Xueji Zhang
  • About author:
    ** E-mail: (Liang Zhao);
  • Supported by:
    National Natural Science Foundation of China(21675011); National Natural Science Foundation of China(21727815); Fundamental Research Funds for Central Universities(FRF-TP-17-001A2)

液体活检的主要检测对象——循环肿瘤DNA(circulating tumor DNA, ctDNA)是人体血液循环系统中具有一定特征的(包括突变、缺失、插入、重排、拷贝数变异、甲基化等)来自肿瘤细胞基因组的DNA片段,其主要来源于凋亡或坏死的肿瘤细胞。ctDNA 的检测和分析能够提供肿瘤中的基因组信息,例如,基因组中的拷贝数变异、突变和甲基化富集等。相较于其他的肿瘤标志物,ctDNA相对稳定,提取技术相对成熟,与肿瘤的大小和发展具有一定的相关性,是一种新兴的、有前景的肿瘤生物标志物,在精准医疗中发挥着越来越重要的作用。不过ctDNA含量极低,背景游离DNA(cell free DNA, cfDNA)含量高,个体间差异大,且需要提前预判检测的位点和突变,因此,利用新方法和新技术对它进行全面检测分析是必不可少的。目前,针对 ctDNA 的检测方法和平台种类繁多,在此,我们总结了从数字PCR到下一代测序的ctDNA检测的研究进展,包括一些商业化的仪器和一些仍在实验室发展中的设备并对利用这些新兴技术分析检测ctDNA的发展趋势做了展望。

Circulating tumor DNA(ctDNA), the main item of liquid biopsy, is DNA fragments from tumor genome that carries certain characteristics(including single nucleotide variation, deletion, insertion, rearrangement, copy number variation, and methylation) in the human blood circulation system. It mainly originates from apoptotic or necrotic tumor cells. The detection and analysis of ctDNA can provide genomic information in tumors, such as copy number variation, single nucleotide mutation, and methylation enrichment across the genome. It has a certain correlation with tumor size and development and considered as an emerging and promising tumor biomarker for cancer progression, reoccurrence, and routine monitoring after surgery. Compared with other tumor markers, the isolation method is relatively simple due to the stability of ctDNA. However, the extremely low abundance of ctDNA, the high content of background cell free DNA(cfDNA), the large difference between individuals, and the need of predicted detection sites in advance make it necessary to analyze ctDNA in a comprehensive way. Herein, we summarize the recent progress on ctDNA detection from digital PCR to next generation sequencing, including some commercialized apparatuses and certain methods that have recently been developed.

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图1 循环肿瘤DNA(ctDNA)起源示意图[20]
Fig. 1 Schematic illustration of circulating tumor DNA(ctDNA) origin[20]
图2 实验室中的数字PCR技术:(a)单个分隔体积最小(36 fL)的数字PCR微流控芯片原理示意图[96];(b)百万级分隔的digital PCR微流控芯片原理示意图[97];(c)自供电集成微流控即时医疗低成本(SIMPLE)芯片[98]
Fig. 2 Digital PCR technology in the lab.(a) Schematic diagram of the microfluidic digital PCR chip with the smallest single separation volume(36 fL)[96].(b) The microfluidic digital PCR chip with 1 million of partitions[97].(c) Self-powered integrated microfluidic point-of-care low-cost enabling(SIMPLE) chip[98]
图3 利用阶梯乳化微液滴生成技术的digital PCR微流控芯片:(a) 芯片器件的快速组装以及阶梯乳化生成微液滴;(b) 芯片上喷嘴间距480 μm的显微照片;(c) 喷嘴间距240 μm的显微照片;(d) 集成化8样品产生液滴装置;(e) 微液滴生成后单层平铺显微照片。标尺:200 μm[99]
Fig. 3 Microfluidic digital PCR chip based on step emulsification microdroplets generation.(a) Rapid assembly of chip devices and step emulsification to generate microdroplets.(b) Micrograph of nozzle spacing 480 μm on the chip.(c) Micrograph of nozzle spacing 240 μm on the chip.(d) Device of theintegrate 8 samples droplets generation.(e) Monolayer micrograph after microdroplets generation. Scale bar=200 μm[99]
图4 (a)靶向扩增子深度测序(TAm-Seq)的示意图[112]。(b)深度测序肿瘤个体化建档法(CAPP-Seq)的示意图及其在ctDNA评估中的应用[114]。(c)全外显子测序(WES)用于ctDNA分析的流程示意图[118]
Fig. 4 (a) Illustration of targeted amplicon sequencing(TAm-Seq)[112].(b) Schematic depicting CAPP-Seq selectors and its application in ctDNA assessment[114].(c) Workflow of WES for ctDNA analysis[118]
图5 基于生物信息学和微流控芯片技术的测序分析在的ctDNA检测中具有巨大的应用价值
Fig. 5 Bioinformatics and microfluidic technology based next generation sequencing presents a great potential value in ctDNA analysis
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