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Techniques of using circulating tumor DNA as a liquid biopsy component in cancer management. ​

文献信息 ​

DOI10.1016/j.csbj.2018.10.002
PMID30364656
期刊Computational and structural biotechnology journal
影响因子4.1
JCR 分区Q2
发表年份2018
被引次数180
关键词无细胞DNA（cfDNA）, 循环肿瘤DNA（ctDNA）, 液体活检
文献类型Journal Article, Review
ISSN2001-0370
页码370-378
期号16()
作者Maha Elazezy, Simon A Joosse

一句话小结 ​

本文综述了循环肿瘤DNA（ctDNA）在癌症精准医学中的应用，强调其在液体活检中作为生物标志物的重要性，能够提供肿瘤基因组信息并监测肿瘤动态。尽管ctDNA检测技术已取得进展，但仍面临标准化和提高灵敏度与特异性等挑战，亟需克服以推动其临床应用。

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无细胞DNA（cfDNA） · 循环肿瘤DNA（ctDNA） · 液体活检

摘要 ​

在癌症的临床管理中，精准医学可以通过一种被称为“液体活检”的诊断平台实现。这种方法利用血液中生物标志物的检测来进行预后和预测。其中，最新的研究重点之一是循环肿瘤DNA（ctDNA），它是液体活检领域中正在调查的血液来源标志物。ctDNA是由肿瘤细胞通过不同机制释放的，因此可以提供关于患者体内肿瘤基因组组成的信息。通过长期的ctDNA基础液体活检，可以监测肿瘤动态，以预测和评估药物反应和/或耐药性。然而，由于ctDNA高度碎片化，且其在大量正常循环DNA的背景下浓度可能极低，因此筛查临床相关突变具有挑战性。尽管在过去几年中ctDNA的检测和分析已取得显著进展，目前面临的挑战包括标准化以及提高现有技术的单分子灵敏度与完美特异性的结合。本文综述了ctDNA在癌症患者临床管理中的潜在作用、当前所采用的技术以及为实现基于ctDNA的液体活检以推动精准医学所需克服的障碍。

英文摘要 ​

Precision medicine in the clinical management of cancer may be achieved through the diagnostic platform called "liquid biopsy". This method utilizes the detection of biomarkers in blood for prognostic and predictive purposes. One of the latest blood born markers under investigation in the field of liquid biopsy in cancer patients is circulating tumor DNA (ctDNA). ctDNA is released by tumor cells through different mechanisms and can therefore provide information about the genomic make-up of the tumor currently present in the patient. Through longitudinal ctDNA-based liquid biopsies, tumor dynamics may be monitored to predict and assess drug response and/or resistance. However, because ctDNA is highly fragmented and because its concentration can be extremely low in a high background of normal circulating DNA, screening for clinical relevant mutations is challenging. Although significant progress has been made in advancing the detection and analysis of ctDNA in the last few years, the current challenges include standardization and increasing current techniques to single molecule sensitivity in combination with perfect specificity. This review focuses on the potential role of ctDNA in the clinical management of cancer patients, the current technologies that are being employed, and the hurdles that still need to be taken to achieve ctDNA-based liquid biopsy towards precision medicine.

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主要研究问题 ​

  1. 在使用ctDNA进行液体活检时，如何克服其低浓度和高背景噪声的问题？
  2. ctDNA的检测技术目前有哪些最新进展，它们在临床应用中表现如何？
  3. 未来ctDNA在个性化癌症治疗中的潜在应用场景是什么？
  4. 除了ctDNA，还有哪些其他生物标志物可以用于液体活检，比较它们的优缺点？
  5. 如何评估ctDNA监测在预测药物反应和耐药性方面的有效性？

核心洞察 ​

研究背景和目的 ​

随着精准医学的发展，液体活检作为一种新兴的诊断平台，通过血液中的生物标志物检测，旨在实现癌症的预后和预测。循环肿瘤DNA（ctDNA）是肿瘤细胞通过多种机制释放到血液中的DNA片段，能够反映患者当前肿瘤的基因组特征。本文综述了ctDNA在癌症管理中的潜在作用、当前的检测技术及其面临的挑战。

主要方法/材料/实验设计 ​

研究主要集中在以下几个方面：

  1. ctDNA的释放机制：

    • 通过细胞凋亡和坏死被动释放
    • 通过细胞外囊泡主动分泌

  2. ctDNA的提取和检测技术：

    • 提取方法：
      • 磁珠法
      • 硅胶柱法
      • 酚-氯仿法
    • 检测技术：
      • 下一代测序（NGS）
      • 数字PCR（ddPCR）
      • 实时PCR
      • 质谱技术
      • 甲基化特异性PCR（MS-PCR）

以下是技术路线的流程图：

Mermaid diagram

关键结果和发现 ​

  • ctDNA的浓度与肿瘤体积和患者的整体生存期存在一定关联。
  • 通过检测ctDNA中的特定突变，可以有效监测肿瘤进展和药物反应。
  • 不同的检测技术在灵敏度和特异性上存在差异，数字PCR在检测已知突变方面表现优异，而下一代测序则适合广泛的基因组分析。

主要结论/意义/创新性 ​

ctDNA作为液体活检的关键成分，能够提供有关肿瘤基因组动态变化的重要信息。通过监测ctDNA，医生可以更好地预测患者对治疗的反应及潜在的耐药机制。尽管目前技术不断进步，但仍需解决标准化和灵敏度的问题，以便在临床实践中更广泛地应用。

研究局限性和未来方向 ​

  • 当前技术的标准化程度不足，导致不同实验室结果的可比性差。
  • ctDNA的提取和检测仍面临低浓度和高背景噪声的挑战。
  • 未来的研究应集中在优化提取方法、提高检测灵敏度及结合其他生物标志物（如CTC和外泌体）来提升临床管理效果。

参考文献 ​

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引用本文的文献 ​

  1. The Potential Clinical Utility of Circulating Tumor DNA in Esophageal Adenocarcinoma: From Early Detection to Therapy. - Juliann E Kosovec;Ali H Zaidi;Tamar S Pounardjian;Blair A Jobe - Frontiers in oncology (2018)
  2. Clinical relevance of circulating molecules in cancer: focus on gastrointestinal stromal tumors. - Gloria Ravegnini;Giulia Sammarini;César Serrano;Margherita Nannini;Maria A Pantaleo;Patrizia Hrelia;Sabrina Angelini - Therapeutic advances in medical oncology (2019)
  3. Comparative Analysis of Two Methods for the Detection of EGFR Mutations in Plasma Circulating Tumor DNA from Lung Adenocarcinoma Patients. - Ming-Szu Hung;Jr-Hau Lung;Yu-Ching Lin;Yu-Hung Fang;Shu-Yi Huang;Yuan-Yuan Jiang;Meng-Jer Hsieh;Ying-Huang Tsai - Cancers (2019)
  4. Liquid Biopsy as a Tool for Differentiation of Leiomyomas and Sarcomas of Corpus Uteri. - Dana Dvorská;Henrieta Škovierová;Dušan Braný;Erika Halašová;Zuzana Danková - International journal of molecular sciences (2019)
  5. Aberrant Methylation Status of Tumour Suppressor Genes in Ovarian Cancer Tissue and Paired Plasma Samples. - Dana Dvorská;Dušan Braný;Bálint Nagy;Marián Grendár;Robert Poka;Beáta Soltész;Marianna Jagelková;Katarína Zelinová;Zora Lasabová;Pavol Zubor;Zuzana Danková - International journal of molecular sciences (2019)
  6. Liquid Biopsy in Oligometastatic Prostate Cancer-A Biologist's Point of View. - Ewelina Stelcer;Marek Konkol;Aleksandra Głȩboka;Wiktoria Maria Suchorska - Frontiers in oncology (2019)
  7. Opportunities, Challenges, and Prospects in Electrochemical Biosensing of Circulating Tumor DNA and its Specific Features. - Susana Campuzano;Verónica Serafín;Maria Gamella;María Pedrero;Paloma Yáñez-Sedeño;José M Pingarrón - Sensors (Basel, Switzerland) (2019)
  8. Low Abundance of Circulating Tumor DNA in Localized Prostate Cancer. - S Thomas Hennigan;Shana Y Trostel;Nicholas T Terrigino;Olga S Voznesensky;Rachel J Schaefer;Nichelle C Whitlock;Scott Wilkinson;Nicole V Carrabba;Rayann Atway;Steven Shema;Ross Lake;Amalia R Sweet;David J Einstein;Fatima Karzai;James L Gulley;Peter Chang;Glenn J Bubley;Steven P Balk;Huihui Ye;Adam G Sowalsky - JCO precision oncology (2019)
  9. The Different Facets of Liquid Biopsy: A Kaleidoscopic View. - Zahra Eslami-S;Luis Enrique Cortés-Hernández;Laure Cayrefourcq;Catherine Alix-Panabières - Cold Spring Harbor perspectives in medicine (2020)
  10. Selecting short length nucleic acids localized in exosomes improves plasma EGFR mutation detection in NSCLC patients. - Yoonjung Kim;Saeam Shin;Boyeon Kim;Kyung-A Lee - Cancer cell international (2019)

... (170 更多 篇文献)

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