Liquid biopsy: current technology and clinical applications.

文献信息

DOI	10.1186/s13045-022-01351-y
PMID	36096847
期刊	Journal of hematology & oncology
影响因子	40.4
JCR 分区	Q1
发表年份	2022
被引次数	379
关键词	循环肿瘤细胞, 液体活检, 精准医学, 游离DNA, 循环肿瘤DNA
文献类型	Journal Article, Review, Research Support, N.I.H., Extramural
ISSN	1756-8722
页码	131
期号	15(1)
作者	Mina Nikanjam, Shumei Kato, Razelle Kurzrock

一句话小结

液体活检作为精准肿瘤医学的重要工具，通过提取和分析循环外源性核酸和循环肿瘤细胞，在癌症的早期诊断、治疗反应预测和肿瘤负担评估等方面展现出显著的应用潜力。尽管存在技术挑战和生物标志物的复杂性，该领域的持续研究有望推动对新型体液样本的探索，进一步提升癌症管理的效果。

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循环肿瘤细胞 · 液体活检 · 精准医学 · 游离DNA · 循环肿瘤DNA

摘要

液体活检在癌症分子特征分析中越来越受到重视，能够实现精准肿瘤医学的应用。循环外源性核酸（游离DNA；cfDNA）、循环肿瘤DNA（ctDNA）和循环肿瘤细胞（CTCs）可以从血液和其他体液中提取。本综述将重点介绍液体活检的当前技术和临床应用。ctDNA/cfDNA已通过多种技术进行提取和分析，例如滴定数字聚合酶链反应（ddPCR）、珠子、乳液、扩增和磁性（BEAMing）、标记扩增子深度测序（TAm-Seq）、基于深度测序的癌症个性化分型（CAPP-Seq）、全基因组亚硫酸盐测序（WGBS-Seq）、全外显子组测序（WES）和全基因组测序（WGS）。CTCs则通过基于生物标志物的细胞捕获以及基于生物物理和其他特性的正向或负向富集进行分离。ctDNA/cfDNA和CTCs在多种临床应用中发挥了重要作用：利用序列样本区分独特的免疫检查点抑制剂反应模式；基于基线液体活检特征预测免疫检查点抑制剂的反应；基于序列采样预测对靶向治疗、化疗及免疫治疗（包括CAR-T细胞）的反应和耐药性；评估来自多个转移部位的脱落DNA；评估潜在的可干预改变；分析预后和肿瘤负担，包括手术后的情况；研究难以进行活检的肿瘤；以及在早期阶段检测癌症。然而，后者可能受到少量肿瘤衍生成分进入循环的限制；此外，所有癌症中的cfDNA评估可能会受到不确定潜能的克隆性造血的干扰，尤其是在老年人中。CTCs的分离技术上可能比cfDNA更具挑战性，但允许进行功能性检测，并评估CTCs衍生的DNA、RNA和蛋白质，包括单细胞分析。血液活检比组织活检侵入性更小，因此适合进行序列采集，这可以实时提供重要的分子信息。总之，液体活检是一种强大的工具，这项技术的显著进展已影响到精准肿瘤医学的多个方面，从早期诊断到难治性转移性疾病的管理。未来的研究可能会集中在血液以外的体液上，例如腹水、渗出液、尿液和脑脊液，以及甲基化模式和外泌体等元素。

英文摘要

Liquid biopsies are increasingly used for cancer molecular profiling that enables a precision oncology approach. Circulating extracellular nucleic acids (cell-free DNA; cfDNA), circulating tumor DNA (ctDNA), and circulating tumor cells (CTCs) can be isolated from the blood and other body fluids. This review will focus on current technologies and clinical applications for liquid biopsies. ctDNA/cfDNA has been isolated and analyzed using many techniques, e.g., droplet digital polymerase chain reaction, beads, emulsion, amplification, and magnetics (BEAMing), tagged-amplicon deep sequencing (TAm-Seq), cancer personalized profiling by deep sequencing (CAPP-Seq), whole genome bisulfite sequencing (WGBS-Seq), whole exome sequencing (WES), and whole genome sequencing (WGS). CTCs have been isolated using biomarker-based cell capture, and positive or negative enrichment based on biophysical and other properties. ctDNA/cfDNA and CTCs are being exploited in a variety of clinical applications: differentiating unique immune checkpoint blockade response patterns using serial samples; predicting immune checkpoint blockade response based on baseline liquid biopsy characteristics; predicting response and resistance to targeted therapy and chemotherapy as well as immunotherapy, including CAR-T cells, based on serial sampling; assessing shed DNA from multiple metastatic sites; assessing potentially actionable alterations; analyzing prognosis and tumor burden, including after surgery; interrogating difficult-to biopsy tumors; and detecting cancer at early stages. The latter can be limited by the small amounts of tumor-derived components shed into the circulation; furthermore, cfDNA assessment in all cancers can be confounded by clonal hematopoeisis of indeterminate potential, especially in the elderly. CTCs can be technically more difficult to isolate that cfDNA, but permit functional assays, as well as evaluation of CTC-derived DNA, RNA and proteins, including single-cell analysis. Blood biopsies are less invasive than tissue biopsies and hence amenable to serial collection, which can provide critical molecular information in real time. In conclusion, liquid biopsy is a powerful tool, and remarkable advances in this technology have impacted multiple aspects of precision oncology, from early diagnosis to management of refractory metastatic disease. Future research may focus on fluids beyond blood, such as ascites, effusions, urine, and cerebrospinal fluid, as well as methylation patterns and elements such as exosomes.

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主要研究问题

核心洞察

研究背景和目的

液体活检技术是一种通过分析体液（通常是血液）来进行肿瘤分子检测的方法，近年来在癌症精准医学中得到了广泛应用。本文旨在综述当前液体活检的技术和临床应用，包括循环细胞外核酸（cfDNA）、循环肿瘤DNA（ctDNA）和循环肿瘤细胞（CTCs）的检测方法及其在癌症管理中的应用。

主要方法/材料/实验设计

液体活检的技术主要包括以下几种方法：

ctDNA/cfDNA的检测技术
- 滴定数字PCR (ddPCR)：能够检测极低比例的基因组材料，适用于识别稀有突变。
- BEAMing：结合PCR与流式细胞术，具有高灵敏度。
- 标签扩增深度测序 (TAm-Seq)：可同时测序大量DNA分子，灵敏度高。
- 癌症个性化深度测序 (CAPP-Seq)：用于识别患者特异性突变。
- 全基因组测序 (WGS) 和 全外显子测序 (WES)：用于全面评估肿瘤基因组。
- 全基因组亚硫酸盐测序 (WGBS-Seq)：用于DNA甲基化分析。
CTCs的检测技术
- 免疫捕获法：使用特定的表面标志物捕获CTCs。
- 生物物理特性分离：根据CTCs的大小和密度进行分离。
- 负向富集法：去除背景细胞，富集CTCs。

关键结果和发现

临床应用：
- 液体活检可用于免疫检查点抑制剂的反应预测，ctDNA变化可早期指示疗效。
- 通过监测ctDNA和CTCs的动态变化，可以提前识别耐药性和疾病进展。
- ctDNA和CTCs在不同癌症类型中的可行性和有效性已被广泛验证。
技术优势：
- 液体活检相较于传统组织活检更为非侵入性，便于进行序列采集和实时监测。
- 液体活检能够从多个转移部位获取信息，提供肿瘤异质性的更全面视角。

主要结论/意义/创新性

液体活检作为一种新兴技术，已在癌症的早期诊断、疗效监测、预后评估等方面显示出巨大潜力。其非侵入性特点使其成为癌症管理中的重要工具。未来研究应关注液体活检在不同体液中的应用及其在早期癌症筛查中的潜力。

研究局限性和未来方向

局限性：
- ctDNA和CTCs的检测可能受到肿瘤负荷低和血液中小量成分的影响。
- CTCs的分离技术复杂，且缺乏统一的标志物。
未来方向：
- 探索其他体液（如尿液、脑脊液、腹水等）的液体活检应用。
- 研究液体活检在癌症早期检测中的潜力，尤其是甲基化模式和外泌体等新型生物标志物。

通过不断的技术创新和应用扩展，液体活检有望在未来的癌症管理中发挥更加重要的作用。

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... (369 更多篇文献)

Liquid biopsy: current technology and clinical applications. ​

文献信息 ​

一句话小结 ​

在麦伴科研 (maltsci.com) 搜索更多文献 ​

摘要 ​

英文摘要 ​

麦伴智能科研服务 ​

主要研究问题 ​

核心洞察 ​

研究背景和目的 ​

主要方法/材料/实验设计 ​

关键结果和发现 ​

主要结论/意义/创新性 ​

研究局限性和未来方向 ​

参考文献 ​

引用本文的文献 ​