文章：

液体活检的时代到来：朝着循环肿瘤DNA的实施

Liquid biopsies come of age: towards implementation of circulating tumour DNA

原文发布日期：2017-02-24

DOI: 10.1038/nrc.2017.7

类型: Review Article

开放获取: 否

要点：

1. Cell-free DNA (cfDNA) is released predominantly by cell death into the bloodstream, although active secretion may have a role. Since the discovery of fetal cfDNA in the maternal circulation, cfDNA analysis has been rapidly implemented in clinical practice for noninvasive prenatal testing.
2. Mutations were first detected in cfDNA more than two decades ago, and interest in circulating tumour DNA (ctDNA) as a noninvasive cancer diagnostic has increased considerably with the development of molecular methods that permit the sensitive detection and monitoring of multiple classes of mutation.
3. ctDNA may have utility at almost every stage of the management of patients with cancer, including diagnosis, minimally invasive molecular profiling, treatment monitoring, the detection of residual disease and the identification of resistance mutations. ctDNA analysis may be broadly considered as a tool both for quantitative analysis of disease burden and for genomic analysis.
4. The identification of ctDNA in individuals before a cancer diagnosis, and in presymptomatic individuals, suggests the possibility of ctDNA analysis as a tool for earlier detection and screening. Noninvasive cancer classification or subtyping has also emerged as a possibility, although for early detection, both technical and biological factors introduce challenges to the detection of mutant DNA in plasma and its interpretation.
5. Monitoring multiple mutations in parallel can enhance the sensitivity of ctDNA detection, can be used to assess the clonal evolution of patients' disease and may identify resistance mutations before clinical progression is observed.
6. ctDNA analysis is beginning to transition from the research setting into the clinic. The US Food and Drug Administration and the European Medicines Agency have approved ctDNA tests for specific indications in the absence of evaluable tumour tissue. Analysis of gene panels in plasma has now become available as a potential clinical tool. Large studies are under way to establish the overall performance and clinical utility of such assays when a tumour biopsy is not available for analysis.
7. Potential applications of ctDNA have been demonstrated by a number of proof-of-principle studies. Prospective clinical trials are beginning to assess the clinical utility of ctDNA analysis for molecular profiling and disease monitoring. The increasing acceptance of ctDNA is enabling the field to move from exploratory ctDNA studies towards clinical trials in which ctDNA guides decision-making.
8. In order to fully exploit the potential utility of liquid biopsies, it is essential that the biology of cfDNA and ctDNA is explored further. The mechanisms of release and degradation, and the factors that affect the representation of ctDNA in plasma, are poorly understood. The nature of ctDNA will be clarified through both large, well-annotated clinical studies and in vivo studies in which variables can be controlled.

要点翻译：

1. 游离DNA（cfDNA）主要通过细胞死亡释放进入血液，尽管主动分泌也可能发挥一定作用。自发现母体循环中存在胎儿游离DNA以来，cfDNA分析已迅速应用于无创产前检测的临床实践。
2. 二十多年前首次在cfDNA中检测到突变，随着分子技术的发展使得多种突变类型的灵敏检测和监测成为可能，循环肿瘤DNA（ctDNA）作为无创癌症诊断标志物的关注度显著提升。
3. ctDNA几乎在癌症患者管理的各个阶段都具有应用潜力，包括诊断、微创分子分型、治疗监测、微小残留病变检测和耐药突变识别。ctDNA分析可广泛视为疾病负荷定量分析和基因组分析的双重工具。
4. 在癌症确诊前个体及症状出现前个体中检测到ctDNA，表明其可能成为早期检测和筛查的工具。无创癌症分类或分型也已成为可能，但就早期检测而言，技术和生物学因素均对血浆中突变DNA的检测及解读带来挑战。
5. 并行监测多个突变可提高ctDNA检测灵敏度，可用于评估患者疾病的克隆进化，并可能在临床进展出现前识别耐药突变。
6. ctDNA分析正从研究领域向临床过渡。美国食品药品监督管理局和欧洲药品管理局已批准在无法获取可评估肿瘤组织时，将ctDNA检测用于特定适应症。血浆基因panel分析现已作为潜在临床工具投入使用。当无法进行肿瘤活检时，多项大型研究正在评估此类检测的整体性能及临床效用。
7. 多项概念验证研究已证实ctDNA的潜在应用价值。前瞻性临床试验正开始评估ctDNA分析在分子分型和疾病监测中的临床效用。随着对ctDNA认可度的提升，该领域正从探索性研究转向以ctDNA指导决策的临床试验。
8. 为充分发挥液体活检的潜在价值，必须进一步探索cfDNA和ctDNA的生物学特性。目前对ctDNA的释放和降解机制，以及影响其在血浆中呈现度的因素仍知之甚少。通过大规模、具有完善临床注释的研究和可控制变量的体内研究，将有助于阐明ctDNA的本质特性。

英文摘要：

Improvements in genomic and molecular methods are expanding the range of potential applications for circulating tumour DNA (ctDNA), both in a research setting and as a 'liquid biopsy' for cancer management. Proof-of-principle studies have demonstrated the translational potential of ctDNA for prognostication, molecular profiling and monitoring. The field is now in an exciting transitional period in which ctDNA analysis is beginning to be applied clinically, although there is still much to learn about the biology of cell-free DNA. This is an opportune time to appraise potential approaches to ctDNA analysis, and to consider their applications in personalized oncology and in cancer research.

摘要翻译： 

基因组学和分子方法的进步正在拓展循环肿瘤DNA（ctDNA）的潜在应用范围，无论是在研究环境中，还是作为癌症管理的“液体活检”。原理验证研究已证明ctDNA在预后评估、分子分型及监测方面具有转化潜力。该领域正处于一个激动人心的过渡期——ctDNA分析正开始走向临床应用，尽管我们对游离DNA的生物学仍知之甚少。此时正是评估ctDNA分析潜在策略、并思考其在个体化肿瘤学和癌症研究中应用的恰当时机。

原文链接：

Liquid biopsies come of age: towards implementation of circulating tumour DNA