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Liquid biopsies: genotyping circulating tumor DNA. ​

文献信息 ​

DOI10.1200/JCO.2012.45.2011
PMID24449238
期刊Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子41.9
JCR 分区Q1
发表年份2014
被引次数1135
关键词液体活检, 循环肿瘤DNA, 基因分型, 肿瘤动态, 基因组改变
文献类型Journal Article, Research Support, Non-U.S. Gov't, Review
ISSN0732-183X
页码579-86
期号32(6)
作者Luis A Diaz, Alberto Bardelli

一句话小结 ​

本研究探讨了循环无细胞DNA（cfDNA）在肿瘤基因分型中的应用，指出其能够克服传统肿瘤组织取样的局限性，并通过实时监测肿瘤动态提供重要的临床信息。研究表明，cfDNA的分析不仅提高了肿瘤检测的灵敏度和准确性，还为液体活检在临床和研究中的多种应用开辟了新的可能性。

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液体活检 · 循环肿瘤DNA · 基因分型 · 肿瘤动态 · 基因组改变

摘要 ​

在临床肿瘤学中，对肿瘤组织进行基因分型以寻找可操作的体细胞遗传改变已成为常规做法。尽管这些序列改变提供了大量信息，但取样肿瘤组织存在显著的固有局限性；肿瘤组织仅代表某一时刻的快照，且由于肿瘤异质性可能导致选择偏倚，此外，获取肿瘤组织也可能比较困难。细胞凋亡或坏死的细胞会将无细胞DNA（cfDNA）片段释放到血液中，循环无细胞DNA的负荷与肿瘤分期和预后相关。此外，近年来在DNA分析的灵敏度和准确性方面的进展，使得对cfDNA进行基因分型以识别肿瘤中的体细胞基因组改变成为可能。检测和定量肿瘤突变的能力已被证明在实时追踪肿瘤动态方面有效，同时也作为一种液体活检，可用于多种以前无法实现的临床和研究应用。

英文摘要 ​

Genotyping tumor tissue in search of somatic genetic alterations for actionable information has become routine practice in clinical oncology. Although these sequence alterations are highly informative, sampling tumor tissue has significant inherent limitations; tumor tissue is a single snapshot in time, is subject to selection bias resulting from tumor heterogeneity, and can be difficult to obtain. Cell-free fragments of DNA are shed into the bloodstream by cells undergoing apoptosis or necrosis, and the load of circulating cell-free DNA (cfDNA) correlates with tumor staging and prognosis. Moreover, recent advances in the sensitivity and accuracy of DNA analysis have allowed for genotyping of cfDNA for somatic genomic alterations found in tumors. The ability to detect and quantify tumor mutations has proven effective in tracking tumor dynamics in real time as well as serving as a liquid biopsy that can be used for a variety of clinical and investigational applications not previously possible.

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主要研究问题 ​

  1. 液体活检在不同类型肿瘤中的应用效果如何？
  2. 相比于传统组织活检，液体活检在监测肿瘤动态方面的优势是什么？
  3. 如何提高液体活检中cfDNA分析的灵敏度和准确性？
  4. 在临床实践中，液体活检如何帮助制定个性化治疗方案？
  5. 目前液体活检技术面临哪些挑战和限制，未来的研究方向是什么？

核心洞察 ​

研究背景和目的 ​

随着肿瘤基因组学的发展，肿瘤组织基因分型已成为临床肿瘤学的常规实践。然而，肿瘤组织取样存在显著的局限性，如肿瘤异质性和获取难度。研究旨在探讨循环肿瘤DNA（ctDNA）的检测作为一种液体活检的方法，以克服组织活检的局限性，并为肿瘤的动态监测和治疗决策提供新途径。

主要方法/材料/实验设计 ​

本研究采用多种先进的基因组技术来检测和分析cfDNA和ctDNA。关键方法包括：

  • 数字PCR和下一代测序(NGS)：用于高灵敏度地识别复杂DNA混合物中的稀有突变。
  • BEAMing和PAP：用于定量分析肿瘤来源的DNA。

以下是研究的技术路线图：

Mermaid diagram

关键结果和发现 ​

  • ctDNA的检测与肿瘤负担密切相关，肿瘤体积越大，循环中ctDNA的浓度越高。
  • 在IV期肿瘤患者中，ctDNA的检测灵敏度接近100%。
  • 研究表明，ctDNA可以作为监测肿瘤动态的有效生物标志物，能够在治疗前后反映肿瘤负担的变化。

主要结论/意义/创新性 ​

研究表明，ctDNA检测作为一种液体活检技术，具有较高的特异性和灵敏度，能够提供与肿瘤组织相同的分子信息。ctDNA的分析不仅能够帮助监测肿瘤的动态变化，还能识别靶向治疗的遗传决定因素，具有重要的临床应用潜力。该技术的创新性在于它能够在非侵入性条件下实时监测肿瘤的分子特征，克服了传统组织活检的局限。

研究局限性和未来方向 ​

尽管ctDNA检测在晚期肿瘤中显示出良好的敏感性，但在早期疾病和微小残留病的检测中仍存在挑战。未来的研究应集中在以下几个方面：

  • 提高ctDNA检测的灵敏度，以便能够在早期阶段检测到低水平的ctDNA。
  • 扩大ctDNA分析的应用范围，涵盖更多类型的肿瘤。
  • 进一步验证ctDNA作为预测复发和监测治疗反应的生物标志物的有效性。

通过对ctDNA的深入研究，可能会为个性化肿瘤治疗提供新的思路和方法。

参考文献 ​

  1. Heteroplasmic mitochondrial DNA mutations in normal and tumour cells. - Yiping He;Jian Wu;Devin C Dressman;Christine Iacobuzio-Donahue;Sanford D Markowitz;Victor E Velculescu;Luis A Diaz;Kenneth W Kinzler;Bert Vogelstein;Nickolas Papadopoulos - Nature (2010)
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  3. Detection of mutations in EGFR in circulating lung-cancer cells. - Shyamala Maheswaran;Lecia V Sequist;Sunitha Nagrath;Lindsey Ulkus;Brian Brannigan;Chey V Collura;Elizabeth Inserra;Sven Diederichs;A John Iafrate;Daphne W Bell;Subba Digumarthy;Alona Muzikansky;Daniel Irimia;Jeffrey Settleman;Ronald G Tompkins;Thomas J Lynch;Mehmet Toner;Daniel A Haber - The New England journal of medicine (2008)
  4. Quantitative analysis of cell-free DNA in the plasma of gastric cancer patients. - Jong-Lyul Park;Hyun Ja Kim;Bo Youl Choi;Han-Chul Lee;Hay-Ran Jang;Kyu Sang Song;Seung-Moo Noh;Seon-Young Kim;Dong Soo Han;Yong Sung Kim - Oncology letters (2012)
  5. The future of epigenetic therapy in solid tumours--lessons from the past. - Nilofer Azad;Cynthia A Zahnow;Charles M Rudin;Stephen B Baylin - Nature reviews. Clinical oncology (2013)
  6. Use of research biopsies in clinical trials: are risks and benefits adequately discussed? - Michael J Overman;Janhavi Modak;Scott Kopetz;Ravi Murthy;James C Yao;Marshall E Hicks;James L Abbruzzese;Alda L Tam - Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2013)
  7. Detection and quantification of mutations in the plasma of patients with colorectal tumors. - Frank Diehl;Meng Li;Devin Dressman;Yiping He;Dong Shen;Steve Szabo;Luis A Diaz;Steven N Goodman;Kerstin A David;Hartmut Juhl;Kenneth W Kinzler;Bert Vogelstein - Proceedings of the National Academy of Sciences of the United States of America (2005)
  8. Pyrophosphorolysis-activated polymerization (PAP): application to allele-specific amplification. - Q Liu;S S Sommer - BioTechniques (2000)
  9. Analysis of circulating tumor DNA to monitor metastatic breast cancer. - Sarah-Jane Dawson;Dana W Y Tsui;Muhammed Murtaza;Heather Biggs;Oscar M Rueda;Suet-Feung Chin;Mark J Dunning;Davina Gale;Tim Forshew;Betania Mahler-Araujo;Sabrina Rajan;Sean Humphray;Jennifer Becq;David Halsall;Matthew Wallis;David Bentley;Carlos Caldas;Nitzan Rosenfeld - The New England journal of medicine (2013)
  10. Fetal-specific DNA methylation ratio permits noninvasive prenatal diagnosis of trisomy 21. - Elisavet A Papageorgiou;Alex Karagrigoriou;Evdokia Tsaliki;Voula Velissariou;Nigel P Carter;Philippos C Patsalis - Nature medicine (2011)

引用本文的文献 ​

  1. Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies. - Simonetta M Leto;Livio Trusolino - Journal of molecular medicine (Berlin, Germany) (2014)
  2. Pharmacologic biomarkers in the development of stratified cancer medicine. - William Douglas Figg;David R Newell - Clinical cancer research : an official journal of the American Association for Cancer Research (2014)
  3. Bioinformatic approaches to augment study of epithelial-to-mesenchymal transition in lung cancer. - Tim N Beck;Adaeze J Chikwem;Nehal R Solanki;Erica A Golemis - Physiological genomics (2014)
  4. Realizing the potential of plasma genotyping in an age of genotype-directed therapies. - Jason J Luke;Geoffrey R Oxnard;Cloud P Paweletz;D Ross Camidge;John V Heymach;David B Solit;Bruce E Johnson; - Journal of the National Cancer Institute (2014)
  5. Gefitinib treatment in EGFR mutated caucasian NSCLC: circulating-free tumor DNA as a surrogate for determination of EGFR status. - Jean-Yves Douillard;Gyula Ostoros;Manuel Cobo;Tudor Ciuleanu;Rebecca Cole;Gael McWalter;Jill Walker;Simon Dearden;Alan Webster;Tsveta Milenkova;Rose McCormack - Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (2014)
  6. Liquid biopsy in gastrointestinal stromal tumors: a novel approach. - Margherita Nannini;Annalisa Astolfi;Milena Urbini;Guido Biasco;Maria A Pantaleo - Journal of translational medicine (2014)
  7. Challenges in circulating tumour cell research. - Catherine Alix-Panabières;Klaus Pantel - Nature reviews. Cancer (2014)
  8. Diagnostic value of circulating free DNA for the detection of EGFR mutation status in NSCLC: a systematic review and meta-analysis. - Jie Luo;Li Shen;Di Zheng - Scientific reports (2014)
  9. Genotyping cell-free tumor DNA in the blood to detect residual disease and drug resistance. - Giulia Siravegna;Alberto Bardelli - Genome biology (2014)
  10. Cancer immunoprevention--the next frontier. - Marie-Anne D Smit;Elizabeth M Jaffee;Eric R Lutz - Cancer prevention research (Philadelphia, Pa.) (2014)

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