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An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. ​

文献信息 ​

DOI10.1038/nm.3519
PMID24705333
期刊Nature medicine
影响因子50.0
JCR 分区Q1
发表年份2014
被引次数1089
关键词循环肿瘤DNA, 深度测序, 非小细胞肺癌, 个性化癌症治疗, 生物标志物
文献类型Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.
ISSN1078-8956
页码548-54
期号20(5)
作者Aaron M Newman, Scott V Bratman, Jacqueline To, Jacob F Wynne, Neville C W Eclov, Leslie A Modlin, Chih Long Liu, Joel W Neal, Heather A Wakelee, Robert E Merritt, Joseph B Shrager, Billy W Loo, Ash A Alizadeh, Maximilian Diehn

一句话小结 ​

本研究介绍了一种新型的循环肿瘤DNA（ctDNA）检测方法——深度测序个性化癌症谱系（CAPP-Seq），其在非小细胞肺癌（NSCLC）患者中的应用显示出超过95%的肿瘤突变识别率和96%的灵敏度，尤其在低频突变检测方面表现优异。CAPP-Seq的高灵敏度和早期评估能力为癌症监测和个性化治疗提供了新的前景，有望在临床上广泛应用。

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循环肿瘤DNA · 深度测序 · 非小细胞肺癌 · 个性化癌症治疗 · 生物标志物

摘要 ​

循环肿瘤DNA（ctDNA）是一种有前景的生物标志物，可用于非侵入性评估癌症负担，但现有的ctDNA检测方法在灵敏度或患者覆盖面方面不足，限制了其广泛的临床应用。在此，我们介绍了深度测序个性化癌症谱系（CAPP-Seq），这是一种经济且超灵敏的ctDNA定量方法。我们将CAPP-Seq应用于非小细胞肺癌（NSCLC），设计涵盖多种体细胞改变，能够识别超过95%的肿瘤突变。我们在100%的II-IV期NSCLC患者中检测到了ctDNA，在I期患者中则有50%的检测结果为阳性，且对突变等位基因频率低至约0.02%的灵敏度达96%。ctDNA水平与肿瘤体积高度相关，并能够区分残余疾病与治疗相关的影像学变化，ctDNA水平的测量使得相较于放射学方法能够更早进行治疗反应评估。最后，我们利用CAPP-Seq评估了无活检的肿瘤筛查和基因分型。我们设想CAPP-Seq能够在临床上常规应用，以检测和监测多种恶性肿瘤，从而促进个性化癌症治疗。

英文摘要 ​

Circulating tumor DNA (ctDNA) is a promising biomarker for noninvasive assessment of cancer burden, but existing ctDNA detection methods have insufficient sensitivity or patient coverage for broad clinical applicability. Here we introduce cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. We implemented CAPP-Seq for non-small-cell lung cancer (NSCLC) with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumors. We detected ctDNA in 100% of patients with stage II-IV NSCLC and in 50% of patients with stage I, with 96% specificity for mutant allele fractions down to ∼0.02%. Levels of ctDNA were highly correlated with tumor volume and distinguished between residual disease and treatment-related imaging changes, and measurement of ctDNA levels allowed for earlier response assessment than radiographic approaches. Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.

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主要研究问题 ​

  1. CAPP-Seq方法在其他类型癌症的应用效果如何？
  2. 如何提高CAPP-Seq在早期癌症筛查中的敏感性？
  3. CAPP-Seq的成本效益分析与传统检测方法相比如何？
  4. 在临床实践中，如何整合ctDNA检测与其他生物标志物的使用？
  5. CAPP-Seq技术的局限性是什么，未来可能的改进方向有哪些？

核心洞察 ​

研究背景和目的 ​

循环肿瘤DNA（ctDNA）作为一种有前景的生物标志物，能够非侵入性地评估癌症负担。然而，现有的方法在灵敏度和患者覆盖率方面存在不足，限制了其广泛的临床应用。本文提出了一种新的方法——癌症个性化分析深度测序（CAPP-Seq），旨在提供一种经济且超灵敏的ctDNA定量方法，特别针对非小细胞肺癌（NSCLC）。

主要方法/材料/实验设计 ​

CAPP-Seq方法的设计流程如下：

Mermaid diagram
  1. 选择器设计：针对NSCLC设计选择器，覆盖多个肿瘤驱动基因的突变区域，基于COSMIC和TCGA数据，最终选择521个外显子和13个内含子，覆盖约125 kb的基因组区域。
  2. 深度测序：对90个样本进行深度测序，确保约10,000倍的覆盖率，以优化ctDNA的检测灵敏度。
  3. 数据分析：使用VarScan和FACTERA算法进行突变检测和融合点特征分析，建立ctDNA检测指数以评估肿瘤负担。

关键结果和发现 ​

  • CAPP-Seq在NSCLC患者中检测到的ctDNA灵敏度为100%（II-IV期）和50%（I期），特异性为96%。
  • ctDNA水平与肿瘤体积显著相关，能够区分残留病灶与治疗相关的影像学变化。
  • CAPP-Seq在前期和后期治疗样本中表现出良好的灵敏度和特异性，AUC值分别为0.89和0.91。
  • 通过ctDNA监测，能够有效评估患者对治疗的反应及残留病灶。

主要结论/意义/创新性 ​

CAPP-Seq作为一种新的ctDNA定量方法，具有高灵敏度和特异性，覆盖几乎所有NSCLC患者，且无需患者特定优化，成本低廉。该方法能够在临床上常规应用于多种恶性肿瘤的检测与监测，促进个性化癌症治疗的实现。

研究局限性和未来方向 ​

  • CAPP-Seq的检测灵敏度仍需进一步提升，以应对ctDNA浓度低于检测阈值的患者。
  • 未来可通过优化捕获融合的效率，增加对拷贝数变异（CNVs）的覆盖，扩展CAPP-Seq的临床应用范围。
  • 进一步的研究将集中在将CAPP-Seq应用于其他类型的肿瘤和生物样本的检测上，以验证其普遍适用性。

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引用本文的文献 ​

  1. Detecting cancer by monitoring circulating tumor DNA. - Paul T Spellman;Joe W Gray - Nature medicine (2014)
  2. Circulating tumor DNA moves further into the spotlight. - Mark Sausen;Sonya Parpart;Luis A Diaz - Genome medicine (2014)
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  4. Lung cancer screening beyond low-dose computed tomography: the role of novel biomarkers. - Naveed Hasan;Rohit Kumar;Mani S Kavuru - Lung (2014)
  5. 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)
  6. FACTERA: a practical method for the discovery of genomic rearrangements at breakpoint resolution. - Aaron M Newman;Scott V Bratman;Henning Stehr;Luke J Lee;Chih Long Liu;Maximilian Diehn;Ash A Alizadeh - Bioinformatics (Oxford, England) (2014)
  7. Strategies for modern biomarker and drug development in oncology. - Alan D Smith;Desam Roda;Timothy A Yap - Journal of hematology & oncology (2014)
  8. Single-tube, highly parallel mutation enrichment in cancer gene panels by use of temperature-tolerant COLD-PCR. - Elena Castellanos-Rizaldos;Katherine Richardson;Rui Lin;Grant Wu;Mike G Makrigiorgos - Clinical chemistry (2015)
  9. Current challenges for detection of circulating tumor cells and cell-free circulating nucleic acids, and their characterization in non-small cell lung carcinoma patients. What is the best blood substrate for personalized medicine? - Marius Ilie;Véronique Hofman;Elodie Long;Olivier Bordone;Eric Selva;Kevin Washetine;Charles Hugo Marquette;Paul Hofman - Annals of translational medicine (2014)
  10. Genomic profiling of breast cancers. - Christina Curtis - Current opinion in obstetrics & gynecology (2015)

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