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Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. ​

文献信息 ​

DOI10.1038/nature22364
PMID28445469
期刊Nature
影响因子48.5
JCR 分区Q1
发表年份2017
被引次数913
关键词循环肿瘤DNA, 肺癌, 系统发育分析, 复发, 亚克隆
文献类型Journal Article, Research Support, Non-U.S. Gov't
ISSN0028-0836
页码446-451
期号545(7655)
作者Christopher Abbosh, Nicolai J Birkbak, Gareth A Wilson, Mariam Jamal-Hanjani, Tudor Constantin, Raheleh Salari, John Le Quesne, David A Moore, Selvaraju Veeriah, Rachel Rosenthal, Teresa Marafioti, Eser Kirkizlar, Thomas B K Watkins, Nicholas McGranahan, Sophia Ward, Luke Martinson, Joan Riley, Francesco Fraioli, Maise Al Bakir, Eva Grönroos, Francisco Zambrana, Raymondo Endozo, Wenya Linda Bi, Fiona M Fennessy, Nicole Sponer, Diana Johnson, Joanne Laycock, Seema Shafi, Justyna Czyzewska-Khan, Andrew Rowan, Tim Chambers, Nik Matthews, Samra Turajlic, Crispin Hiley, Siow Ming Lee, Martin D Forster, Tanya Ahmad, Mary Falzon, Elaine Borg, David Lawrence, Martin Hayward, Shyam Kolvekar, Nikolaos Panagiotopoulos, Sam M Janes, Ricky Thakrar, Asia Ahmed, Fiona Blackhall, Yvonne Summers, Dina Hafez, Ashwini Naik, Apratim Ganguly, Stephanie Kareht, Rajesh Shah, Leena Joseph, Anne Marie Quinn, Phil A Crosbie, Babu Naidu, Gary Middleton, Gerald Langman, Simon Trotter, Marianne Nicolson, Hardy Remmen, Keith Kerr, Mahendran Chetty, Lesley Gomersall, Dean A Fennell, Apostolos Nakas, Sridhar Rathinam, Girija Anand, Sajid Khan, Peter Russell, Veni Ezhil, Babikir Ismail, Melanie Irvin-Sellers, Vineet Prakash, Jason F Lester, Malgorzata Kornaszewska, Richard Attanoos, Haydn Adams, Helen Davies, Dahmane Oukrif, Ayse U Akarca, John A Hartley, Helen L Lowe, Sara Lock, Natasha Iles, Harriet Bell, Yenting Ngai, Greg Elgar, Zoltan Szallasi, Roland F Schwarz, Javier Herrero, Aengus Stewart, Sergio A Quezada, Karl S Peggs, Peter Van Loo, Caroline Dive, C Jimmy Lin, Matthew Rabinowitz, Hugo J W L Aerts, Allan Hackshaw, Jacqui A Shaw, Bernhard G Zimmermann, Charles Swanton

一句话小结 ​

本研究通过对100名非小细胞肺癌患者术后血浆中的循环肿瘤DNA（ctDNA）进行系统发育分析，成功识别出早期复发的独立预测因子，并发现耐药迹象，表明该方法能够有效追踪肿瘤进化动态及亚克隆特征。研究结果为非侵入性监测肺癌复发提供了新的理论依据，并可能为未来的ctDNA驱动治疗策略开辟新路径。

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循环肿瘤DNA · 肺癌 · 系统发育分析 · 复发 · 亚克隆

摘要 ​

早期检测非小细胞肺癌初次手术后的复发以及对新兴亚克隆的特征描述，这些亚克隆可能会在转移部位播种，可能为限制肿瘤复发提供新的治疗方法。目前尚未证明能够非侵入性地追踪早期肺癌的进化动态在循环肿瘤DNA（ctDNA）中的应用。在此，我们采用肿瘤特异性的系统发育方法，对首批100名TRACERx（通过治疗跟踪非小细胞肺癌的进化（Rx））研究参与者的ctDNA进行分析，其中包括一名同时参与PEACE（晚期癌症环境的死后评估）尸检研究的患者。我们识别出ctDNA释放的独立预测因子，并分析肿瘤体积检测的限制。通过对术后血浆进行盲法分析，我们观察到辅助化疗耐药的证据，并识别出极有可能经历肺癌复发的患者。最后，我们展示了系统发育ctDNA分析能够追踪肺癌复发和转移的亚克隆特性，为ctDNA驱动的治疗研究提供了一种新方法。

英文摘要 ​

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

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主要研究问题 ​

  1. 在早期肺癌的演化中，ctDNA分析如何帮助识别不同的亚克隆及其对治疗的影响？
  2. 该研究如何利用ctDNA分析来预测术后复发的风险，具体的生物标志物有哪些？
  3. 研究中提到的化疗耐药性是如何通过ctDNA分析得以识别的，是否有特定的机制？
  4. 在非小细胞肺癌的治疗中，ctDNA的进化动态如何影响临床决策和个性化治疗方案？
  5. 未来的研究如何进一步利用phylogenetic ctDNA分析来改善早期肺癌的监测和治疗效果？

核心洞察 ​

研究背景和目的 ​

非小细胞肺癌（NSCLC）是导致癌症死亡的主要原因，术后复发的早期检测及其亚克隆特征的表征可能为新疗法提供思路，以限制肿瘤复发。本研究旨在通过对早期NSCLC患者的循环肿瘤DNA（ctDNA）进行系统的进化分析，探索其在术后复发检测和肿瘤动态追踪中的应用。

主要方法/材料/实验设计 ​

本研究基于TRACERx（Tracking Non-small Cell Lung Cancer Evolution through therapy）研究，选取了100名早期NSCLC患者。采用多区域外显子测序（M-Seq）构建肿瘤的系统发育树，并设计个性化的多重PCR检测特定的单核苷酸变异（SNVs）。以下是研究的技术路线：

Mermaid diagram

关键结果和发现 ​

  1. ctDNA检测率：在96名早期NSCLC患者中，46名（48%）的术前ctDNA样本检测到至少两个SNVs。
  2. 影响因素：ctDNA的检测与肿瘤的组织学亚型、肿瘤坏死、淋巴血管浸润及肿瘤大小等临床病理特征相关。尤其是鳞状细胞癌（LUSC）检测到ctDNA的比例显著高于腺癌（LUAD）。
  3. 复发预测：在24名患者的术后随访中，93%的复发患者在临床复发前的ctDNA检测中发现了至少两个SNVs，且ctDNA的检测能够提前70天预测复发。

主要结论/意义/创新性 ​

本研究表明，ctDNA的系统发育分析不仅能够追踪肿瘤的演化过程，还能够为个性化治疗提供依据。通过检测ctDNA，可以识别出术后复发的高风险患者，并指导后续的治疗决策。该研究为肿瘤的个性化治疗及监测提供了新的思路和方法。

研究局限性和未来方向 ​

  1. 局限性：本研究的样本量相对较小，且仅针对特定类型的NSCLC患者，结果的普适性尚需进一步验证。
  2. 未来方向：未来的研究可以扩展到更大规模的患者群体，探索ctDNA在不同类型肿瘤中的应用潜力，并结合其他生物标志物提高复发预测的准确性。此外，ctDNA的实时监测和个性化治疗策略的开发也将是未来研究的重点。

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引用本文的文献 ​

  1. Lung cancer: Tracing tumour evolution. - Diana Romero - Nature reviews. Clinical oncology (2017)
  2. Cancer genomics: Tracking cancer evolution. - Carolina Perdigoto - Nature reviews. Genetics (2017)
  3. Medical research: Personalized test tracks cancer relapse. - Alberto Bardelli - Nature (2017)
  4. Circular RNAs: Biogenesis, Function and Role in Human Diseases. - John Greene;Anne-Marie Baird;Lauren Brady;Marvin Lim;Steven G Gray;Raymond McDermott;Stephen P Finn - Frontiers in molecular biosciences (2017)
  5. Cancer genomics: Human metastases under scrutiny. - G Steven Bova - Nature (2017)
  6. ALK Status Assessment with Liquid Biopsies of Lung Cancer Patients. - Paul Hofman - Cancers (2017)
  7. Circulating tumor DNA for personalized lung cancer monitoring. - Clare Fiala;Eleftherios P Diamandis - BMC medicine (2017)
  8. Unravelling biology and shifting paradigms in cancer with single-cell sequencing. - Timour Baslan;James Hicks - Nature reviews. Cancer (2017)
  9. Mechanisms and clinical implications of tumor heterogeneity and convergence on recurrent phenotypes. - Jasmine A McQuerry;Jeffrey T Chang;David D L Bowtell;Adam Cohen;Andrea H Bild - Journal of molecular medicine (Berlin, Germany) (2017)
  10. Progress and prospects of early detection in lung cancer. - Sean Blandin Knight;Phil A Crosbie;Haval Balata;Jakub Chudziak;Tracy Hussell;Caroline Dive - Open biology (2017)

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