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Techniques of using circulating tumor DNA as a liquid biopsy component in cancer management. ​

Literature Information ​

DOI10.1016/j.csbj.2018.10.002
PMID30364656
JournalComputational and structural biotechnology journal
Impact Factor4.1
JCR QuartileQ2
Publication Year2018
Times Cited180
KeywordsCell-free DNA (cfDNA), Circulating tumor DNA (ctDNA), Liquid biopsy
Literature TypeJournal Article, Review
ISSN2001-0370
Pages370-378
Issue16()
AuthorsMaha Elazezy, Simon A Joosse

TL;DR ​

This review highlights the emerging role of circulating tumor DNA (ctDNA) in precision medicine for cancer management, emphasizing its potential in monitoring tumor dynamics and predicting treatment responses through liquid biopsies. Despite advances in detection technologies, challenges like standardization and achieving single-molecule sensitivity remain critical to fully realize ctDNA's clinical applications.

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Cell-free DNA (cfDNA) · Circulating tumor DNA (ctDNA) · Liquid biopsy

Abstract ​

Precision medicine in the clinical management of cancer may be achieved through the diagnostic platform called "liquid biopsy". This method utilizes the detection of biomarkers in blood for prognostic and predictive purposes. One of the latest blood born markers under investigation in the field of liquid biopsy in cancer patients is circulating tumor DNA (ctDNA). ctDNA is released by tumor cells through different mechanisms and can therefore provide information about the genomic make-up of the tumor currently present in the patient. Through longitudinal ctDNA-based liquid biopsies, tumor dynamics may be monitored to predict and assess drug response and/or resistance. However, because ctDNA is highly fragmented and because its concentration can be extremely low in a high background of normal circulating DNA, screening for clinical relevant mutations is challenging. Although significant progress has been made in advancing the detection and analysis of ctDNA in the last few years, the current challenges include standardization and increasing current techniques to single molecule sensitivity in combination with perfect specificity. This review focuses on the potential role of ctDNA in the clinical management of cancer patients, the current technologies that are being employed, and the hurdles that still need to be taken to achieve ctDNA-based liquid biopsy towards precision medicine.

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Primary Questions Addressed ​

  1. What are the emerging technologies that enhance the sensitivity and specificity of ctDNA detection in liquid biopsies?
  2. How does the use of ctDNA compare to traditional biopsy methods in terms of patient outcomes and monitoring?
  3. What are the implications of ctDNA fragmentation on the interpretation of genomic data in cancer treatment?
  4. How can ctDNA-based liquid biopsies be integrated into routine clinical practice for cancer management?
  5. What are the potential future directions for research in ctDNA applications beyond cancer diagnostics?

Key Findings ​

Research Background and Purpose ​

The review discusses the emerging role of circulating tumor DNA (ctDNA) as a critical component of liquid biopsy in cancer management. Liquid biopsy, a non-invasive diagnostic approach, allows for the detection of biomarkers in blood to monitor tumor dynamics, predict treatment responses, and assess resistance to therapies. The purpose of this review is to provide an overview of ctDNA properties, its clinical applications, the technologies used for its detection, and the challenges faced in its implementation for precision medicine.

Main Methods/Materials/Experimental Design ​

The review categorizes the techniques for ctDNA analysis into two main strategies: targeted and untargeted approaches. Targeted methods focus on known mutations, while untargeted approaches allow for broader genomic analysis.

Mermaid diagram

The review also highlights the various detection technologies used, including:

  1. Next-Generation Sequencing (NGS): Allows for high-throughput sequencing and detection of mutations.
  2. Digital PCR Platforms: Such as droplet digital PCR (ddPCR) and BEAMing for precise quantification of mutations.
  3. Real-Time PCR: A cost-effective method for rapid mutation detection.
  4. Mass-Spectrometry: Used for high-sensitivity detection of mutations.
  5. Methylation-Specific PCR: For detecting hypermethylation in ctDNA.

Key Results and Findings ​

  • ctDNA is released into circulation through cell death and active secretion, making it a promising biomarker for cancer monitoring.
  • High levels of ctDNA correlate with tumor burden and can indicate treatment resistance.
  • Technologies such as NGS and digital PCR demonstrate high sensitivity for detecting mutations, but challenges remain regarding standardization and low ctDNA concentrations in early-stage cancers.
  • The review identifies specific mutations (e.g., in PIK3CA, KRAS) that are clinically relevant for tracking disease progression and treatment response.

Main Conclusions/Significance/Innovation ​

The review concludes that ctDNA holds significant potential for enhancing cancer diagnostics and management through non-invasive monitoring of tumor dynamics. The integration of ctDNA analysis with other liquid biopsy components, such as circulating tumor cells (CTCs) and exosomal RNA, may provide a comprehensive view of tumor heterogeneity and treatment efficacy. Innovations in detection technologies continue to improve sensitivity and specificity, making ctDNA a valuable tool in precision medicine.

Research Limitations and Future Directions ​

Despite the advances in ctDNA research, several limitations exist:

  • The low concentration of ctDNA in blood makes detection challenging, especially in early-stage cancers.
  • There is a lack of standardization in sample collection and analysis methods.
  • High costs and complexity of some technologies hinder widespread clinical adoption.

Future research should focus on:

  • Developing standardized protocols for ctDNA analysis.
  • Investigating the biological mechanisms behind ctDNA release.
  • Exploring the combination of ctDNA with other biomarkers to enhance diagnostic capabilities.
  • Addressing the challenges of data management and bioinformatics in interpreting ctDNA results for clinical use.

References ​

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Literatures Citing This Work ​

  1. The Potential Clinical Utility of Circulating Tumor DNA in Esophageal Adenocarcinoma: From Early Detection to Therapy. - Juliann E Kosovec;Ali H Zaidi;Tamar S Pounardjian;Blair A Jobe - Frontiers in oncology (2018)
  2. Clinical relevance of circulating molecules in cancer: focus on gastrointestinal stromal tumors. - Gloria Ravegnini;Giulia Sammarini;César Serrano;Margherita Nannini;Maria A Pantaleo;Patrizia Hrelia;Sabrina Angelini - Therapeutic advances in medical oncology (2019)
  3. Comparative Analysis of Two Methods for the Detection of EGFR Mutations in Plasma Circulating Tumor DNA from Lung Adenocarcinoma Patients. - Ming-Szu Hung;Jr-Hau Lung;Yu-Ching Lin;Yu-Hung Fang;Shu-Yi Huang;Yuan-Yuan Jiang;Meng-Jer Hsieh;Ying-Huang Tsai - Cancers (2019)
  4. Liquid Biopsy as a Tool for Differentiation of Leiomyomas and Sarcomas of Corpus Uteri. - Dana Dvorská;Henrieta Škovierová;Dušan Braný;Erika Halašová;Zuzana Danková - International journal of molecular sciences (2019)
  5. Aberrant Methylation Status of Tumour Suppressor Genes in Ovarian Cancer Tissue and Paired Plasma Samples. - Dana Dvorská;Dušan Braný;Bálint Nagy;Marián Grendár;Robert Poka;Beáta Soltész;Marianna Jagelková;Katarína Zelinová;Zora Lasabová;Pavol Zubor;Zuzana Danková - International journal of molecular sciences (2019)
  6. Liquid Biopsy in Oligometastatic Prostate Cancer-A Biologist's Point of View. - Ewelina Stelcer;Marek Konkol;Aleksandra Głȩboka;Wiktoria Maria Suchorska - Frontiers in oncology (2019)
  7. Opportunities, Challenges, and Prospects in Electrochemical Biosensing of Circulating Tumor DNA and its Specific Features. - Susana Campuzano;Verónica Serafín;Maria Gamella;María Pedrero;Paloma Yáñez-Sedeño;José M Pingarrón - Sensors (Basel, Switzerland) (2019)
  8. Low Abundance of Circulating Tumor DNA in Localized Prostate Cancer. - S Thomas Hennigan;Shana Y Trostel;Nicholas T Terrigino;Olga S Voznesensky;Rachel J Schaefer;Nichelle C Whitlock;Scott Wilkinson;Nicole V Carrabba;Rayann Atway;Steven Shema;Ross Lake;Amalia R Sweet;David J Einstein;Fatima Karzai;James L Gulley;Peter Chang;Glenn J Bubley;Steven P Balk;Huihui Ye;Adam G Sowalsky - JCO precision oncology (2019)
  9. The Different Facets of Liquid Biopsy: A Kaleidoscopic View. - Zahra Eslami-S;Luis Enrique Cortés-Hernández;Laure Cayrefourcq;Catherine Alix-Panabières - Cold Spring Harbor perspectives in medicine (2020)
  10. Selecting short length nucleic acids localized in exosomes improves plasma EGFR mutation detection in NSCLC patients. - Yoonjung Kim;Saeam Shin;Boyeon Kim;Kyung-A Lee - Cancer cell international (2019)

... (170 more literatures)

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