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Circulating mutant DNA to assess tumor dynamics. ​

Literature Information ​

DOI10.1038/nm.1789
PMID18670422
JournalNature medicine
Impact Factor50.0
JCR QuartileQ1
Publication Year2008
Times Cited1389
Keywordscirculating tumor DNA, tumor dynamics, personalized therapy
Literature TypeComparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.
ISSN1078-8956
Pages985-90
Issue14(9)
AuthorsFrank Diehl, Kerstin Schmidt, Michael A Choti, Katharine Romans, Steven Goodman, Meng Li, Katherine Thornton, Nishant Agrawal, Lori Sokoll, Steve A Szabo, Kenneth W Kinzler, Bert Vogelstein, Luis A Diaz

TL;DR ​

This study demonstrates that a highly sensitive method for quantifying circulating tumor DNA (ctDNA) in patients undergoing treatment for colorectal cancer can effectively monitor tumor dynamics, providing a promising tool for personalized cancer management. The findings suggest that this approach could be extended to other cancer types, potentially improving the precision of disease monitoring and treatment response evaluation.

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circulating tumor DNA · tumor dynamics · personalized therapy

Abstract ​

The measurement of circulating nucleic acids has transformed the management of chronic viral infections such as HIV. The development of analogous markers for individuals with cancer could similarly enhance the management of their disease. DNA containing somatic mutations is highly tumor specific and thus, in theory, can provide optimum markers. However, the number of circulating mutant gene fragments is small compared to the number of normal circulating DNA fragments, making it difficult to detect and quantify them with the sensitivity required for meaningful clinical use. In this study, we applied a highly sensitive approach to quantify circulating tumor DNA (ctDNA) in 162 plasma samples from 18 subjects undergoing multimodality therapy for colorectal cancer. We found that ctDNA measurements could be used to reliably monitor tumor dynamics in subjects with cancer who were undergoing surgery or chemotherapy. We suggest that this personalized genetic approach could be generally applied to individuals with other types of cancer.

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Primary Questions Addressed ​

  1. How can the sensitivity of detecting circulating mutant DNA be improved for better clinical application?
  2. What are the potential challenges in applying ctDNA monitoring to other types of cancer beyond colorectal cancer?
  3. In what ways could circulating tumor DNA analysis change the current treatment protocols for cancer patients?
  4. What role do somatic mutations play in the effectiveness of personalized therapy for cancer management?
  5. How does the quantity of circulating mutant DNA correlate with tumor progression and patient outcomes in different cancer types?

Key Findings ​

Research Background and Objective ​

The study investigates the potential of circulating tumor DNA (ctDNA) as a biomarker for monitoring tumor dynamics in colorectal cancer patients undergoing multimodality therapy. Given that ctDNA is highly tumor-specific and can reflect changes in tumor burden, the research aims to establish a sensitive method for quantifying ctDNA in plasma samples and evaluate its effectiveness compared to traditional biomarkers like carcinoembryonic antigen (CEA).

Main Methods/Materials/Experimental Design ​

The study utilized a modified BEAMing (beads, emulsion, amplification, and magnetics) technique to quantify ctDNA from 162 plasma samples of 18 colorectal cancer patients. The workflow for the methodology is illustrated below:

Mermaid diagram
  1. Mutation Identification: Somatic mutations were identified through direct sequencing of tumor tissue from each patient.
  2. Plasma Sample Collection: Plasma samples were collected before and after surgery, and during follow-up.
  3. DNA Quantification: The total number of DNA fragments in plasma was quantified using real-time PCR.
  4. BEAMing Assay: The modified BEAMing technique was employed to detect and quantify the fraction of mutant DNA fragments, allowing for high sensitivity in detecting low concentrations of ctDNA.

Key Results and Findings ​

  • ctDNA was detectable in all patients prior to surgery, with levels varying significantly.
  • A median decrease of 99% in ctDNA levels was observed in patients who underwent complete tumor resection, while those with incomplete resections showed variable changes, including increases in ctDNA.
  • At the first follow-up, 16 out of 20 patients with detectable ctDNA experienced recurrence, while no recurrences occurred in patients with undetectable ctDNA levels.
  • ctDNA showed higher sensitivity and a stronger correlation with disease recurrence compared to CEA levels, which had a lower detection rate and a less significant predictive value for recurrence.

Main Conclusions/Significance/Innovation ​

The study concludes that ctDNA is a promising and more reliable biomarker for monitoring tumor dynamics in colorectal cancer compared to traditional markers like CEA. The ability to detect and quantify ctDNA can provide insights into tumor burden and treatment response, enabling personalized therapeutic approaches. This research suggests that ctDNA could be applied to various cancer types, similar to the use of viral nucleic acids in HIV management.

Research Limitations and Future Directions ​

  • Limitations: The study's small sample size and the requirement for individual mutation identification limit its broader applicability. Additionally, the reliance on direct sequencing for mutation detection can be time-consuming.
  • Future Directions: Further research is needed to validate the findings in larger cohorts and explore the application of ctDNA in other cancer types. Advances in sequencing technologies could simplify mutation identification, potentially allowing for more widespread clinical use of ctDNA monitoring.
AspectFindings
Detection Sensitivity100% for ctDNA vs. 56% for CEA
ctDNA Decrease After SurgeryMedian 99% decrease in complete resections
Recurrence PredictionSignificant correlation with detectable ctDNA (P = 0.006)
Comparison with CEActDNA more sensitive and predictive than CEA (P < 0.001)

References ​

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  2. BEAMing up for detection and quantification of rare sequence variants. - Meng Li;Frank Diehl;Devin Dressman;Bert Vogelstein;Kenneth W Kinzler - Nature methods (2006)
  3. BEAMing: single-molecule PCR on microparticles in water-in-oil emulsions. - Frank Diehl;Meng Li;Yiping He;Kenneth W Kinzler;Bert Vogelstein;Devin Dressman - Nature methods (2006)
  4. Circulating free DNA in plasma or serum as biomarker of carcinogenesis: practical aspects and biological significance. - Emmanuelle Gormally;Elodie Caboux;Paolo Vineis;Pierre Hainaut - Mutation research (2007)
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Literatures Citing This Work ​

  1. Pancreatic cancer. - Donghui Li;Keping Xie;Robert Wolff;James L Abbruzzese - Lancet (London, England) (2004)
  2. Nanotubes, exosomes, and nucleic acid-binding peptides provide novel mechanisms of intercellular communication in eukaryotic cells: implications in health and disease. - Mattias Belting;Anders Wittrup - The Journal of cell biology (2008)
  3. Quantification of circulating cell-free DNA in the plasma of cancer patients during radiation therapy. - Chao Cheng;Motoko Omura-Minamisawa;Yun Kang;Takamitsu Hara;Izumi Koike;Tomio Inoue - Cancer science (2009)
  4. Sensitive digital quantification of DNA methylation in clinical samples. - Meng Li;Wei-Dong Chen;Nickolas Papadopoulos;Steven N Goodman;Niels Christian Bjerregaard;Søren Laurberg;Bernard Levin;Hartmut Juhl;Nadir Arber;Helen Moinova;Kris Durkee;Kerstin Schmidt;Yiping He;Frank Diehl;Victor E Velculescu;Shibin Zhou;Luis A Diaz;Kenneth W Kinzler;Sanford D Markowitz;Bert Vogelstein - Nature biotechnology (2009)
  5. A simple biological imaging system for detecting viable human circulating tumor cells. - Toru Kojima;Yuuri Hashimoto;Yuichi Watanabe;Shunsuke Kagawa;Futoshi Uno;Shinji Kuroda;Hiroshi Tazawa;Satoru Kyo;Hiroyuki Mizuguchi;Yasuo Urata;Noriaki Tanaka;Toshiyoshi Fujiwara - The Journal of clinical investigation (2009)
  6. Two-round coamplification at lower denaturation temperature-PCR (COLD-PCR)-based sanger sequencing identifies a novel spectrum of low-level mutations in lung adenocarcinoma. - Jin Li;Coren A Milbury;Cheng Li;G Mike Makrigiorgos - Human mutation (2009)
  7. Analysis of cancer mutation signatures in blood by a novel ultra-sensitive assay: monitoring of therapy or recurrence in non-metastatic breast cancer. - Zhenbin Chen;Jinong Feng;Carolyn H Buzin;Qiang Liu;Lawrence Weiss;Kemp Kernstine;George Somlo;Steve S Sommer - PloS one (2009)
  8. Detection of BRAF mutations in the tumour and serum of patients enrolled in the AZD6244 (ARRY-142886) advanced melanoma phase II study. - R E Board;G Ellison;M C M Orr;K R Kemsley;G McWalter;L Y Blockley;S P Dearden;C Morris;M Ranson;M V Cantarini;C Dive;A Hughes - British journal of cancer (2009)
  9. Levels of plasma circulating cell free nuclear and mitochondrial DNA as potential biomarkers for breast tumors. - Corina Kohler;Ramin Radpour;Zeinab Barekati;Reza Asadollahi;Johannes Bitzer;Edward Wight;Nicole Bürki;Claude Diesch;Wolfgang Holzgreve;Xiao Yan Zhong - Molecular cancer (2009)
  10. Genetic inactivation of AKT1, AKT2, and PDPK1 in human colorectal cancer cells clarifies their roles in tumor growth regulation. - Kajsa Ericson;Christine Gan;Ian Cheong;Carlo Rago;Yardena Samuels;Victor E Velculescu;Kenneth W Kinzler;David L Huso;Bert Vogelstein;Nickolas Papadopoulos - Proceedings of the National Academy of Sciences of the United States of America (2010)

... (1379 more literatures)

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