Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Circulating mutant DNA to assess tumor dynamics

Nature Medicine volume 14, pages 985–990 (2008)Cite this article

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 (pages 914–915).

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Measurement of ctDNA.
Figure 2: Representative flow cytometric data obtained from BEAMing.
Figure 3: Recurrence-free survival, as detected by ctDNA and CEA.
Figure 4: Comparison of ctDNA, CEA and imaging dynamics in individual study subjects.

References

  1. Wood, L.D. et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108–1113 (2007).

    Article  CAS  Google Scholar 

  2. Nagrath, S. et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450, 1235–1239 (2007).

    Article  CAS  Google Scholar 

  3. Cristofanilli, M. et al. Circulating tumor cells, disease progression and survival in metastatic breast cancer. N. Engl. J. Med. 351, 781–791 (2004).

    Article  CAS  Google Scholar 

  4. Sidransky, D. Emerging molecular markers of cancer. Nat. Rev. Cancer 2, 210–219 (2002).

    Article  CAS  Google Scholar 

  5. Goebel, G., Zitt, M., Zitt, M. & Muller, H.M. Circulating nucleic acids in plasma or serum (CNAPS) as prognostic and predictive markers in patients with solid neoplasias. Dis. Markers 21, 105–120 (2005).

    Article  CAS  Google Scholar 

  6. Fleischhacker, M. & Schmidt, B. Circulating nucleic acids (CNAs) and cancer—a survey. Biochim. Biophys. Acta 1775, 181–232 (2007).

    CAS  PubMed  Google Scholar 

  7. Gormally, E., Caboux, E., Vineis, P. & Hainaut, P. Circulating free DNA in plasma or serum as biomarker of carcinogenesis: practical aspects and biological significance. Mutat. Res. 635, 105–117 (2007).

    Article  CAS  Google Scholar 

  8. Diehl, F. et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc. Natl. Acad. Sci. USA 102, 16368–16373 (2005).

    Article  CAS  Google Scholar 

  9. Dressman, D., Yan, H., Traverso, G., Kinzler, K.W. & Vogelstein, B. Transforming single DNA molecules into fluorescent magnetic particles for detection and enumeration of genetic variations. Proc. Natl. Acad. Sci. USA 100, 8817–8822 (2003).

    Article  CAS  Google Scholar 

  10. Goldstein, M.J. & Mitchell, E.P. Carcinoembryonic antigen in the staging and follow-up of patients with colorectal cancer. Cancer Invest. 23, 338–351 (2005).

    Article  Google Scholar 

  11. Li, H., Fan, X. & Houghton, J. Tumor microenvironment: the role of the tumor stroma in cancer. J. Cell. Biochem. 101, 805–815 (2007).

    Article  CAS  Google Scholar 

  12. Hacia, J.G. & Collins, F.S. Mutational analysis using oligonucleotide microarrays. J. Med. Genet. 36, 730–736 (1999).

    Article  CAS  Google Scholar 

  13. Shendure, J., Mitra, R.D., Varma, C. & Church, G.M. Advanced sequencing technologies: methods and goals. Nat. Rev. Genet. 5, 335–344 (2004).

    Article  CAS  Google Scholar 

  14. Rago, C. et al. Serial Assessment of human tumor burdens in mice by the analysis of circulating DNA. Cancer Res. 67, 9364–9370 (2007).

    Article  CAS  Google Scholar 

  15. Diehl, F. et al. BEAMing: single-molecule PCR on microparticles in water-in-oil emulsions. Nat. Methods 3, 551–559 (2006).

    Article  CAS  Google Scholar 

  16. Li, M., Diehl, F., Dressman, D., Vogelstein, B. & Kinzler, K.W. BEAMing up for detection and quantification of rare sequence variants. Nat. Methods 3, 95–97 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank G.Traverso for useful discussions; D. Heslop, C. Vaughn and D. Edelstein for their help with plasma collection; and L. Fayad for help with the interpretation of imaging studies. This work was supported by the Virginia and D.K. Ludwig Fund for Cancer Research, the Miracle Foundation, the US National Colorectal Cancer Research Alliance and US National Institutes of Health grants CA43460, CA57345, CA62924 and CA129825.

Author information

Author notes

  1. Frank Diehl and Kerstin Schmidt: These authors contributed equally to this work.

Authors and Affiliations

  1. The Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and Sidney Kimmel Cancer Center at the Johns Hopkins Medical Institutions, Baltimore, 21231, Maryland, USA

    Frank Diehl, Kerstin Schmidt, Katharine Romans, Meng Li, Katherine Thornton, Nishant Agrawal, Steve A Szabo, Kenneth W Kinzler, Bert Vogelstein & Luis A Diaz Jr

  2. Department of Surgery, Johns Hopkins Medical Institutions, 1650 Orleans Street, Cancer Research Building I, Room 590, Baltimore, 21205, Maryland, USA

    Michael A Choti

  3. Department of Biostatistics, Johns Hopkins Medical Institutions, 1650 Orleans Street, Cancer Research Building I, Room 590, Baltimore, 21205, Maryland, USA

    Steven Goodman

  4. Department of Pathology, Johns Hopkins Medical Institutions, 1650 Orleans Street, Cancer Research Building I, Room 590, Baltimore, Maryland, 21205, USA

    Lori Sokoll

Authors
  1. Frank Diehl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kerstin Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael A Choti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Katharine Romans
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Steven Goodman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Meng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Katherine Thornton
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nishant Agrawal
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lori Sokoll
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Steve A Szabo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kenneth W Kinzler
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Bert Vogelstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Luis A Diaz Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

F.D., K.S. and M.L. optimized the BEAMing assay and performed these experiments. F.D., K.S., N.A. and S.A.S. performed tissue and plasma DNA purification and quantification. S.G. was responsible for statistical analysis. L.S. performed CEA measurements. M.A.C., K.R., K.T. and L.A.D., Jr. developed the clinical protocol and collected clinical samples. F.D., K.S., K.K., B.V. and L.A.D., Jr. developed the experimental plan and wrote the manuscript.

Corresponding authors

Correspondence to Bert Vogelstein or Luis A Diaz Jr.

Ethics declarations

Competing interests

Under agreements between the Johns Hopkins University and Exact Sciences, Genzyme Molecular Oncology and Beckman Instruments, K.W.K. and B.V. are entitled to a share of the royalties received by the University on sales of products related to certain of the genes described in this paper. The University and these authors also own stock in Exact Sciences and Genzyme, which is subject to certain restrictions under University policy. K.W.K., B.V., F.D., K.S., M.L. and L.A.D., Jr. are listed as inventors on patent applications filed by the University that are relevant to the results described in this paper. The terms of these arrangements are being managed by the University in accordance with its conflict of interest policies.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–5, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 1678 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Diehl, F., Schmidt, K., Choti, M. et al. Circulating mutant DNA to assess tumor dynamics. Nat Med 14, 985–990 (2008). https://doi.org/10.1038/nm.1789

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.1789

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing