Circulating Tumor DNA in Blood and Its Utilization as a Potential Biomarker for Cancer

Czech version

Authors: E. Ondroušková; R. Hrstka
Authors‘ workplace: Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno
Published in: Klin Onkol 2015; 28(Supplementum 2): 69-74
doi: https://doi.org/10.14735/amko20152S69

Overview

Pursuing sensitive methods for detection and monitoring of oncologic diseases, that would limit the stress for patients, represents a long‑standing challenge in cancer diagnostics. As an ideal non‑invasive biomarkers may be considered‑ biological molecules that can be detected in blood and that provide most relevant picture about the state and development of disease. In fact, all types of cancer cells carry somatic mutations that enable the cells to escape from regulation and to grow and progress. These mutations are only present in the DNA of tumor cells and thus are hallmarks of cancer cells. Genotyping of tumor tissues becomes a common technique in clinical oncology, but it has its limits. Tissue biopsy only yields information about a very small area of tumor at the time of extraction and in some cases it is difficult or impossible to obtain the tissue sample. Furthermore, it is an invasive method that can stress patients. Analysis of circulating tumor DNA from blood – the so‑ called liquid biopsy – represents one possible solution. Dying tumor cells release fragments of their DNA into the blood stream. From blood, they can be isolated and subjected to analysis using new, sensitive and precise methods that detect genomic changes. These changes are evolving over time because cancer disease is characterized by evolution and ability to select new mutations that bring growth advantages or resistance to treatment. Our inability to capture the heterogeneity during tumor development is one of the major reasons responsible for failure of cancer treatment. Recent technological progress in detection and characterization of circulating DNA could enable tumor evolution monitoring in real time and become a guideline for an accurate and prompt treatment choice.

Key words:
circulating tumor DNA – tumor biomarkers – biopsy – liquid biopsy – blood – mutation

This study was supported by the European Regional Development Fund and the State Budget of the Czech Republic – RECAMO, CZ.1.05./2.1.00/03.0101, by the project MEYS – NPS I – LO1413, GACR 13-00956S, MH CZ – DRO (MMCI, 00209805) and BBMRI_CZ (LM2010004).

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Submitted:
7. 4. 2015

Accepted:
3. 7. 2015

Sources

1. Mandel P, Metais P. Les acides nucleiques du plasma sanguin chez l‘homme. C R Seances Soc Biol Fil 1948; 142(3– 4): 241– 243.

2. Leon SA, Shapiro B, Sklaroff DM et al. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res 1977; 37(3): 646– 650.

3. Vasioukhin V, Anker P, Maurice P et al. Point mutations of the N‑ ras gene in the blood plasma DNA of patients with myelodysplastic syndrome or acute myelogenous leukaemia. Br J Haematol 1994; 86(4): 774– 779.

4. Stroun M, Anker P, Lyautey J et al. Isolation and characterization of DNA from the plasma of cancer patients. Eur J Cancer Clin Oncol 1987; 23(6): 707– 712.

5. Stroun M, Lyautey J, Lederrey C et al. About the possible origin and mechanism of circulating DNA apoptosis and active DNA release. Clin Chim Acta 2001; 313(1– 2): 139– 142.

6. Lipson EJ, Velculescu VE, Pritchard TS, et al. Circulating tumor DNA analysis as a real‑ time method for monitoring tumor burden in melanoma patients undergoing treatment with immune checkpoint blockade. J Immunother Cancer 2014; 2(1): 42. doi: 10.1186/ s40425‑ 014‑ 0042‑ 0.

7. Bettegowda C, Sausen M, Leary RJ et al. Detection of circulating tumor DNA in early‑ and late‑stage human malignancies. Sci Transl Med 2014; 6(224): 224ra24. doi: 10.1126/ scitranslmed.3007094.

8. Hamakawa T, Kukita Y, Kurokawa Y et al. Monitoring gastric cancer progression with circulating tumour DNA. Br J Cancer 2015; 112(2): 352– 356. doi: 10.1038/ bjc.2014.609.

9. Gonzalez‑ Masia JA, Garcia‑ Olmo D, Garcia‑ Olmo DC. Circulating nucleic acids in plasma and serum (CNAPS): applications in oncology. Onco Targets Ther 2013; 6: 819– 832. doi: 10.2147/ OTT.S44668.

10. Yong E. Cancer biomarkers: written in blood. Nature 2014; 511(7511): 524– 526. doi: 10.1038/ 511524a.

11. Gerlinger M, Rowan AJ, Horswell S et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366(10): 883– 892. doi: 10.1056/ NEJMoa1113205.

12. Jacobs EL, Haskell CM. Clinical use of tumor markers in oncology. Curr Probl Cancer 1991; 15(6): 299– 360.

13. Djavan B, Keffer JH, Molberg K et al. False‑ positive serum prostate‑ specific antigen values in a patient with non‑Hodgkin lymphoma of the kidney. Urology 1995; 45(5): 875– 878.

14. Wood LD, Parsons DW, Jones S et al. The genomic landscapes of human breast and colorectal cancers. Science 2007; 318(5853): 1108– 1113.

15. Diehl F, Schmidt K, Choti MA et al. Circulating mutant DNA to assess tumor dynamics. Nat Med 2008; 14(9): 985– 990. doi: 10.1038/ nm.1789.

16. Levy M, Benesova L, Lipska L et al. Utility of cell‑free tumour DNA for post‑surgical follow‑up of colorectal cancer patients. Anticancer Res 2012; 32(5): 1621– 1626.

17. Gadgeel SM, Cote ML, Schwartz AG et al. Parameters for individualizing systemic therapy in non‑small cell lung cancer. Drug Resist Updat 2010; 13(6): 196– 204. doi: 10.1016/ j.drup.2010.10.001.

18. Rosell R, Vergnenegre A, Liu B et al. Biomarkers in lung oncology. Pulm Pharmacol Ther 2010; 23(6): 508– 514.

19. Murtaza M, Dawson SJ, Tsui DW et al. Non‑ invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 2013; 497(7447): 108– 112. doi: 10.1038/ nature12065.

20. Diaz LA Jr, Williams RT, Wu J et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 2012; 486(7404): 537– 540. doi: 10.1038/ nature11219.

21. Mack PC, Holland WS, Burich RA et al. EGFR mutations detected in plasma are associated with patient outcomes in erlotinib plus docetaxel‑treated non‑small cell lung cancer. J Thorac Oncol 2009; 4(12): 1466– 1472. doi: 10.1097/ JTO.0b013e3181bbf239.

22. Board RE, Wardley AM, Dixon JM et al. Detection of PIK3CA mutations in circulating free DNA in patients with breast cancer. Breast Cancer Res Treat 2010; 120(2): 461– 467. doi: 10.1007/ s10549‑ 010‑ 0747‑ 9.

23. Rothe F, Laes JF, Lambrechts D et al. Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer. Ann Oncol 2014; 25(10): 1959– 1965. doi: 10.1093/ annonc/ mdu288.

24. Newman AM, Bratman SV, To J et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med 2014; 20(5): 548– 554. doi: 10.1038/ nm.3519.

25. Ziegler A, Zangemeister‑ Wittke U, Stahel RA. Circulating DNA: a new diagnostic gold mine? Cancer Treat Rev 2002; 28(5): 255– 271.

26. Lee TH, Montalvo L, Chrebtow V et al. Quantitation of genomic DNA in plasma and serum samples: higher concentrations of genomic DNA found in serum than in plasma. Transfusion 2001; 41(2): 276– 282.

27. Rolfo C, Castiglia M, Hong D et al. Liquid biopsies in lung cancer: the new ambrosia of researchers. Biochim Biophys Acta 2014; 1846(2): 539– 546.

28. Hrstka R, Kolarova T, Michalova E et al. Development of PCR methods and their applications in oncological research and practice. Klin Onkol 2014; 27 (Suppl 1): S69– S74. doi: 10.14735/ amko20141S69.

29. Wang J, Ramakrishnan R, Tang Z et al. Quantifying EGFR alterations in the lung cancer genome with nanofluidic digital PCR arrays. Clin Chem 2010; 56(4): 623– 632. doi: 10.1373/ clinchem.2009.134973.

30. Diehl F, Li M, Dressman D et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci U S A 2005; 102(45): 16368– 16373.

31. Couraud S, Vaca‑ Paniagua F, Villar S et al. Noninvasive diagnosis of actionable mutations by deep sequencing of circulating free DNA in lung cancer from never‑ smokers: a proof‑ of‑ concept study from BioCAST/ IFCT‑ 1002. Clin Cancer Res 2014; 20(17): 4613– 4624. doi: 10.1158/ 1078‑ 0432.CCR‑ 13‑ 3063.

32. De Mattos‑ Arruda L, Weigelt B, Cortes J et al. Capturing intra‑ tumor genetic heterogeneity by de novo mutation profiling of circulating cell‑free tumor DNA: a proof‑ of‑ principle. Ann Oncol 2014; 25(9): 1729– 1735. doi: 10.1093/ annonc/ mdu239.

33. Forshew T, Murtaza M, Parkinson C et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med 2012; 4(136): 136ra68. doi: 10.1126/ scitranslmed.3003726.

34. Kinde I, Wu J, Papadopoulos N et al. Detection and quantification of rare mutations with massively parallel sequencing. Proc Natl Acad Sci U S A 2011; 108(23): 9530– 9535. doi: 10.1073/ pnas.1105422108.

35. Shaw JA, Page K, Blighe K et al. Genomic analysis of circulating cell‑free DNA infers breast cancer dormancy. Genome Res 2012; 22(2): 220– 231. doi: 10.1101/ gr.123497.111.

36. Heitzer E, Ulz P, Belic J et al. Tumor‑associated copy number changes in the circulation of patients with prostate cancer identified through whole‑ genome sequencing. Genome Med 2013; 5(4): 30. doi: 10.1186/ gm434.

37. Leary RJ, Sausen M, Kinde I et al. Detection of chromosomal alterations in the circulation of cancer patients with whole‑ genome sequencing. Sci Transl Med 2012; 4(162): 162ra154. doi: 10.1126/ scitranslmed.3004742.

38. Kopreski MS, Benko FA, Borys DJ et al. Somatic mutation screening: identification of individuals harboring K‑ ras mutations with the use of plasma DNA. J Natl Cancer Inst 2000; 92(11): 918– 923.

39. Morgan SR, Whiteley J, Donald E et al. Comparison of KRAS mutation assessment in tumor DNA and circulating free DNA in plasma and serum samples. Clin Med Insights Pathol 2012; 5: 15– 22. doi: 10.4137/ CPath.S8798.

40. Leary RJ, Kinde I, Diehl F et al. Development of personalized tumor biomarkers using massively parallel sequencing. Sci Transl Med 2010; 2(20): 20ra14. doi: 10.1126/ scitranslmed.3000702.

41. Chen Z, Feng J, Buzin CH et al. Analysis of cancer mutation signatures in blood by a novel ultra‑ sensitive assay: monitoring of therapy or recurrence in non‑metastatic breast cancer. PLoS One 2009; 4(9): e7220. doi: 10.1371/ journal.pone.0007220.

42. Dawson SJ, Tsui DW, Murtaza M et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 2013; 368(13): 1199– 1209. doi: 10.1056/ NEJMoa1213261.

43. Higgins MJ, Jelovac D, Barnathan E et al. Detection of tumor PIK3CA status in metastatic breast cancer using peripheral blood. Clin Cancer Res 2012; 18(12): 3462– 3469. doi: 10.1158/ 1078‑ 0432.CCR‑ 11‑ 2696.

44. Yung TK, Chan KC, Mok TS et al. Single‑molecule detection of epidermal growth factor receptor mutations in plasma by microfluidics digital PCR in non‑small cell lung cancer patients. Clin Cancer Res 2009; 15(6): 2076– 2084. doi: 10.1158/ 1078‑ 0432.CCR‑ 08‑ 2622.

45. Carreira S, Romanel A, Goodall J et al. Tumor clone dynamics in lethal prostate cancer. Sci Transl Med 2014; 6(254): 254ra125. doi: 10.1126/ scitranslmed.3009448.

46. National Human Genome Research Institute. [homepage on the Internet]. Available from: http:/ / www.genome.gov/ dmd/ img.cfm?node=Photos/Graphics& id=92951.