Circulating Cell-Free DNA for Molecular Diagnostics and Therapeutic Monitoring

  • Natasha B. Hunter
  • Julia A. Beaver
  • Ben Ho ParkEmail author


The presence of cell-free circulating DNA has been known for many years, but only recently has this knowledge been translated for diagnosis and therapeutic monitoring. However, the ability to detect and sequence rare DNA molecules in the circulation, such as fetal genetic anomalies and cancer DNA, required advances in technology that have only recently become available. In this chapter, we review the history of circulating DNA, technologies for identifying and measuring it, and applications, especially as a cancer biomarker, that promise to emerge as new standards of care for clinical medicine.


Circulating cell-free DNA Plasma tumor DNA Liquid biopsy Molecular diagnostics Cancer diagnostics Biomarker development Genetic sequencing technology Genetic mutations 


  1. 1.
    Mandel P, Metais P. Not AvailableC R Seances Soc Biol Fil. 1948;142(3–4):241–3.PubMedGoogle Scholar
  2. 2.
    Lam NY, et al. Plasma DNA as a prognostic marker for stroke patients with negative neuroimaging within the first 24 h of symptom onset. Resuscitation. 2006;68(1):71–8.CrossRefGoogle Scholar
  3. 3.
    Antonatos D, et al. Cell-free DNA levels as a prognostic marker in acute myocardial infarction. Ann N Y Acad Sci. 2006;1075:278–81.CrossRefGoogle Scholar
  4. 4.
    Saukkonen K, et al. Association of cell-free plasma DNA with hospital mortality and organ dysfunction in intensive care unit patients. Intensive Care Med. 2007;33(9):1624–7.CrossRefGoogle Scholar
  5. 5.
    Sandhu HS, et al. Measurement of circulating neuron-specific enolase mRNA in diabetes mellitus. Ann N Y Acad Sci. 2008;1137:258–63.CrossRefGoogle Scholar
  6. 6.
    Choi JJ, Reich CF 3rd, Pisetsky DS. The role of macrophages in the in vitro generation of extracellular DNA from apoptotic and necrotic cells. Immunology. 2005;115(1):55–62.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Stroun M, et al. The origin and mechanism of circulating DNA. Ann N Y Acad Sci. 2000;906:161–8.CrossRefGoogle Scholar
  8. 8.
    Jahr S, et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res. 2001;61(4):1659–65.PubMedGoogle Scholar
  9. 9.
    Diehl F, 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):16368–73.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Diehl F, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14(9):985–90.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    De Mattos-Arruda L, et al. Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma. Nat Commun. 2015;6:8839.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Pan W, et al. Brain tumor mutations detected in cerebral spinal fluid. Clin Chem. 2015;61(3):514–22.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Lo YM, et al. Rapid clearance of fetal DNA from maternal plasma. Am J Hum Genet. 1999;64(1):218–24.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Fleischhacker M, Schmidt B. Circulating nucleic acids (CNAs) and cancer--a survey. Biochim Biophys Acta. 2007;1775(1):181–232.PubMedGoogle Scholar
  15. 15.
    Emlen W, Mannik M. Effect of DNA size and strandedness on the in vivo clearance and organ localization of DNA. Clin Exp Immunol. 1984;56(1):185–92.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Chang CP, et al. Elevated cell-free serum DNA detected in patients with myocardial infarction. Clin Chim Acta. 2003;327(1–2):95–101.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Wimberger P, et al. Impact of platinum-based chemotherapy on circulating nucleic acid levels, protease activities in blood and disseminated tumor cells in bone marrow of ovarian cancer patients. Int J Cancer. 2011;128(11):2572–80.CrossRefGoogle Scholar
  18. 18.
    Lo YM, et al. Plasma DNA as a prognostic marker in trauma patients. Clin Chem. 2000;46(3):319–23.PubMedGoogle Scholar
  19. 19.
    Chiu TW, et al. Plasma cell-free DNA as an indicator of severity of injury in burn patients. Clin Chem Lab Med. 2006;44(1):13–7.CrossRefGoogle Scholar
  20. 20.
    Rhodes A, et al. Plasma DNA concentration as a predictor of mortality and sepsis in critically ill patients. Crit Care. 2006;10(2):R60.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Herzenberg LA, et al. Fetal cells in the blood of pregnant women: detection and enrichment by fluorescence-activated cell sorting. Proc Natl Acad Sci U S A. 1979;76(3):1453–5.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Lo YM, et al. Presence of fetal DNA in maternal plasma and serum. Lancet. 1997;350(9076):485–7.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Lo YM, Chiu RW. Prenatal diagnosis: progress through plasma nucleic acids. Nat Rev Genet. 2007;8(1):71–7.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Li Y, et al. Cell-free DNA in maternal plasma: is it all a question of size? Ann N Y Acad Sci. 2006;1075:81–7.CrossRefGoogle Scholar
  25. 25.
    Lo YM, et al. Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet. 1998;62(4):768–75.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Lun FM, et al. Microfluidics digital PCR reveals a higher than expected fraction of fetal DNA in maternal plasma. Clin Chem. 2008;54(10):1664–72.CrossRefGoogle Scholar
  27. 27.
    Chiu RW, et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ. 2011;342:c7401.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Lo YM. Fetal RhD genotyping from maternal plasma. Ann Med. 1999;31(5):308–12.CrossRefGoogle Scholar
  29. 29.
    Fan HC, et al. Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. Proc Natl Acad Sci U S A. 2008;105(42):16266–71.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Chiu RW, et al. Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma. Proc Natl Acad Sci U S A. 2008;105(51):20458–63.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Chiu RW, Lo YM. Clinical applications of maternal plasma fetal DNA analysis: translating the fruits of 15 years of research. Clin Chem Lab Med. 2013;51(1):197–204.PubMedGoogle Scholar
  32. 32.
    Liao GJ, Gronowski AM, Zhao Z. Non-invasive prenatal testing using cell-free fetal DNA in maternal circulation. Clin Chim Acta. 2014;428:44–50.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    (ACOG), A.C.o.O.a.G., Cell-free DNA Screening for Fetal Aneuploidy. Society for Maternal-Fetal Medicine, Committee on Genetics. 2015.Google Scholar
  34. 34.
    Lo YM, et al. Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. Sci Transl Med. 2010;2(61):61ra91.CrossRefGoogle Scholar
  35. 35.
    Leon SA, et al. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res. 1977;37(3):646–50.PubMedGoogle Scholar
  36. 36.
    Allen D, et al. Role of cell-free plasma DNA as a diagnostic marker for prostate cancer. Ann N Y Acad Sci. 2004;1022:76–80.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Chun FK, et al. Circulating tumour-associated plasma DNA represents an independent and informative predictor of prostate cancer. BJU Int. 2006;98(3):544–8.CrossRefGoogle Scholar
  38. 38.
    Schwarzenbach H, et al. Detection and monitoring of cell-free DNA in blood of patients with colorectal cancer. Ann N Y Acad Sci. 2008;1137:190–6.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Li BT, et al. A prospective study of total plasma cell-free DNA as a predictive biomarker for response to systemic therapy in patients with advanced non-small-cell lung cancers. Ann Oncol. 2016;27(1):154–9.CrossRefGoogle Scholar
  40. 40.
    Giacona MB, et al. Cell-free DNA in human blood plasma: length measurements in patients with pancreatic cancer and healthy controls. Pancreas. 1998;17(1):89–97.CrossRefGoogle Scholar
  41. 41.
    Chen X, et al. Detecting tumor-related alterations in plasma or serum DNA of patients diagnosed with breast cancer. Clin Cancer Res. 1999;5(9):2297–303.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Heid CA, et al. Real time quantitative PCR. Genome Res. 1996;6(10):986–94.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Branford S. Chronic myeloid leukemia: molecular monitoring in clinical practice. Hematology Am Soc Hematol Educ Program. 2007:376–83.Google Scholar
  44. 44.
    Yu M, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013;339(6119):580–4.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Morley AA. Digital PCR: a brief history. Biomol Detect Quantif. 2014;1(1):1–2.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Vogelstein B, Kinzler KW. Digital PCR. Proc Natl Acad Sci U S A. 1999;96(16):9236–41.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Goodwin S, McPherson JD, McCombie WR. Coming of age: ten years of next-generation sequencing technologies. Nat Rev Genet. 2016;17(6):333–51.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Forshew T, et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med. 2012;4(136):136ra68.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Kinde I, et al. Detection and quantification of rare mutations with massively parallel sequencing. Proc Natl Acad Sci U S A. 2011;108(23):9530–5.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Kennedy SR, et al. Detecting ultralow-frequency mutations by duplex sequencing. Nat Protoc. 2014;9(11):2586–606.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Leary RJ, et al. Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. Sci Transl Med. 2012;4(162):162ra154.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Castells A, et al. K-ras mutations in DNA extracted from the plasma of patients with pancreatic carcinoma: diagnostic utility and prognostic significance. J Clin Oncol. 1999;17(2):578–84.CrossRefGoogle Scholar
  53. 53.
    Kopreski MS, 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):918–23.CrossRefGoogle Scholar
  54. 54.
    Dianxu F, et al. A prospective study of detection of pancreatic carcinoma by combined plasma K-ras mutations and serum CA19-9 analysis. Pancreas. 2002;25(4):336–41.CrossRefGoogle Scholar
  55. 55.
    Garcia JM, et al. Extracellular tumor DNA in plasma and overall survival in breast cancer patients. Genes Chromosomes Cancer. 2006;45(7):692–701.CrossRefGoogle Scholar
  56. 56.
    Boddy JL, et al. Prospective study of quantitation of plasma DNA levels in the diagnosis of malignant versus benign prostate disease. Clin Cancer Res. 2005;11(4):1394–9.CrossRefGoogle Scholar
  57. 57.
    Schwarzenbach H, et al. Comparative evaluation of cell-free tumor DNA in blood and disseminated tumor cells in bone marrow of patients with primary breast cancer. Breast Cancer Res. 2009;11(5):R71.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Schwarzenbach H, et al. Cell-free tumor DNA in blood plasma as a marker for circulating tumor cells in prostate cancer. Clin Cancer Res. 2009;15(3):1032–8.CrossRefGoogle Scholar
  59. 59.
    Toro PV, et al. Comparison of cell stabilizing blood collection tubes for circulating plasma tumor DNA. Clin Biochem. 2015;48:993.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Bettegowda C, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra24.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Hadano N, et al. Prognostic value of circulating tumour DNA in patients undergoing curative resection for pancreatic cancer. Br J Cancer. 2016;115(1):59–65.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Gerlinger M, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883–92.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Yachida S, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467(7319):1114–7.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Higgins MJ, et al. Detection of tumor PIK3CA status in metastatic breast cancer using peripheral blood. Clin Cancer Res. 2012;18(12):3462–9.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    De Mattos-Arruda L, 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):1729–35.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Rothé F, Laes J-F, Lambrechts D, Smeets D, Vincent D, Maetens M, Fumagalli D, Michiels S, Stylianos D, Moerman C, Detiffe J-P, Larsimont D, Awada A, Piccart M, Sotiriou C, Ignatiadis M. Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer. Ann Oncol. 2014;25:1959.CrossRefGoogle Scholar
  67. 67.
    Parsons HA, et al. Individualized molecular analyses guide efforts (IMAGE): a prospective study of molecular profiling of tissue and blood in metastatic triple negative breast cancer. Clin Cancer Res. 2017;23(2):379–86.Google Scholar
  68. 68.
    Tomasetti C, et al. Only three driver gene mutations are required for the development of lung and colorectal cancers. Proc Natl Acad Sci U S A. 2015;112(1):118–23.CrossRefGoogle Scholar
  69. 69.
    Ryan BM, et al. A prospective study of circulating mutant KRAS2 in the serum of patients with colorectal neoplasia: strong prognostic indicator in postoperative follow up. Gut. 2003;52(1):101–8.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Wang S, et al. Potential clinical significance of a plasma-based KRAS mutation analysis in patients with advanced non-small cell lung cancer. Clin Cancer Res. 2010;16(4):1324–30.CrossRefGoogle Scholar
  71. 71.
    Diehl F, et al. Analysis of mutations in DNA isolated from plasma and stool of colorectal cancer patients. Gastroenterology. 2008;135(2):489–98.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Husain H, et al. Monitoring daily dynamics of early tumor response to targeted therapy by detecting circulating tumor DNA in urine. Clin Cancer Res. 2017;23:4716.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Oshiro C, et al. PIK3CA mutations in serum DNA are predictive of recurrence in primary breast cancer patients. Breast Cancer Res Treat. 2015;150(2):299–307.CrossRefGoogle Scholar
  74. 74.
    Olsson E, et al. Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. EMBO Mol Med. 2015;7(8):1034–47.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Pietrasz D, et al. Plasma circulating tumor DNA in pancreatic cancer patients is a prognostic marker. Clin Cancer Res. 2017;23(1):116–23.CrossRefGoogle Scholar
  76. 76.
    Tie J, et al. Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol. 2015;26:1715.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Garcia-Murillas I, et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med. 2015;7(302):302ra133.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Lebofsky R, et al. Circulating tumor DNA as a non-invasive substitute to metastasis biopsy for tumor genotyping and personalized medicine in a prospective trial across all tumor types. Mol Oncol. 2015;9(4):783–90.CrossRefGoogle Scholar
  79. 79.
    Taniguchi K, et al. Quantitative detection of EGFR mutations in circulating tumor DNA derived from lung adenocarcinomas. Clin Cancer Res. 2011;17(24):7808–15.CrossRefGoogle Scholar
  80. 80.
    Piotrowska Z, et al. Heterogeneity underlies the emergence of EGFRT790 wild-type clones following treatment of T790M-positive cancers with a third-generation EGFR inhibitor. Cancer Discov. 2015;5(7):713–22.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Ishii H, et al. Digital PCR analysis of plasma cell-free DNA for non-invasive detection of drug resistance mechanisms in EGFR mutant NSCLC: correlation with paired tumor samples. Oncotarget. 2015;6(31):30850–8.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Que D, et al. EGFR mutation status in plasma and tumor tissues in non-small cell lung cancer serves as a predictor of response to EGFR-TKI treatment. Cancer Biol Ther. 2016;17(3):320–7.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Oxnard GR, et al. Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clin Cancer Res. 2014;20(6):1698–705.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Chabon JJ, et al. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun. 2016;7:11815.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Rosell R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239–46.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
  87. 87.
    Chu D, et al. ESR1 mutations in circulating plasma tumor DNA from metastatic breast cancer patients. Clin Cancer Res. 2016;22(4):993–9.Google Scholar
  88. 88.
    Schiavon G, et al. Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med. 2015;7(313):313ra182.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Fribbens C, et al. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2016;34:2961.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Wang P, et al. Sensitive detection of mono- and polyclonal ESR1 mutations in primary tumors, metastatic lesions and cell free DNA of breast cancer patients. Clin Cancer Res. 2016;22(5):1130–7.Google Scholar
  91. 91.
    Diaz LA Jr, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486(7404):537–40.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Misale S, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486(7404):532–6.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Xu JM, et al. PIK3CA mutations contribute to acquired cetuximab resistance in patients with metastatic colorectal cancer. Clin Cancer Res. 2017;23:4602.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Siravegna G, et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med. 2015;21(7):795–801.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Shinozaki M, et al. Utility of circulating B-RAF DNA mutation in serum for monitoring melanoma patients receiving biochemotherapy. Clin Cancer Res. 2007;13(7):2068–74.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Cohen JD, et al. Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers. Proc Natl Acad Sci U S A. 2017;114(38):10202–7.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Desmedt C, Brown DN, Szekely B, Smeets D, Szasz MA, Adnet P, Rothé F, Nagy Z, Farago Z, Tokes A, Zardavas D, Zoppoli G, Ignatiadis M, Pusztai L, Piccart M, Larsimont D, Lambrechts D, Kulka J, Sotiriou C. Unraveling breast cancer progression through geographical and temporal sequencing, in AACR 2014. San Diego; 2014.Google Scholar
  98. 98.
    Lee J, et al. A polycythemia vera JAK2 mutation masquerading as a duodenal cancer mutation. J Natl Compr Cancer Netw. 2016;14(12):1495–8.CrossRefGoogle Scholar
  99. 99.
    Steensma DP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126(1):9–16.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Guo S, et al. Identification of methylation haplotype blocks aids in deconvolution of heterogeneous tissue samples and tumor tissue-of-origin mapping from plasma DNA. Nat Genet. 2017;49(4):635–42.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    O'Driscoll L, et al. Feasibility and relevance of global expression profiling of gene transcripts in serum from breast cancer patients using whole genome microarrays and quantitative RT-PCR. Cancer Genomics Proteomics. 2008;5(2):94–104.PubMedGoogle Scholar
  102. 102.
    Schutz E, et al. Graft-derived cell-free DNA, a noninvasive early rejection and graft damage marker in liver transplantation: a prospective, observational, multicenter cohort study. PLoS Med. 2017;14(4):e1002286.CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Simo-Servat O, Simo R, Hernandez C. Circulating biomarkers of diabetic retinopathy: an overview based on physiopathology. J Diabetes Res. 2016;2016:5263798.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Bradshaw G, et al. Dysregulated MicroRNA expression profiles and potential cellular, circulating and polymorphic biomarkers in Non-Hodgkin Lymphoma. Genes (Basel). 2016;7(12):130.CrossRefGoogle Scholar
  105. 105.
    Sapp RM, et al. Circulating microRNAs in acute and chronic exercise: more than mere biomarkers. J Appl Physiol (1985). 2017;122(3):702–17.CrossRefGoogle Scholar
  106. 106.
    Zonta E, Nizard P, Taly V. Assessment of DNA integrity, applications for cancer research. Adv Clin Chem. 2015;70:197–246.CrossRefGoogle Scholar
  107. 107.
    Visvanathan K, et al. Monitoring of serum DNA methylation as an early independent marker of response and survival in metastatic breast cancer: TBCRC 005 prospective biomarker study. J Clin Oncol. 2017;35(7):751–8.CrossRefGoogle Scholar
  108. 108.
    Tang Y, et al. Promoter DNA methylation analysis reveals a combined diagnosis of CpG-based biomarker for prostate cancer. Oncotarget. 2017;8(35):58199–209.Google Scholar
  109. 109.
    Hagrass HA, Pasha HF, Ali AM. Estrogen receptor alpha (ERalpha) promoter methylation status in tumor and serum DNA in Egyptian breast cancer patients. Gene. 2014;552(1):81–6.CrossRefGoogle Scholar
  110. 110.
    Grumaz S, et al. Next-generation sequencing diagnostics of bacteremia in septic patients. Genome Med. 2016;8(1):73.CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Shoham Y, et al. Admission cell free DNA as a prognostic factor in burns: quantification by use of a direct rapid fluorometric technique. Biomed Res Int. 2014;2014:306580.CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Lam NY, et al. Time course of early and late changes in plasma DNA in trauma patients. Clin Chem. 2003;49(8):1286–91.CrossRefGoogle Scholar
  113. 113.
    Hu Q, et al. Elevated levels of plasma mitochondrial DNA are associated with clinical outcome in intra-abdominal infections caused by severe trauma. Surg Infect. 2017;18:610.CrossRefGoogle Scholar
  114. 114.
    Long Y, et al. Diagnosis of sepsis with cell-free DNA by next-generation sequencing technology in ICU patients. Arch Med Res. 2016;47(5):365–71.CrossRefGoogle Scholar
  115. 115.
    Hou YQ, et al. Branched DNA-based Alu quantitative assay for cell-free plasma DNA levels in patients with sepsis or systemic inflammatory response syndrome. J Crit Care. 2016;31(1):90–5.CrossRefGoogle Scholar
  116. 116.
    Rainer TH, et al. Plasma beta-globin DNA as a prognostic marker in chest pain patients. Clin Chim Acta. 2006;368(1–2):110–3.CrossRefGoogle Scholar
  117. 117.
    O’Connell GC, et al. Circulating extracellular DNA levels are acutely elevated in ischaemic stroke and associated with innate immune system activation. Brain Inj. 2017:1–7.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  • Natasha B. Hunter
    • 1
  • Julia A. Beaver
    • 1
  • Ben Ho Park
    • 1
    Email author
  1. 1.The Sidney Kimmel Comprehensive, Cancer Center at Johns HopkinsBaltimoreUSA

Personalised recommendations