Circulating nucleic acids in plasma and serum

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Free, extra-cellular nucleic acid (CNAPS) can found circulating in the plasma or serum. The nucleic acid in question can be RNA, mitochondrial DNA or genomic DNA, but DNA is generally used as it is less labile than RNA.

While only small levels are detectable in health, higher levels are observed in disease, for instance malignancy and SLE. In malignancy, mutations from the tumour can be detected in this pool of nucleic acid. Similarly, fetal DNA can be detected in small amounts in maternal circulation.[1] CNAPS represents a phenomenon which may be exploited for diagnosis.


Historical Aspects

The phenomenon of extra-cellular DNA was first described in 1948 even prior to the publication of Watson and Crick's landmark paper on the structure of DNA.[2] The implications of the 1948 study lay unexplored until interest was rekindled by the discovery of free DNA in systemic lupus erythematosus.[3] Investigation of other diseases revealed increased levels in inflammatory states, other auto-immune disorders and cancer. High levels of free DNA were seen in a variety of cancers, particularly in patients with metastatic disease,[4][5][6] where higher levels generally carries a poorer prognosis.

The circulating DNA present in health is thought to derive from nucleated blood cells.[7][8] Evidence to support tumour cells as the source of this DNA was initially based on biophysical differences between wildtype DNA and apparent tumour DNA.[9] More convincing proof came from the detection of tumour-specific mutations in circulating DNA that matched mutations in the cancer cells, specifically mutated N-ras in patients with myelodysplasia and acute myeloid leukaemia,[10] and defective K-ras pancreatic cancers.[11] Since then, accumulating qualitative and quantitative evidence has demonstrated not only that circulating DNA is increased in individuals with malignancy, but that the same genetic and epigenetic alterations detected in free DNA can also be identified in the tumour cells.

CNAPS in Malignancy

Exact mechanism of release unclear. Could be due to necrosis of malignant tumour cells, apoptosis, phagocytosis of apoptotic cells, or decreased cleareance.

CNAPS in Pregnancy

Fetal DNA crosses the placenta and can be found in the maternal circulation.

In the research context, this DNA has been used experimentally in prenatal diagnosis of:


  1. Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CW, et al. Presence of fetal DNA in maternal plasma and serum. Lancet 1997;350:485-7.
  2. Mandel P and Métais P. Les acides nucléiques du plasma sanguin chez l'homme. C. R. Acad. Sci. Paris 1948 142: 241–243.
  3. Tan EM, Schur PH, Carr RI, Kunkel HG. Deoxybonucleic acid (DNA) and antibodies to DNA in the serum of patients with systemic lupus erythematosus. J Clin Invest. 1966 Nov;45(11):1732-40. (Direct link)
  4. Leon SA, Shapiro B, Sklaroff DM, Yaros MJ. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res. 1977 Mar;37(3):646-50. (Direct link)
  5. Shapiro B, Chakrabarty M, Cohn EM, Leon SA. Determination of circulating DNA levels in patients with benign or malignant gastrointestinal disease. Cancer. 1983 Jun 1;51(11):2116-20.
  6. Fournie GJ, Courtin JP, Laval F, Chale JJ, Pourrat JP, Pujazon MC, Lauque D, Carles P. Plasma DNA as a marker of cancerous cell death. Investigations in patients suffering from lung cancer and in nude mice bearing human tumours. Cancer Lett. 1995 May 8;91(2):221-7.
  7. Lo YM. Circulating nucleic acids in plasma and serum: an overview. Ann N Y Acad Sci. 2001 Sep;945:1-7. Review.
  8. Lui YY, Chik KW, Chiu RW, Ho CY, Lam CW, Lo YM. Predominant hematopoietic origin of cell-free DNA in plasma and serum after sex-mismatched bone marrow transplantation. Clin Chem. 2002 Mar;48(3):421-7.
  9. Stroun M, Anker P, Maurice P, Lyautey J, Lederrey C, Beljanski M. Neoplastic characteristics of the DNA found in the plasma of cancer patients. Oncology. 1989;46(5):318-22.
  10. Vasioukhin V, Anker P, Maurice P, Lyautey J, Lederrey C, Stroun M. 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 Apr;86(4):774-9.
  11. Sorenson GD, Pribish DM, Valone FH, Memoli VA, Bzik DJ, Yao SL. Soluble normal and mutated DNA sequences from single-copy genes in human blood. Cancer Epidemiol Biomarkers Prev. 1994 Jan-Feb;3(1):67-71.
  12. Dhallan R, Guo X, Emche S, Damewood M, Bayliss P, Cronin M, Barry J, Betz J, Franz K, Gold K, Vallecillo B, Varney J. A non-invasive test for prenatal diagnosis based on fetal DNA present in maternal blood: a preliminary study. Lancet. 2007 Feb 10; 369(9560):474-81.(Link to article – subscription may be required.)
  13. Norton ME, Jacobsson B, Swamy GK, Laurent LC, Ranzini AC, Brar H, Tomlinson MW, Pereira L, Spitz JL, Hollemon D, Cuckle H, Musci TJ, Wapner RJ. Cell-free DNA Analysis for Noninvasive Examination of Trisomy. The New England journal of medicine. 2015 Apr 1.(Epub ahead of print) (Link to article – subscription may be required.)
  14. Bianchi DW, Parker RL, Wentworth J, Madankumar R, Saffer C, Das AF, Craig JA, Chudova DI, Devers PL, Jones KW, Oliver K, Rava RP, Sehnert AJ. DNA sequencing versus standard prenatal aneuploidy screening. The New England journal of medicine. 2014 Feb 27; 370(9):799-808.(Link to article – subscription may be required.)
  15. Finning K, Martin P, Summers J, Massey E, Poole G, Daniels G. Effect of high throughput RHD typing of fetal DNA in maternal plasma on use of anti-RhD immunoglobulin in RhD negative pregnant women: prospective feasibility study. BMJ (Clinical research ed.). 2008 Apr 3.(Epub ahead of print) (Link to article – subscription may be required.)