Origins, structures, and functions of circulating DNA in oncology

Abstract

While various clinical applications especially in oncology are now in progress such as diagnosis, prognosis, therapy monitoring, or patient follow-up, the determination of structural characteristics of cell-free circulating DNA (cirDNA) are still being researched. Nevertheless, some specific structures have been identified and cirDNA has been shown to be composed of many “kinds.” This structural description goes hand-in-hand with the mechanisms of its origins such as apoptosis, necrosis, active release, phagocytosis, and exocytose. There are multiple structural forms of cirDNA depending upon the mechanism of release: particulate structures (exosomes, microparticles, apoptotic bodies) or macromolecular structures (nucleosomes, virtosomes/proteolipidonucleic acid complexes, DNA traps, links with serum proteins or to the cell-free membrane parts). In addition, cirDNA concerns both nuclear and/or mitochondrial DNA with both species exhibiting different structural characteristics that potentially reveal different forms of biological stability or diagnostic significance. This review focuses on the origins, structures and functional aspects that are paradoxically less well described in the literature while numerous reviews are directed to the clinical application of cirDNA. Differentiation of the various structures and better knowledge of the fate of cirDNA would considerably expand the diagnostic power of cirDNA analysis especially with regard to the patient follow-up enlarging the scope of personalized medicine. A better understanding of the subsequent fate of cirDNA would also help in deciphering its functional aspects such as their capacity for either genometastasis or their pro-inflammatory and immunological effects.

A historical and evolutionary perspective on the biological significance of circulating DNA and extracellular vesicles

“…Their fragment sizes typically range from 100 bp to 21 kbp [156,164,165], where the short fragments can be related to the histone octamer structure and apoptosis, while the longer fractions originate from necrotic cells [165]. A high proportion of the cirDNA originating from tumors, however, are more fragmented than that of healthy tissues, releasing DNA fragments smaller than 100 bp [6,166]. Recently, we have reported a size of 2000 bp for the cfDNA of osteosarcoma cell cultures [167].…”

“…The treatment resulted in the lysis of the penicillin-sensitive strain, whose DNA transformed the penicillin-resistant strain to streptomycin-resistant [90,91]. Similar to bacteria, mammalian cells can also take up DNA in vitro and in vivo [6,27,93,94].…”

“…Factors that affect the circulation of cirDNA in the blood can include the activity of DNA-hydrolyzing enzymes in blood and tissues, the DNA's structure, and DNA-protein interactions in the blood [159]. CirDNA can be double stranded and single stranded [6,7,112,156,160,161], is of low molecular weight, and is resistant to RNase and proteinase K [156], but can be hydrolyzed by DNase I, and is cleared predominantly by the liver and, to a lesser extent, the The presence of heavely and weakly labeled nuclei is due to different activities of the genes in cells [132].…”

“…Thus far, many endogenous and exogenous sources of cirDNA in humans have been identified, e.g., apoptosis, necrosis, bacterial, and viral DNA [6]. Although apoptosis and necrosis are considered to be the main processes for producing cirDNA, numerous studies have demonstrated that cirDNA can also be derived from active cellular release mechanisms [7][8][9][10][11][12].…”

Elimination of Nucleoproteins in Systemic Lupus Erythematosus and Antinuclear Autoantibodies Production

“…Normal extracellular DNA concentrations are usually quite low, but the values may substantially difer depending on the detection approach and contamination of plasma with leukocytic DNA [42]. Circulating DNA is found to be not in free state but mainly as a part of mono-and Lupusoligonucleosomes; this conclusion is based upon its particular molecular weight and binding with histones [43].…”