Properties and Application of Cell-Free DNA as a Clinical Biomarker

Abstract

Biomarkers are valuable tools in clinical practice. In 2001, the National Institutes of Health (NIH) standardized the definition of a biomarker as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention. A biomarker has clinical relevance when it presents precision, standardization and reproducibility, suitability to the patient, straightforward interpretation by clinicians, and high sensitivity and/or specificity by the parameter it proposes to identify. Thus, serum biomarkers should have advantages related to the simplicity of the procedures and to the fact that venous blood collection is commonplace in clinical practice. We described the potentiality of cfDNA as a general clinical biomarker and focused on endothelial dysfunction. Circulating cell-free DNA (cfDNA) refers to extracellular DNA present in body fluid that may be derived from both normal and diseased cells. An increasing number of studies demonstrate the potential use of cfDNA as a noninvasive biomarker to determine physiologic and pathologic conditions. However, although still scarce, increasing evidence has been reported regarding using cfDNA in cardiovascular diseases. Here, we have reviewed the history of cfDNA, its source, molecular features, and release mechanism. We also show recent studies that have investigated cfDNA as a possible marker of endothelial damage in clinical settings. In the cardiovascular system, the studies are quite new, and although interesting, stronger evidence is still needed. However, some drawbacks in cfDNA methodologies should be overcome before its recommendation as a biomarker in the clinical setting.

Keywords: biomarker; cfDNA; circulating nucleotide; endothelial dysfunction; vascular damage.

Figure 1

Chronological summary of cfDNA. The timeline shows the main cfDNA discoveries, from the first report in 1948 until the first correlation of cfDNA with vascular dysfunction in 2015. cfDNA: circulating cell-free DNA.

Figure 2

cfDNA sources. cfDNA is released into the human blood circulation by normal cells and cells involved with pathologic processes, including cell death. cfDNA: circulating cell-free DNA.

Figure 3

Potential clinical applications of cfDNA analysis. cfDNA can increase under abnormal conditions thus can be used as noninvasive biomarkers in several diseases and stages. cfDNA: circulating cell-free DNA.

Figure 4

Circulating biomarkers proposed for endothelial dysfunction. Endothelial injury may be due to many conditions, including hypertension, diabetes mellitus, smoking, physical inactivity, aging, among others several clinical complications. Biomarkers are a valuable tool in clinical research and medical practice to identify an endothelial injury. ICAM-1: intercellular adhesion molecule 1; VCAM-1: vascular cell adhesion molecule 1; EMP: endothelial microparticles; VWF: von Willebrand factor; cfDNA: circulating cell-free DNA.