Towards systematic nomenclature for cell-free DNA

Abstract

Cell-free DNA (cfDNA) has become widely recognized as a promising candidate biomarker for minimally invasive characterization of various genomic disorders and other clinical scenarios. However, among the obstacles that currently challenge the general progression of the research field, there remains an unmet need for unambiguous universal cfDNA nomenclature. To address this shortcoming, we classify in this report the different types of cfDNA molecules that occur in the human body based on its origin, genetic traits, and locality. We proceed by assigning existing terms to each of these cfDNA subtypes, while proposing new terms and abbreviations where clarity is lacking and more precise stratification would be beneficial. We then suggest the proper usage of these terms within different contexts and scenarios, focusing mainly on the nomenclature as it relates to the domains of oncology, prenatal testing, and post-transplant surgery surveillance. We hope that these recommendations will serve as useful considerations towards the establishment of universal cfDNA nomenclature in the future. In addition, it is conceivable that many of these recommendations can be transposed to cell-free RNA nomenclature by simply exchanging "DNA" with "RNA" in each acronym/abbreviation. Similarly, when describing DNA and RNA collectively, the suffix can be replaced with "NAs" to indicate nucleic acids.

Fig. 1

Nomenclature for cell-free DNA (cfDNA) in humans. The cfDNA content in biospecimens is biologically and structurally diverse. Assigning proper names to distinct types of cfDNA molecules thus represents an important step towards a common understanding of concepts among researchers. In this figure, we demonstrate how such a nomenclature can be devised in the fields of oncology, prenatal testing, and post-transplant surgery surveillance to differentiate between the different cfDNA types present in biospecimens collected from human body fluids. For the correct interpretation of this figure, three important points should be noted: First, the term cfDNA is appropriate for describing any free-floating DNA present in both circulating (i.e., blood and lymphatic fluids) and non-circulating body fluids (e.g., urine, saliva, and cerebrospinal fluid). Second, in cases where it is necessary (or when it would provide clarity) to distinguish between cfDNA coming from these different sources (e.g., parallel characterization of cfDNA in both body fluid types), the total cfDNA in non-circulating body fluids can retain the term cfDNA, while the total cfDNA in circulation can be termed circulating DNA (cirDNA). Similarly, for describing different cfDNA subtypes that are present only in circulation, the “cf” prefix in the respective abbreviations can simply be replaced by the prefix “cir”. Third, while the terms cirDNA and cfDNA can be used interchangeably, there exist common preferences for either type in certain cases, as indicated by the asterisk symbols. Therefore, the usage of the above terms is often appropriate only in specific experimental settings and other scenarios. Table 2 provides more information on this nomenclature, and indicates the different contexts in which each of the above terms may be useful

Fig. 2

Nomenclature for cell-free DNA (cfDNA) in oncology. In the above representation, we demonstrate how nomenclature can be devised to differentiate between the different types of cancer cell-derived cfDNA fractions present in samples collected from a the circulatory system (blood and lymphatic fluids), b other bodily fluids (e.g., urine, feces, cerebrospinal fluid, bronchial lavage, and sputum), and c cell culture supernatant. Table 2 summarizes the different contexts in which each of the above terms may be useful

Fig. 3

Nomenclature for cell-free DNA (cfDNA) in a prenatal testing and b post-transplant surgery surveillance. Table 2 summarizes the different contexts in which each of the above terms may be useful