Circulating tumor nucleic acids: biology, release mechanisms, and clinical relevance

Abstract

Background: Despite advances in early detection and therapies, cancer is still one of the most common causes of death worldwide. Since each tumor is unique, there is a need to implement personalized care and develop robust tools for monitoring treatment response to assess drug efficacy and prevent disease relapse.

Main body: Recent developments in liquid biopsies have enabled real-time noninvasive monitoring of tumor burden through the detection of molecules shed by tumors in the blood. These molecules include circulating tumor nucleic acids (ctNAs), comprising cell-free DNA or RNA molecules passively and/or actively released from tumor cells. Often highlighted for their diagnostic, predictive, and prognostic potential, these biomarkers possess valuable information about tumor characteristics and evolution. While circulating tumor DNA (ctDNA) has been in the spotlight for the last decade, less is known about circulating tumor RNA (ctRNA). There are unanswered questions about why some tumors shed high amounts of ctNAs while others have undetectable levels. Also, there are gaps in our understanding of associations between tumor evolution and ctNA characteristics and shedding kinetics. In this review, we summarize current knowledge about ctNA biology and release mechanisms and put this information into the context of tumor evolution and clinical utility.

Conclusions: A deeper understanding of the biology of ctDNA and ctRNA may inform the use of liquid biopsies in personalized medicine to improve cancer patient outcomes.

Keywords: Biomarkers; Cell-free DNA; Circulating tumor DNA; Circulating tumor RNA; Clinical application; Liquid biopsy; Precision oncology; Shedding mechanisms.

Fig. 1

Circulating tumor nucleic acid release mechanisms. Circulating tumor nucleic acids may be released passively from tumor bed cells as free or protein-associated fragments or actively as part of extracellular vesicles and lipoprotein complexes

Fig. 2

Heterogeneity of extracellular vesicles and lipoprotein complexes. Overlapping sizes and density hinder the separation and selective isolation of these components, and thus, their composition has yet to be fully described. A combination of multiple isolation techniques provides promising approaches for the comprehensive characterization of extracellular vesicles and lipoprotein complexes [–101]

Fig. 3

Factors determining the levels of circulating tumor nucleic acids. The presence of circulating tumor nucleic acids in the blood is determined by release mechanisms and their degradation and clearance (cNucleases – circulating nucleases)

Fig. 4

Clinical utility of ctDNA in the context of disease evolution over time. The blue line depicts the level of ctDNA that carries a mutation detected in both the primary tumor and the blood. The yellow line shows the level of ctDNA representing a mutation that emerged with treatment resistance. MRD – minimal residual disease, WGS – whole genome sequencing, WES – whole exome sequencing, NGS – next generation sequencing, LOD – limit of detection, ddPCR – digital droplet PCR, qPCR – quantitative PCR)