Cell-Free eccDNAs: A New Type of Nucleic Acid Component for Liquid Biopsy?

Abstract

Extrachromosomal circular DNAs (eccDNAs) are circular DNAs that are originated from chromosomes, but are independent from chromosomal DNA. The eccDNAs are commonly found in various tissues and cell types, and in both normal and diseased conditions. Due to their highly heterogeneous origins and being widely spread in nearly all eukaryotes, the eccDNAs are believed to reflect the genome's plasticity and instability. With the assistance of next-generation sequencing, more eccDNAs have been characterized at the molecular level. Recently, eccDNAs have been reported as cell-free DNAs in the circulation system. Importantly, these circulating eccDNAs have shown some evidence with disease associations, suggesting their potential utility as a new type of biomarker for disease detection, treatment assessment and progress surveillance. However, many challenges need to be addressed before implementing the eccDNAs as a new source of genetic material for liquid biopsy.

Current understanding of extrachromosomal circular DNA in cancer pathogenesis and therapeutic resistance

“…Defining the extrachromosomal DNA that drives the amplification of drug-related genes would aid in providing novel therapeutic perspectives to reverse resistance and ameliorate outcomes. Extrachromosomal circular DNA could promote the amplification of drug resistance-associated genes, and it is a powerful driver of intercellular genetic heterogeneity [120]. The classical MTX resistance gene DHFR was proven to amplify primarily in the form of DMs, contributing to tumor progression and the development of MTX resistance in human colon cancer cells.…”

Progress on the role of extrachromosomal DNA in tumor pathogenesis and evolution

“…Another point worth noting is that the circulating fetal eccDNA molecules are also shorter than those of maternal origin 88 . Due to its closed circular structure, eccDNA molecules may be more resistant to exonuclease 90 . Therefore, eccDNA may exhibit higher stability than their linear counterparts, which may be an advantage for using eccDNA in plasma for liquid biopsy.…”

“…Therefore, eccDNA may exhibit higher stability than their linear counterparts, which may be an advantage for using eccDNA in plasma for liquid biopsy. Of course, many challenges need to be addressed before eccDNA can be used as a new biomarker for liquid biopsy 90 …”

Extrachromosomal Circular DNAs: An Extra Piece of Evidence to Depict Tumor Heterogeneity

“…Importantly, these circulating eccDNAs have shown some disease associations, suggesting their potential utility as a new type of biomarker for disease detection, treatment assessment and progress surveillance. However, many challenges need to be addressed before implementing eccDNAs as a new source of genetic material for liquid biopsy [39]. Taken together, there are expanding horizons for evaluation of the basis of formation of eccDNAs, and the mechanisms adopted by eccDNAs to contribute toward tumor heterogeneity as cellular and noncellular secreted factors.…”

“…Various potential avenues are suggested in the form of gene therapy, small RNA mimetics to interfere with eccDNAs, natural sources of small RNAs and inhibitors of the DNA repair protein system [35][36][37][38][39][40]. Furthermore, evidence from eccDNA research is being translated into avenues for development of cancer biomarkers and diagnostic tools [35][36][37][38][39][40]. This mini-review addresses the recent developments in deciphering a link between eccDNAs and TME that may be translated into future therapeutic and diagnostic avenues.…”