Extrachromosomal circular DNAs: an extra piece of evidence to depict tumor heterogeneity

Abstract

The tumor microenvironment (TME) comprises a heterogeneous number and type of cellular and noncellular components that vary in the context of molecular, genomic and epigenomic levels. The genotypic diversity and plasticity within cancer cells are known to be affected by genomic instability and genome alterations. Besides genomic instability within the chromosomal linear DNA, an extra factor appears in the form of extrachromosomal circular DNAs (eccDNAs; 2-20 kbp) and microDNAs (200-400 bp). This extra heterogeneity within cancer cells in the form of an abundance of eccDNAs adds another dimension to the expression of procancer players, such as oncoproteins, acting as a driver for cancer cell survival and proliferation. This article reviews research into eccDNAs centering around cancer plasticity and hallmarks, and discusses these facts in light of therapeutics and biomarker development.

Keywords: DNA repair; biomarker; eccDNAs; epigenome; neoplasms; tumor heterogeneity; tumor microenvironment.

Figure 1.. Tumor hallmarks.

The updated tumor hallmarks that define the true nature of complexity and heterogeneity of a tumor, encompassing deregulations at various levels including molecular, genetic, epigenetic, eccDNAs, microDNAs, secreted microDNAs and noncoding miRNAs and environmental pressure. CAR-T: Chimeric antigen receptor-T cell therapy; GOF: Gain of function; LOF: Loss of function; OXPHOS: Oxidative phosphorylation.

Figure 2.. Extrachromosomal circular DNAs: origin, mechanisms and use as potential cancer biomarkers and therapeutic agents.

Various factors in the form of stress, carcinogens, the DNA repair system, and normal cellular process such as DNA replication and epigenetic processes that contribute to the eccDNA heterogeneity within a tumor, are depicted. Potential cancer therapeutic avenues in the form of gene therapy, small RNA mimetics and inhibitors of DNA repair system are also highlighted. eccDNA: Extrachromosomal DNA; ECF: Extracytoplasmic function; HR: Homologous recombination; MMR: Mismatch repair; NHEJ: Nonhomologous end joining.