Extrachromosomal Circular DNA in Cancer: Mechanisms and Clinical Applications

Abstract

Extrachromosomal circular DNA (eccDNA) has emerged as a critical area of cancer research due to its ubiquitous presence in tumour cells and significant role in tumorigenesis, progression and drug resistance. Recent studies demonstrate that eccDNA promotes cancer progression by influencing genomic instability, amplifying oncogenes, regulating gene expression and enhancing tumour cell adaptability to adverse conditions. While the precise mechanisms underlying eccDNA formation and its biological functions remain unclear, its potential applications in cancer diagnosis, prognosis and targeted therapy are gaining increasing recognition. This review summarises the latest advancements in eccDNA research, highlighting its potential as both a biomarker and a therapeutic target. Additionally, it emphasises the translational potential of eccDNA in clinical diagnostics and personalised treatment strategies, offering new perspectives for future cancer research and innovative therapies.

Keywords: biomarkers; drug resistance; eccDNA; extrachromosomal circular DNA; therapeutic targets; tumour.

FIGURE 1

Statistics of eccDNAs in eccDNAdb [11]. (A) Distribution of eccDNAs in human cancers: This panel shows the number of eccDNAs identified in various human cancers, highlighting the differences in eccDNA prevalence across cancer types. Notably, glioblastoma, lower‐grade glioma and lung cancer subtypes show a higher abundance of eccDNAs, suggesting a potential role of eccDNAs in the pathogenesis of these cancers. (B) Distribution of eccDNA segments in chromosomes: The bar plots in panel B represent the distribution of eccDNA segments across different chromosomes. Chromosomes 1, 5 and 7 show a higher frequency of eccDNA segments, which could indicate specific regions of the genome more prone to eccDNA formation. (C) Distribution of eccDNA sizes: This panel illustrates the size distribution of eccDNAs, showing that the majority of eccDNAs are relatively small, with a peak at lower size values. The data suggest that smaller eccDNAs are more commonly found in the cancer samples analysed. (D) Distribution of eccDNA segment numbers: Panel D provides insight into the number of segments present within each eccDNA molecule. A significant portion of eccDNAs comprises fewer segments, though a smaller subset contains a higher number of segments, potentially correlating with more complex rearrangements or alterations in the genome. (E) Distribution of eccDNA copy counts: The final panel presents the distribution of eccDNA copy numbers. Most eccDNAs are found in low copy numbers, but a substantial fraction of the samples show higher copy counts, which may be indicative of eccDNA amplification events that could have diagnostic or prognostic implications.

FIGURE 2

Schematic summary of the multifaceted roles played by eccDNA in cancer.