![]() 1) this uneven segregation accelerates cancer progression in changing environments. Furthermore, unlike the circular neochromosomes and ring chromosomes that contain centromeres, studies have found that the eccDNA/ecDNA elements, in the context of this review, lack centromeres, resulting in their uneven segregation from parental cells to daughter cells during cell division (Fig. ![]() In addition, circle-derived genomic rearrangements further contribute to the aberrant expression of cancer-relevant genes, such as doublecortin-like kinase 1 (DCLK1) and telomerase reverse transcriptase (TERT). The oncogenes amplified in circular DNA structures were shown to lead to high levels of mRNA transcripts, such as epidermal growth factor receptor (EGFR), mouse double minute 2 (MDM2), and cyclin D1 (CCND1). Of particular interest in this context is that most extrachromosomal circular DNA can amplify genes, including oncogenes in cancers, and can influence gene expression profiles, contributing to oncogenesis. Using a combination of whole-genome sequencing (WGS), cytogenetic analyses and structural modeling, Turner’s group identified that extrachromosomal circular DNA is common and highly amplified in many types of cancers, but these molecules can vary greatly among different cells from a single individual, confirming previous studies. An early example of the importance of extrachromosomal circular DNA elements in tumorigenesis was the discovery of DM structures in malignant tumors from children. Numerous studies have been conducted to investigate the relationship between extrachromosomal circular DNA and cancer biology, and these DNA elements may serve as promising biomarkers for cancer research and treatment. These circular DNA molecules that exist in cancer cells can be divided into at least two classes based on their different sizes and copy numbers: (i) small-usually less than 10 Kb, termed eccDNA, e.g., microDNA and (ii) large–often greater than 1 Mb, termed ecDNA, e.g., double minutes (DMs). Since the discovery of extrachromosomal circular DNA, biomedical research has led to the general view that tumor-associated extrachromosomal circular DNA has an adverse effect on human health and accelerates malignant behaviors. These circular DNA elements carry sequences that are homologous to genomic DNA, but are distinct from mitochondrial DNA and viral covalently closed circular DNA. Other research groups further identified the existence of extrachromosomal circular DNA in cells by karyotype preparations or by chloride density gradients. Extrachromosomal circular DNA, first described by Hotta’s group in 1964, is highly conserved across multiple species.
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