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Small Ring Has Big Potential: Insights Into Extrachromosomal DNA in Cancer Yihao Wang1,2, Rui Huang1,2, Guopei Zheng1,2 and Jianfeng Shen1,2*

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Small Ring Has Big Potential: Insights Into Extrachromosomal DNA in Cancer Yihao Wang1,2, Rui Huang1,2, Guopei Zheng1,2 and Jianfeng Shen1,2* Wang et al. Cancer Cell Int (2021) 21:236 https://doi.org/10.1186/s12935-021-01936-6 Cancer Cell International REVIEW Open Access Small ring has big potential: insights into extrachromosomal DNA in cancer Yihao Wang1,2, Rui Huang1,2, Guopei Zheng1,2 and Jianfeng Shen1,2* Abstract Recent technical advances have led to the discovery of novel functions of extrachromosomal DNA (ecDNA) in mul- tiple cancer types. Studies have revealed that cancer-associated ecDNA shows a unique circular shape and contains oncogenes that are more frequently amplifed than that in linear chromatin DNA. Importantly, the ecDNA-mediated amplifcation of oncogenes was frequently found in most cancers but rare in normal tissues. Multiple reports have shown that ecDNA has a profound impact on oncogene activation, genomic instability, drug sensitivity, tumor heterogeneity and tumor immunology, therefore may ofer the potential for cancer diagnosis and therapeutics. Nevertheless, the underlying mechanisms and future applications of ecDNA remain to be determined. In this review, we summarize the basic concepts, biological functions and molecular mechanisms of ecDNA. We also provide novel insights into the fundamental role of ecDNA in cancer. Keywords: EcDNA, Oncogene amplifcation, Chromosomal rearrangement, Epigenetic modifcation, Tumor heterogeneity Introduction ecDNA that is rarely seen in normal cells, eccDNA is pre- Extrachromosomal DNA (ecDNA) is a particular type sent in both normal cells and cancer cells, and eccDNA of DNA molecule outside of the chromosome that is may promote tumorigenesis through the selection of usually 1–3 Mb in length [1]. EcDNA does not contain telomere extension and modulation of genomic instabil- centromeres or telomeres, but it has regulatory regions ity [10, 11]. In ring-chromosomes, the ends of the DNA that control the expression of the encoded genes [2, 3]. sequence are fused together to form a ring shape [12]. Studies have shown that ecDNA accounts for nearly Neochromosomes contain centromere and telomere 30% of all DNA particles outside of the chromosome [4, sequences, with a typical sequence length of 30–600 Mb 5]. In addition, there are two major categories of extra- [7, 8]. Neochromosomes have been shown to contain chromosomal DNA particles that difer from ecDNA high copy numbers of oncogenes and can be created in sequence length: (1) extrachromosomal small circu- through chromothripsis [9]. lar DNA (eccDNA) and (2) ring- or neochromosome Recent fndings have revealed the essential roles (Table 1) [6–9]. eccDNA is a double-stranded circular of ecDNA in cancer [1, 2, 12–14]. ecDNA is widely molecule less than 1 Mb in length that consists of mul- expressed in multiple types of cancers, including highly tiple copies of genome-originated repetitive non-coding aggressive glioblastoma and sarcoma, but not in normal DNA sequences and telomeric circles (e.g. small polydis- tissues [2, 15]. Te presence of ecDNA is also associated persed circular DNA and microDNA) [10]. In contrast to with the rapid amplifcation of oncogenes and elevated intra-tumoral heterogeneity [15]. Moreover, the lack of *Correspondence: [email protected] centromeres in ecDNA leads to the discordant inherit- 1 Department of Ophthalmology, Ninth People’s Hospital, Shanghai ance of ecDNA elements during mitosis, contributing to JiaoTong University School of Medicine, Shanghai 200025, China the hyper-activity of oncogene expression. Tese features Full list of author information is available at the end of the article of ecDNA endow cancer cells with the ability of quick © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wang et al. Cancer Cell Int (2021) 21:236 Page 2 of 11 Table 1 Characteristics of ecDNA, eccDNA, neo and ring chromosome Size Single/double Sequence feature Defnition Origination Refs. strand ecDNA 1-3 Mb, visible Double Oncogene amplif- Extrachromosomal BFB cycle, translo- [1, 3] under cation, regula- DNA (double cation-deletion- microscope tory regions, no minutes) amplifcation, centromeres or episome and telomeres chromothripsis eccDNA < 1 Mb. Invisible Single or double Small regulatory Extrachromosomal Telomere circle, [93, 94] under microscope RNA small circular DNA spcDNA, miDNA, episome Neo 30–600 Mb, visible Double Contains cen- Structurally abnor- Chromothripsis [7, 9] chromosome under microscope tromere or mal chromosome and BFB cycles telomere with telomere aggregation Ring chromosome 1.4–7.3 cms. Visible Double Circular or linear Breaks of telomeric End joining of DNA [6] under microscope form, contains ends, end-to-end double-strand centromere and fusion of the cen- breaks, telomere_ telomere tric chromosome subtelomere junction, or rear- rangement adaptation toward the microenvironment, therefore pro- from 3,212 patients across a variety of cancer types. Te moting intra-tumoral heterogeneity [1, 16]. Te study of association between oncogene amplifcation and ecDNA ecDNA in cancer is still in its infancy. In this review, we structure was observed, however such association could summarize the recent fndings of ecDNA regarding the not be applied to the breakpoint; and the distributions of structure, biogenesis, function and therapeutic potentials oncogene amplicons were highly nonrandom [15]. Tese in cancer. results demonstrate that not only the inherited “genetic code,” but also the topology and three-dimensional chro- The biological features of ecDNA matin landscape play critical roles in maintaining proper Structure function of the cancer genome [1, 15, 18]. Early attempts to uncover the structure of ecDNA were limited due to technical obstacles. Recent advances in Biogenesis next-generation sequencing technologies (e.g. whole Te biological source of ecDNA generation includes genome sequencing) and computational analytical endogenous DNA damage (e.g. DNA replication stress), approaches have led to the discovery that ecDNA pre- exogenous stress (e.g. carcinogens and pathogens) and sents in a circular shape and can replicate independently aberrations in the DNA damage repair machinery [19]. outside of chromosomes [2, 16, 17]. In addition, ecDNA Both ecDNA and homogeneously staining regions contains not only complete genes, but also regulatory (HSR) of chromosomes can be formed through gene elements such as upstream promoters and enhancers transcription and dramatically increase the complex- [2, 3]. Importantly, rewiring of adjacent enhancers along ity and plasticity of the genome [20–22]. Nevertheless, with endogenous enhancers was observed in ecDNA the underlying mechanisms of ecDNA biogenesis are [3]. In certain circumstances, ecDNA can incorporate not fully understood. In addition to simple self-ligation DNA segments from diferent chromosomes to form chi- after DNA breaks, ecDNA can also be generated in meric sequences, which may subsequently “invade” and multiple other ways [23, 24], and several models have re-integrate into other chromosomes to generate novel been proposed, such as the breakage-fusion-bridge DNA sequences [2]. In comparison with linear DNA, cycle [25], translocation-deletion-amplifcation [26], ecDNA has a highly accessible chromatin state and sig- episome [27] and chromothripsis [28] models. Te nifcantly higher levels of H3K27ac, a well-established diverse genome compositions of ecDNA in multiple histone marker for super enhancers [2, 3]. Tese struc- cancers imply complex multiple-step procedures in its tural characteristics of ecDNA markedly elevate the formation, including the generation of DNA fragments expression levels of oncogenes in ecDNA and afect chro- from DNA damage (e.g. double-strand breaks), tandem matin rearrangement to promote intra-tumoral hetero- duplication [29], breakage-fusion-bridge cycle [30] and geneity [16]. Verhaak et al. analyzed circular DNA data chromothripsis-mediated chromatin rearrangement Wang et al. Cancer Cell Int (2021) 21:236 Page 3 of 11 [31]. Non-homologous end-joining or microhomology- Source sequences mediated end-joining repair mechanisms facilitate the Studies have shown the source sequences of ecDNA rewiring of these DNA fragments in a random order, originate from multiple genomic sites from various indi- contributing to the generation of ecDNA [15, 32]. vidual chromosomes [23]. Storlazzi et al. demonstrated Importantly, ecDNA can self-replicate in the absence of that ecDNA exhibits a high degree of heterogeneity in the tumor suppressors [1]. However, contradictory results sequence source, even within a single cell [37, 38]. Bioin- have been reported
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