Novel Insights Into Extrachromosomal DNA: Redefining the Onco-Drivers Of
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Gu et al. Journal of Experimental & Clinical Cancer Research (2020) 39:215 https://doi.org/10.1186/s13046-020-01726-4 REVIEW Open Access Novel insights into extrachromosomal DNA: redefining the onco-drivers of tumor progression Xiang Gu1,2†, Jie Yu1,2†, Peiwei Chai1,2†, Shengfang Ge1,2* and Xianqun Fan1,2* Abstract Extrachromosomal DNA (ecDNA), gene-encoding extrachromosomal particles of DNA, is often present in tumor cells. Recent studies have revealed that oncogene amplification via ecDNA is widespread across a diverse range of cancers. ecDNA is involved in increasing tumor heterogeneity, reverting tumor phenotypes, and enhancing gene expression and tumor resistance to chemotherapy, indicating that it plays a significant role in tumorigenesis. In this review, we summarize the characteristics and genesis of ecDNA, connect these characteristics with their concomitant influences on tumorigenesis, enumerate the oncogenes encoded by ecDNA in multiple cancers, elaborate the roles of ecDNA in tumor pathogenesis and progression, and propose the considerable research and therapeutic prospects of ecDNA in cancer. Keywords: Extrachromosomal DNA, Oncogene, Tumorigenesis Background base pairs [9, 10]. These particles have been proved to be Genetic material guarantees the transmission of genetic circular by biophysical methods and DNA sequencing. information from parents to their offspring. With the Verhaak et al. divided these particles into two types based exception of some viruses, DNA is the carrier of genetic on the size and resultant functions [11]. Small particles, material, which was first identified by Frederick Griffith in which are called extrachromosomal circular DNA a Streptococcus pneumoniae transformation experiment (eccDNA), are usually less than 1 kb; consequently, they [1–3]. DNA is present in a compacted and dynamic com- are undetectable by light microscopy and lack full-length plex called chromatin in the cell nucleus. During the genes [12–14]. Investigations of eccDNA have revealed its metaphase of cell division, chromatin organizes into highly association with aging, as eccDNA containing ribosomal condensed chromosomes [4]. DNA also exists in organ- DNA genes accumulates in old cells and contributes to elles including mitochondria and chloroplasts, which the aging of yeast cells. The probable mechanism is de- probably evolved from microorganisms such as α- scribed by the titration hypothesis, which indicates that proteobacteria and cyanobacterium invading host cells the accumulated eccDNA might precipitate the compo- and starting a symbiotic life form [5–8]. In addition, it has nents of replication and/or transcription elements, and been reported that extrachromosomal particles of DNA eventually trigger the senescence and the eventual death exist, the size of which varies from dozens to millions of of old cells [15, 16]. Cohen et al. revealed that small poly- dispersed circular DNA (spcDNA), one type of eccDNA, is related to chromosomal instability (CIN), which is a * Correspondence: [email protected]; [email protected] †Xiang Gu, Jie Yu and Peiwei Chai contributed equally to this work. characteristic of malignant cells since the spcDNA mole- 1Department of Ophthalmology, Ninth People’s Hospital, Shanghai JiaoTong cules were frequently found in either intrinsically unstable University School of Medicine, Shanghai 20025, P. R. China cells including tumor cells or in cells exposed to an Full list of author information is available at the end of the article © The Author(s). 2020 Open Access 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://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gu et al. Journal of Experimental & Clinical Cancer Research (2020) 39:215 Page 2 of 10 external carcinogen treatment, indicating that spcDNA ecDNA is acentric with uneven segregation at cell division may be a possible marker of CIN [17, 18]. Extrachromo- The centromere, which consists of repetitive DNA, is somal DNA (ecDNA), the focus of this review, includes the region where sister chromatids remain connected relatively large particles generally ranging from 1 to 3 Mb, until mitosis and has a unique histone—CenpA. The with a median size of 1.26 Mb, which are therefore visible centromere is the ‘landing platform’ for the kinetochore, by light microscopy and encompass whole genes as well as a large protein structure that binds to microtubules in regulatory regions [11, 19–21]. ecDNA was first discov- mitosis and ensures accurate sister chromatid separation ered as paired small chromatin bodies in neuroblastoma and chromosome segregation [40, 41]. Because centro- (NB) cells called double minutes (DMs) [10]. Jack et al. meres lack ecDNA, ecDNA segregates unevenly at cell performed a scanning electron microscopy (SEM) study of division, allowing daughter cells to possess up to twice DMs and demonstrated that the identical sister minutes as many ecDNA particles as their corresponding mother appeared as two spherical chromatin bodies intercon- cells [31]. Uneven segregation of ecDNA leads to genetic nected by chromatin fibers [22]. Later, Turner et al. per- material distribution uncertainty, which may result in a formed whole-genome sequencing (WGS), structural rapid increase in oncogene copy number in a short modeling and cytogenetic analyses of 17 different cancer period and increase intratumoral heterogeneity, enhan- types and found that only 30% of ecDNA in tumor cells is cing tumor fitness to changing environments [32]. paired; thus, ecDNA is used as a general term to refer to large, gene-containing extrachromosomal particles of The resultant heterogeneity in cancer with ecDNA DNA, including both DMs and single body forms, with deCarvalho et al. revealed that ecDNA presented single minutes showing no apparent partners nearby. The divergent inheritance patterns and clonal selection existence of ecDNA has been confirmed in various types dynamics through an extensive genomic and transcrip- of cancers and cancer cell lines [23]. Unlike the smaller tomic analysis of 13 glioblastoma (GBM) tumor samples eccDNA particles, ecDNA is sufficiently large enough to and neurosphere-forming cultures and orthotopic xeno- contain one or multiple full genes, including oncogenes, graft models established from these samples, inferring and oncogenes located on ecDNA were first reported to the uneven inheritance of ecDNA between offspring map MYCN to DMs in NB [24]. Subsequent studies con- cells, which may explain the rapidly enhanced genomic firmed the existence of oncogene amplification on ecDNA heterogeneity during GBM evolution [42]. Xu et al. in multiple types of cancer [25–28]. Although oncogene characterized DMs in paired diagnosis and relapse amplification via ecDNA has been recognized, ecDNA tumors from 4 GBM patients and found that identical was thought to be rare in cancer for a long time; therefore, oncogenes could amplify on different DMs at diagnosis the role of ecDNA in tumorigenesis has received little at- and relapse, reflecting the primed evolution and rapidly tention [29, 30]. This perception was maintained until an increasing heterogeneity of DMs [43]. unbiased approach was developed to detect ecDNA by in- tegrating WGS and cytogenetic image analysis. The results ecDNA can be eliminated by micronucleus formation showed that oncogene amplification via ecDNA is wide- Oncogenes on DMs are unstable, and DMs can be elimi- spread in different cancers, thus arousing people’s interest nated in tumor cells by incorporating DMs into the in extrachromosomal oncogene amplification when cytoplasmic micronucleus when they are exposed to exploring tumorigenesis [23]. In this review, we focus on DNA replication inhibitors such as a low dose of the characteristics and genesis of ecDNA and emphasize hydroxyurea (HU) and radiation [34, 35]. In addition, in- its role in tumorigenesis. hibition of ERK1/2 activation, one of the main mitogen- activated protein kinase (MAPK) signaling pathways, also breaks DNA to eliminate DMs [36]. Acentric DMs Characteristics of ecDNA were found to segregate by adhering to the chromosome The rapid development of new techniques enables deter- arm during cell division, a process is called ‘hitchhiking’ mination of the unique characteristics of ecDNA. Com- (Fig. 1.a). When cells are exposed to a low dose of HU, pared to chrDNA, ecDNA is acentric with uneven DMs aggregate and detach from the chromosome; sub- segregation at cell division, leading to increased intratu- sequently, the aggregated DMs generate micronuclei moral heterogeneity and enhanced fitness to changing (Fig. 1.b). The