Small ring has big potential: insights into extrachromosomal DNA in cancer

Abstract

Recent technical advances have led to the discovery of novel functions of extrachromosomal DNA (ecDNA) in multiple cancer types. Studies have revealed that cancer-associated ecDNA shows a unique circular shape and contains oncogenes that are more frequently amplified than that in linear chromatin DNA. Importantly, the ecDNA-mediated amplification 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 offer 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.

3D chromatin architecture and transcription regulation in cancer

“…Extrachromosomal DNA (ecDNA) is a double-strand DNA molecule without centromeres and telomeres outside of the chromosome, usually 1–3 Mb in length [ 257 ]. The formation of ecDNA may be a combination of several processes, including replication slippage, episome formation, DNA double-strand-break based events, rolling, translocation–excision–deletion–amplification, and chromothripsis (see reviews by Gu et al [ 258 ] and Wang et al [ 259 ]). Its behaviours in cancers have drawn great attention in recent years, involving important aspects in tumorigenesis, including tumour heterogeneity, oncogene amplification, drug resistance, and senescence (see reviews by Wang et al [ 259 ] and Qiu et al [ 260 ]).…”

Revisiting characteristics of oncogenic extrachromosomal DNA as mobile enhancers on neuroblastoma and glioma cancers

“… Extrachromosomal small circular DNA eccDNA Single or double < 1 Mb. invisible under microscope Telomere circle, spcDNA, miDNA, episome Small regulatory RNA tumurgenic through selective teleomeric extension, modifying geneome stability [ 9 , 66 , 71 , 107 ] Extrachromosomal DNA (double minutes) ecDNA Double 1–3 Mb, visible under microscope BFB cycle, translocation/deletion amplification, episome and chromothripsis Oncogene amplification, regulatory regions, no centromeres or telomeres Oncogene amplification, chromosome, rearrangement Gene fusions, epigenetic/Histone, modification, nucleosome accessibility, signaling pathways regulation intra-tumoral heterogeneity autophagy, metastasis and invasiveness, senescence antitumor immunity [ 1 , 9 , 25 , 108 ] …”

“…ecDNAs have the main role in various cellular pathways such as oncogene amplification, chromosome rearrangements and cell processes, which are related to cancer development including metastasis/invasion, autophagy, drug resistance, medication response, and clinical outcome [ 66 ]. Oncogene amplification is a key factor in carcinogenesis.…”

“…In some cases, EGFRvIII and MDM2 amplification leads to Erlotinib resistance [ 9 , 43 , 66 , 90 , 108 ] Colon DHFR , c-MYC , BRCA1 Silencing BRCA1 gene decreased the number of DM-amplified oncogenes and the number of DM copies in ecDNA by down-regulating DHFR. In addition, MTX-resistant cells containing DM increased susceptibility to MTX [ 9 , 41 , 71 , 109 , 110 ] Neuroblastoma MYCN The chromosomal genome needs to be remodeled, amplified, TERT stimulated, DCLK1 inhibited, and the presence of MYCN eliminated on ecDNA to increase HU sensitivity [ 75 , 99 ] Cervical DHFR Promoting MTX resistance by DHFR amplification [ 111 ] Ovarian MYCN , EIF5AR , CA125 Decreased levels of ecDNA-form CA125 after HU [ 66 , 108 , 112 ] Breast DHFR , HER2 Induced resistance to MTX by DM-form amplified DHFR is not affected by the loss of HER2 on ecDNA and trastuzamab therapy [ 9 , 73 , 113 ] Leukemia c-MYC Drug sensitivity ptomotion by down-regulating the c-MYC [ 114 ] Oral squamous cell carcinoma MDR1 Enhancing HU sensitivity by Loss of MDR1 [ …”

The landscape of extrachromosomal circular DNA (eccDNA) in the normal hematopoiesis and leukemia evolution

“…Extrachromosomal circular DNA (eccDNA) was currently reported to generate in the process of DNA damage and the corresponding DNA repair [1,2]. According to their different sizes and copy numbers, they can be divided into microDNA (<1 Mb) and ecDNA/ ring chromosome (>1 Mb) [3][4][5][6]. The difference between ecDNA and ring chromosomes is ecDNA lacks centromeres and telomeres [7].…”