If you have ever seen an image of the chromosomes (also known as a karyotype) inside a cancer cell, you know that their genetic material can get mixed around to end up looking like a child’s arts and crafts project. A part of chromosome 3 might suddenly be fused to chromosome 14, or chromosome 4 might have acquired a piece of chromosome 5 in the middle. One of the hallmarks of cancer is genomic instability, meaning that cancer cells accumulate DNA mutations and other defects such as chromosomal rearrangements at a much higher rate than healthy cells . This genomic instability allows cancer to acquire favourable traits more easily, such as amplification of oncogenes or downregulation of tumour suppressor genes . Extrachromosomal circular DNA (ecDNA) are small circular DNA molecules that can be found in healthy cells. However, ecDNA can likely be a driver in carcinogenesis when associated with cancer cells by playing a role in genome instability .
ecDNA was first discovered in 1964, and research since the ‘80s has been accumulating that ecDNA can facilitate carcinogenesis by the amplification of oncogenes [3-6]. These small ecDNAs often do not contain centromeres and, consequently, during DNA replication, there is no way to separate ecDNA evenly over the two daughter cells as usually happens with chromosomes [7, 8]. When a cell generates an ecDNA, duplication of the ecDNA will occur before cell division and, as distribution of ecDNA will happen at random, one daughter cell might inherit two ecDNA copies while the other daughter cell will inherit none. In the next cell duplication, the daughter cell that inherited two ecDNA copies will duplicate these to make four ecDNA copies, which in turn might be all four inherited by one daughter cell. In this way, when an ecDNA contains an oncogene, some cancer cells are able to accumulate multiple copies of the oncogene leading to its amplification . For a long time, oncogene amplification was the only known oncogenic driver capability of ecDNA. However, recently, new research indicates that ecDNA can also drive oncogenic genome remodelling .
Koche et al. studied patient-derived neuroblastoma cells using a combination of whole genome sequencing and Circle-sequencing, which allows for the characterizing of circular DNA and its potential presence in chromosomes . They found that most chromosomal rearrangements overlapped in sequence with ecDNA found in these cells . It is thus likely that ecDNA can also be reinserted into the genome, causing the formation of insertions at places of integration . When these insertions occur inside tumour suppressor genes, this can lead to their knockdown and subsequently allow for carcinogenesis. For example, the integration of an ecDNA into the DCLK1 tumour suppressor gene has been shown to be associated with decreased expression of DCLK1 . Furthermore, ecDNA integration may also have the potential to enhance oncogene expression. For example, ecDNA integration in a region closely located to the TERT oncogene was associated with increased TERT expression . Thus, by the formation of these insertions, ecDNA has the potential of modulating the expression of tumour suppressor genes and oncogenes, and thereby appears to be an important driver of oncogenic genome remodelling. While this has so far only been shown in neuroblastoma, many cancers have been shown to contain ecDNA, indicating that ecDNA mediated oncogenic genome remodelling may play a role in other cancers as well .
Thus, ecDNA appears to be one of the players that allows for genomic instability in cancer, which can lead to oncogene amplification and oncogenic genome remodelling. Further research into how cancer cells acquire genome instability and, subsequently, traits that drive carcinogenesis will help us get a clearer picture of how cancer develops.
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