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Extrachromosomal DNA: The discovery of the leading cause of cancer

Written by Naphat Permpredanun '24

Edited by Jacqueline Cho '24

Figure 1: Human mitochondrial DNA showing the 37 genes

(Source: Emmanuel Douzery)


Cancer research is a popular topic in medicine due to the complexity and fatality of the disease. According to the National Cancer Institute, "an estimated 609,360 people will die of cancer in the United States, and roughly 1.9 million people will be diagnosed with cancer in the United States." Moreover, cancer cells, which emerge from the accumulation of damaged cells that can be cancerous, can evade our immune system or suppress critical elements of the usual immune response. This suppression lessens patients' resistance to infection and other diseases, creating more problems in treating the symptoms of cancers and their complications. Researchers attempting to find the root cause of cancer at the genetic level have identified a putative structure that may cause cancers called “extrachromosomal DNA” (ecDNA) in cancer cells.


ecDNA is a circular DNA molecule that exists widely in nature and is independent of conventional chromosomes. In eukaryotes, such as humans, ecDNA can usually be found in organelles like mitochondria for cell division. Cancer cells contain these ecDNAs, which amplify themselves within the body and invade the immune system, thereby affecting body function. These ecDNAs are called “oncogenes,” or genes that could potentially cause cancer.

Since researchers find ecDNA as a cause of cancer, they decide to find the simple solution to stop them from spreading. One prominent example is using tumor suppressor genes. These genes encode a protein that regulates cell division, keeping it in check. When a mutation inactivates a tumor suppressor gene, the protein it encodes is not produced or does not function properly. This approach, however, does not apply to oncogenes since when the cancer cells emerge, these suppressors lose their function.


With all simple solutions are invalid, researchers change their approach from proposing the solution directly to finding the impact from ecDNA and solving them accordingly. However the problem that they found is that “the impact of nonchromosomal oncogene inheritance—random identity by descent—is poorly understood. Also [the impact of ecDNA on somatic variation and selection is unclear]” (Joshua, 2019). Therefore, finding the true impact of ecDNA in cancer was the circulated topics within the medical field at the moment. However, with a recent technologies, the impact of ecDNA, specifically why ecDNA amplification is resistant to the suppressors p53, is defined more clearer. This article will discuss three plausible reasons: [1] random segregation of ecDNA in human cancer cells, [2] intratumoral heterogeneity, and [3] rapid tumor adaptation to stress.


The first notion, which is random segregation, occurs when chromosomes segregate during mitotic cell division, ensuring that each daughter cell has the same DNA content, as shown in Figure 2a. Researchers hypothesize that random segregation also exists in cancer cells and it causes a rapid expansion of the cells. They applied the process of using fluorescent reporter molecules to attach the annealing DNA called FISH method. This methodology allows researchers to follow the division of DNA or RNA under fluorescence microscopy. The result shows that cancer cell lines of different histological types carry different oncogenes on ecDNA, which shows the complexity of treating cancers since the patterns of genes and their segregation are random.

Figure 2 : (Left) The Chromosome Segregation, (Middle) The Gaussian Distribution, (Right) Investigation of the Random segregation using Fluorescence In Situ Hybridization (FISH)

(Source: https://www.nature.com/articles/s41588-022-01177-x)


Another notion on investigating cancers is intratumoral heterogeneity. Intratumoral heterogeneity is “a term that describes the differences between tumors of the same type in different patients, the differences between cancer cells within a single tumor, or the differences between a primary (original) tumor and a secondary tumor” (National Institutes of Health). This plays a significant role in therapy resistance and tumor evolution by evolving the gene structure to be much more complex and more easily adaptable to medicine used in treatment. Researchers claim that this property comes from random segregation using mathematical models as an explanation. They generate the simulation of the tumor using randomly determined computer simulations to check the number of ecDNA that one cell carries. Consequently, the research shows an extreme cell-to-cell difference in each cell, ranging from around 10 to 100.


The final investigation is the rapid tumor adaptation to stress. From the two previous characteristics, researchers have shown that ecDNA contributes to the three pillars of Darwinian evolution: inheritance, variation, and selection. They interrogated whether these ecDNA features enabled more rapid tumor adaptation to stress than possible through chromosomal inheritance. This investigation utilized one of the tumor lines called glioblastoma, composed of GBR39-EC, the cancerous type, and GBR39-HSC, the standard type. These two tumors were tested in extreme environments, such as concentrated glucose treatment, to see the changes in cell growth. While the standard type was sensitive to the glucose solution such that it takes several cell cycles for them to recover their growth rate, the cancerous type took only two cell cycles to recover. This is of considerable concern for researchers since new medicine must be made to continuously regulate cancer growth. It will also become more challenging if the cancerous cells have the opportunity to proliferate throughout the human body.


New genetics and computer science technologies discover three impacts from Extrachromosomal DNA that make the oncogene dangerous: random segregation, intratumoral heterogeneity, and rapid tumor adaptation to stress. With these findings, researchers could develop more tactical solutions regarding the elimination of cancers. For example, knowing the idea of random segregation, researchers could try finding a cure that could deviate based on the resulting gene, which could make the majority of spread slows down, etc.

 

References

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Shakoori AR. Fluorescence in situ hybridization (FISH) and its applications [Internet]. Bhat TA, Wani AA, editors. Chromosome Structure and Aberrations. U.S. National Library of Medicine; 2017 [cited 2022Oct30]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122835/


Verhaak RGW, Bafna V, Mischel PS. Extrachromosomal oncogene amplification in tumor pathogenesis and evolution [Internet]. Nature News. Nature Publishing Group; 2019 [cited 2022Oct30]. Available from: https://www.nature.com/articles/s41568-019-0128-6


What is cancer? [Internet]. National Cancer Institute. [cited 2022Oct30]. Available from: https://www.cancer.gov/about-cancer/understanding/what-is-cancer



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