4th December 2024 (16 Topics)
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Extrachromosomal DNA (ecDNA)
Context
Extrachromosomal DNA (ecDNA), a small fragment of genetic material found outside the main chromosomes in cells, has gained significant attention in cancer biology. Discovered about 50 years ago but initially overlooked due to its rarity, recent research has highlighted its crucial role in cancer development and drug resistance.
What is ecDNA?
- Normally, human cells contain 23 pairs of chromosomes that store our genetic information.
- However, during certain types of cancer, damage to these chromosomes can result in pieces of DNA breaking off and forming small circular structures.
- These fragments are called ecDNA and float freely within the nucleus of the cell.
- Recent Findings: Researchers investigated how ecDNA contributes to cancer growth and resistance to treatment. They discovered that:
- ecDNA in Cancer: EcDNA is present in 17% of tumor samples, with higher prevalence in cancers like liposarcoma, brain tumors, and breast cancer. Interestingly, the presence of ecDNA increases after chemotherapy and is linked to cancer spread (metastasis) and poorer patient outcomes.
- ecDNA and Tumor Growth: EcDNA often carries multiple copies of oncogenes, genes that drive cancer growth. Unlike normal chromosomal DNA, ecDNA is free to move and interact with other ecDNA, forming hubs that significantly increase the activity of oncogenes. This boosts cancer cell growth and accelerates tumor evolution.
- Mendel’s Law Challenged: Normally, when cells divide, genetic material is passed on randomly, as per Mendel’s third law of independent assortment. However, ecDNA doesn’t follow this rule. During cell division, ecDNA is clustered together and passed to daughter cells as a unit. This process, called the “jackpot effect,” allows cancer cells to retain advantageous genetic combinations, making them more resilient and capable of growing more aggressively.
- Vulnerability in Cancer Cells with ecDNA: While ecDNA presents new challenges, it also creates potential weaknesses. The unusual structure and high activity of ecDNA lead to conflicts in the cell's machinery responsible for making RNA, resulting in DNA damage. The cancer cells rely heavily on a protein called CHK1 to repair this damage. When researchers used a drug that blocks CHK1 (BBI-2779), they observed a reduction in tumor growth in mice, particularly in stomach cancer cells containing ecDNA. This suggests that targeting CHK1 could be a new way to treat cancers driven by ecDNA.
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