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Extrachromosomal DNA
Context:
Recent studies have revealed that extrachromosomal DNA (ecDNA) is present in up to 40% of cancer cell lines and 90% of patient-derived brain tumour samples, highlighting its importance in cancer biology.
More on News:
Published in the journal Nature by the eDyNAmiC team, these studies have shown that ecDNA challenges a fundamental law of genetics and plays a crucial role in cancer progression and drug resistance.
Key Findings:
- Prevalence of ecDNA: In a study involving 15,000 cancer patients (from the U.K.’s 100,000 Genomes Project), ecDNA was found in 17% of tumour samples, more prominently in liposarcomas, brain tumours, and breast cancers.
- Its prevalence increased post-chemotherapy and correlated with metastasis and poorer outcomes.
- ecDNA and Cancer Growth: EcDNA often contains multiple copies of oncogenes, genes that drive cancer growth. These oncogenes are more active in ecDNA than in chromosomes, accelerating tumour growth and drug resistance.
What is ecDNA?
- Extrachromosomal DNA was first identified 50 years ago as small fragments in cancer cells, initially thought to be unimportant because it appeared in only 1.4% of tumours.
- Formation: EcDNA forms when DNA breaks away from chromosomes due to processes like chromothripsis or replication errors, creating circular structures that float in the nucleus.
- A study identified environmental factors (smoking, exposure to certain substances) and genetic mutations as triggers for ecDNA formation.
Challenging Mendel’s Law:
- Traditionally, scientists have understood that genes located on the same chromosome are inherited together, while those on different chromosomes are distributed independently. This is known as Mendel’s third law of independent assortment.
- However, the study revealed that ecDNA behaves differently during cell division.
- Instead of being randomly distributed, ecDNA clusters together and is passed on to daughter cells as a group.
- This clustering, referred to as the “jackpot effect,” allows cancer cells to enhance gene interactions and preserve favourable genetic combinations across multiple cell generations.
- Instead of being randomly distributed, ecDNA clusters together and is passed on to daughter cells as a group.
- This discovery overturns the assumption that gene inheritance is random when genes are located on different chromosomes, providing cancer cells with an evolutionary advantage.
Implications for Cancer Treatment:
- Understanding how ecDNA contributes to tumour growth and drug resistance can lead to the development of targeted therapies that specifically address these mechanisms.
- Boundless Bio, a biotech company is working on translating these findings into clinical treatments to target ecDNA vulnerabilities, especially for cancers like glioblastoma, ovarian, and lung cancers, where existing treatments often fail.
