Context: Extrachromosomal DNA (ecDNA) is now taking centerstage in the complex field of cancer biology. Recent research studies explore how ecDNA is formed and it contributes to the progression of cancer and drug resistance.
Relevance of the Topic: Prelims- Extrachromosomal DNA (ecDNA); Mitochondria (mtDNA); Cell-free DNA.
Background: Basics of Cell and DNA
- Each cell in the human body has 23 pairs of chromosomes (46 total chromosomes). Chromosomes are thread-like structures found in the nucleus of cells and are made up of DNA and proteins.
- DNA (deoxyribonucleic acid) is a molecule present in the nucleus of a cell that carries genetic information in the form of genes. Genes encode a complete set of instructions for building and maintaining an organism.
- Majority of DNA is found in the chromosomes (nuclear DNA), however, DNA can also be found as:
- extrachromosomal DNA (ecDNA)
- mitochondria (mtDNA)
- cell-free DNA (cfDNA)
What is extrachromosomal DNA (ecDNA)?
- Extrachromosomal DNA (ecDNA) is any DNA that is found off the chromosomes (either inside or outside the nucleus of a cell).
- Formation of ecDNA:
- There are some natural processes that can damage DNA. For example, in some cancers, chromothripsis occurs (the chromosomes are broken and rearranged). Cells can also make mistakes when making new copies of DNA.
- Such processes could cause a small part of the DNA to break away from the main chromosome and form a circular structure that floats freely inside the nucleus. This is ecDNA.
New Research related to ecDNA:
- Early observation: ecDNA was discovered in cancer cells around 50 years ago. At that time, it was believed to be present in only 1.4% of tumours, and so was ignored.
- Later observations: More sophisticated genomic techniques later revealed that ecDNA is present in nearly 40% of cancer cell lines and in up to 90% in patient-derived brain tumour samples, revealing its pivotal role in cancer biology.
- ecDNA and Cancer growth: (Gist: ecDNA may amplify oncogene expression and thus, lead to higher prevalence of Cancer)
- ecDNA present in tumours often contains multiple copies of oncogenes (mutated genes capable of causing cancer) that are required to activate tumour growth.
- Unlike chromosomal DNA (which is fixed), ecDNA moves freely and can interact with other ecDNA to form hubs (concentrated zones where oncogenes are highly expressed).
- During the transcription process (when cells transcribe ecDNA to mRNA), ecDNA amplifies oncogene expression, making certain oncogenes become four-times more abundant in the cell, than if the DNA came from the chromosomes.
- This anomaly can cause rapid evolution of tumours, onset & spread of cancer and cause drug-resistance.
- Additionally, the prevalence of ecDNA rose after treatments like chemotherapy and could lead to cancer relapse.
1. Cell-free DNA:
- Cell-free DNA (cfDNA) are the fragments of DNA found in bodily fluids (such as blood, urine, saliva, and cerebrospinal fluid).
- They are released into the bloodstream by cells that underwent programmed cell death or an unplanned cell death (due to any injury or disease).
- These degraded (non-functional) fragments of nucleic acids do not possess the ability to replicate or carry out cellular processes.
- However, cfDNA can carry genetic information from the cells they originated from, making them a valuable source for various applications.
Important applications of cfDNA:
- Non-invasive prenatal testing to screen for chromosomal abnormalities in a developing foetus like Down syndrome, Edwards syndrome etc.
- Aid in early-cancer detection by providing information about genetic mutations and alterations present in tumour cells.
- Aid in diagnosis of infectious diseases and in forensics.
- Used as a biomarker for neurological disorders like Alzheimer’s disease etc.
- Provide an early indication of graft rejection in patients who underwent organ transplants.
2. Mitochondrial DNA (mtDNA):
- Some DNA is also present in the mitochondria (mtDNA).
- Mitochondria are cellular organelles found in the cytoplasm.
- They are called powerhouse of the cell as they generate most of the cell's energy currency- ATP (adenosine triphosphate).
- In humans, mtDNA is circular and much smaller (about 16,500 base pairs) compared to nuclear DNA.
- mtDNA codes for a small number of genes, essential for the proper functioning of mitochondria.
- Inheritance: mtDNA is inherited almost exclusively from the mother. (Nuclear DNA comes from both parents)
- Mitochondrial DNA is more prone to mutations compared to nuclear DNA as it is exposed to free radicals generated during energy production, which can damage DNA.
- When Mitochondria are impaired they do not produce sufficient energy. It causes inherited conditions like heart problems, liver failure, brain disorders, blindness and muscular dystrophy. There is no cure for mitochondrial DNA diseases at present.
- Mitochondrial Donation Treatment (three parent baby): Mitochondrial donation involves replacing unhealthy mitochondria in the mother with healthy mitochondria from a donor through in-vitro fertilisation (IVF). This would avoid passing faulty mitochondria to the child.