ecDNA: A New Challenge to the Law of Genetics

Sub : Sci

Sec : Biotech

Why in News

Recent groundbreaking studies published in Nature by an international collaboration, eDyNAmiC, led by Stanford University, have revealed critical insights into extrachromosomal DNA (ecDNA). These findings not only challenge the foundational laws of genetics but also shed light on ecDNA’s significant role in cancer progression, metastasis, and drug resistance.

What is extrachromosomal DNA (ecDNA)?

ecDNA refers to small, circular fragments of genetic material that are separate from chromosomal DNA and float freely within the nucleus.
DNA damage from processes like chromothripsis (chromosomal breakage and rearrangement) or replication errors can cause fragments to break away from chromosomes.
These fragments form ecDNA, often enriched with oncogenes.
Initially dismissed as insignificant, ecDNA was identified 50 years ago in only 1.4% of tumours.
Advances in genomic techniques have since revealed that ecDNA is present in 40% of cancer cell lines and up to 90% of brain tumour samples, underscoring its pivotal role in cancer biology.

Role of ecDNA in Cancer Progression

ecDNA often contains multiple copies of oncogenes, promoting tumour growth and drug resistance.
Unlike chromosomal DNA, ecDNA moves freely, forming hubs where oncogene expression is amplified.
A 2021 study found that ecDNA transcription to mRNA results in oncogene overexpression, accelerating tumour evolution and drug resistance.

Violation of Mendel’s Laws

Unlike chromosomal genes, ecDNA is passed on in clusters during cell division, ensuring coordinated inheritance.
This phenomenon, termed the “jackpot effect”, enhances gene interactions and supports cancer cell survival.

Vulnerability in Cancer Cells

The unique structure of ecDNA and its interactions create stress on cellular machinery, causing DNA damage.
Cancer cells heavily rely on CHK1 protein to repair this damage.
Using a drug called BBI-2779 to block CHK1 selectively killed ecDNA-dependent cancer cells in mice, significantly reducing tumour size.

Way Forward

Improved Diagnostic Techniques: Use advanced methods like fluorescence in-situ hybridization (FISH) for better detection of ecDNA in tumours.
- Fluorescence In Situ Hybridization (FISH): Involves labelling DNA probes with fluorescent dyes to locate specific genes on chromosomes.
Targeted Therapies: Focus on disrupting ecDNA formation and oncogene hubs. Explore CHK1 inhibitors for clinical use.
Collaborative Research: Strengthen international collaborations to accelerate discoveries.