Extrachromosomal DNA (ecDNA)

Context

Recent research has highlighted the presence and role of extrachromosomal DNA (ecDNA) in approximately 50% of cancer types, emphasizing its significance in tumour evolution, genetic heterogeneity, and cancer progression.

What is ecDNA?

• Definition: Circular DNA fragments located outside the chromosomes but within the nucleus of cancer cells.
• Function: Contains amplified oncogenes, forming hubs that enhance oncogene expression and accelerate tumour growth.
• Formation:
  • Arises due to DNA damage, chromosomal rearrangements, or replication errors.
  • Can result from environmental factors like smoking, exposure to carcinogens, or inherent genetic mutations.

Historical Discovery and Evolution

• First identified in cancer cells 50 years ago, initially deemed insignificant due to its low prevalence (~1.4% of tumours).
• Recent genomic advancements revealed a broader presence:
  • Found in 40% of cancer cell lines.
  • Present in up to 90% of patient-derived brain tumour samples.
  • Observed in 17% of tumour samples, particularly prevalent in liposarcomas, brain tumours, and breast cancers.

Violation of Mendel’s Law

• Mendel’s Law of Independent Assortment: Genes on different chromosomes are inherited independently and randomly passed to offspring.
• ecDNA Anomaly:
  • Groups genes into clusters and transmits them collectively during cell division, defying Mendel’s principle.

Significance of ecDNA in Cancer

1. Tumour Evolution:
   • Drives rapid cancer progression through amplified oncogene expression.
2. Genetic Heterogeneity:
   • Contributes to diverse genetic profiles within tumours, complicating treatment.
3. Potential as a Biomarker:
   • Identifying ecDNA presence could aid in cancer diagnosis and prognosis.
4. Therapeutic Targeting:
   • Interrupting ecDNA function offers a potential pathway for innovative cancer therapies.