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Genome-wide Purification of Extrachromosomal Circular DNA from Eukaryotic Cells
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The evolutionary dynamics of extrachromosomal DNA in human cancers

Joshua T Lange1,2, John C Rose3, Celine Y Chen4

  • 1Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.

Nature Genetics
|September 19, 2022
PubMed

Insights

Extrachromosomal DNA (ecDNA) amplification drives aggressive cancers. Random ecDNA inheritance creates significant tumor cell variation, enabling rapid adaptation and predicting poor patient outcomes.

Area of Science:

  • Cancer Biology
  • Genetics
  • Molecular Oncology

Background:

  • Oncogene amplification on extrachromosomal DNA (ecDNA) is a frequent driver of aggressive tumors, leading to drug resistance and reduced survival.
  • The mechanisms of nonchromosomal oncogene inheritance and their influence on somatic variation and selection within tumors remain poorly understood.

Purpose of the Study:

  • To investigate the impact of random ecDNA inheritance on intratumoral heterogeneity and cancer cell adaptation.
  • To elucidate how ecDNA dynamics contribute to aggressive cancer phenotypes and patient outcomes.

Main Methods:

  • Integration of theoretical models for random segregation.
  • Unbiased image analysis of ecDNA.
  • CRISPR-based ecDNA tagging combined with live-cell imaging and CRISPR-C.

Main Results:

  • Demonstrated that random ecDNA inheritance leads to extensive intratumoral ecDNA copy number heterogeneity.
  • Showcased rapid adaptation of cancer cells to metabolic stress and targeted therapies.
  • Observed that ecDNAs enhance host cell survival and can change within a single cell cycle.

Conclusions:

  • The random inheritance pattern of ecDNA significantly contributes to intratumoral heterogeneity and rapid adaptation in cancer.
  • ecDNA properties can predict aggressive cancer features and explain poor patient outcomes.
  • ecDNA facilitates rapid genomic adaptation, a mechanism distinct from chromosomal oncogene amplification.

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