Current understanding of extrachromosomal circular DNA in cancer pathogenesis and therapeutic resistance

Abstract

Extrachromosomal circular DNA was recently found to be particularly abundant in multiple human cancer cells, although its frequency varies among different tumor types. Elevated levels of extrachromosomal circular DNA have been considered an effective biomarker of cancer pathogenesis. Multiple reports have demonstrated that the amplification of oncogenes and therapeutic resistance genes located on extrachromosomal DNA is a frequent event that drives intratumoral genetic heterogeneity and provides a potential evolutionary advantage. This review highlights the current understanding of the extrachromosomal circular DNA present in the tissues and circulation of patients with advanced cancers and provides a detailed discussion of their substantial roles in tumor regulation. Confirming the presence of cancer-related extrachromosomal circular DNA would provide a putative testing strategy for the precision diagnosis and treatment of human malignancies in clinical practice.

Keywords: Biomarkers; Cancer pathogenesis; Clinical utility; Extrachromosomal circular DNA; Oncogene amplification; Therapeutic resistance.

Fig. 1

Inheritance of extrachromosomal circular DNA elements. Environmental stresses cause genomic instability and drive local chromosomal breakage. After then, the self-joining of DNA segments leads to formation of extrachromosomal circular DNA. Because of lacking centromeres, extrachromosomal circular DNA elements can be inherited unequally between daughter cells, contributing to intratumoral heterogeneity and cancer cell progression

Fig. 2

Current understanding of extrachromosomal circular DNA in cancer pathogenesis. Multiple recent studies have demonstrated the increasing importance of extrachromosomal circular DNA on oncogenic features and regulatory capacity in cancer research and treatment

Fig. 3

Models of how extrachromosomal circular DNA is formed. a In response to environmental changes, cells could repair DNA strand break through removing the damaged segments. After then, the small DNA segments could form circular DNA. b Chromothripsis is a single-step catastrophic event that drives chromosome breakage and end-to-end chromosomal fusion, and serves as the underlying driving force linked to local DNA rearrangements and extrachromosomal circular DNA. c The episomes are autonomously replicating submicroscopic precursors of extrachromosomal circular DNA. In cell, The DNA recombination processes can generate the recombinant episome that contains a segment of chromosomal DNA, such as c-Myc-containing DMs. d The BFB cycle involves anaphase bridge formation due to the presence of dicentric chromosomes, followed by bridge breakage, which generates a variety of chromosomal aberrations, including extrachromosomal circular DNA

Fig. 4

Roles of extrachromosomal circular DNA with oncogene variation in therapeutic response. After the formation of extrachromosomal circular DNA, the amplified circular DNA elements are prone to pass on oncogene variations upon amplification, such as EGFRvIII and ALEM. In response to environmental changes, cancer cells might accordingly increase or decrease the copy number of circular DNA elements containing oncogene variations, leading to anticancer therapy resistance