Abstract
Structurally rearranged extrachromosomal circular DNAs (eccDNAs) have been identified in tumor cells, many of which carrying regions related to cancer-driver recurrent oncogenes (e.g. CCND1, EGFR and MYC). In a tumor cell, eccDNAs are carrying regions associated with oncogene amplification (>10-fold amplified-copy numbers in human tumors) and poor outcome across multiple cancers. Even though dual-delivery of pairs of CRISPR/Cas9 guide RNAs into human normal cells was reported to induce circularization of genes and chromosomes, but in bacteria, CRISPR-Cas9 system primarily targets extrachromosomal rearranged elements. Likewise, in cancer cells, it is expected that a designed CRISPR-Cas9 system is able to target extrachromosomal copy-number amplifications and produces double strand breaks to be detrimental to cellular fitness through dictating gene-independent copy-number loss-of-fitness (LOF) effects and anti-proliferative responses. A designed system against amplified amplicons may provide a novel approach for cancer therapy and propose a practical implication for CRISPR-Cas9 as a path in therapeutic strategies of cancer.
Significance Statement Structurally rearranged extrachromosomal circular DNAs (eccDNAs) have been identified in tumor cells. Many of eccDNAs are carrying regions related to cancer-driver recurrent oncogenes (e.g. CCND1, EGFR and MYC). It is expected that a designed CRISPR-Cas9 system is able to target extrachromosomal recurrent oncogenes.
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