Extrachromosomal Circular DNA Drives Oncogenic Genome Remodeling in Neuroblastoma

The circularized sequences were mapped back to their original sites in the genome using additional long-read and single-molecule real-time sequences, the investigators explained, and they validated candidate DNA circles with polymerase chain reaction (PCR) and Sanger sequencing.

Together, these approaches uncovered almost 5,700 small extrachromosomal circular DNAs per tumor, on average, and an average of 0.82 large, copy number-amplified extrachromosomal circular DNA sequences. Even so, the team's follow-up analyses, including RNA sequencing experiments, indicated that rearrangements stemming from extrachromosomal circular DNA from MYCN and other genes may be a recurrent and ongoing source of new mutations through a multi-hit model in neuroblastoma.

The authors concluded that they had demonstrated that the majority of genomic rearrangements in neuroblastoma involve circular DNA, challenging the current understanding about cancer genome remodeling. They envision that their findings extend to other cancers and that further detailed analyses of circle-derived rearrangements will shed new insights into our understanding of cancer genome remodeling. The study was published on December 16, 2019 in the journal Nature Genetics.

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