DNA Circles Reveal Important Implications for Gene Regulation and Clinical Outcomes in Neuroblastoma

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Researchers from Memorial Sloan Kettering Cancer Center (MSK), in collaboration with an international research team, have discovered that DNA circles can contribute to the development of childhood cancers. The team, led by MSK computational biologist Richard Koche and Anton Henssen of Charité University Hospital Berlin, made this discovery by studying extrachromosomal DNA in neuroblastoma cells. Neuroblastoma develops in immature nerve cells and is the most common form of cancer in infants.

Bottom Line: Childhood tumors can provide a good model for studying genetic questions because they have acquired fewer mutations than adult tumors, so there is less background noise muddling the genomic picture.

The scientists analyzed neuroblastoma tissue samples from 93 children. They combined advanced sequencing techniques with pioneering bioinformatics algorithms to construct a detailed genomic map of the circular DNA. The circular DNA was surprisingly pervasive, with each neuroblastoma cell containing an average of 5,000 rings. The sequencing revealed the process by which specific DNA sections separate from a chromosome to form the circles before reintegrating into the chromosome at a different location.

Findings: Researchers found that DNA sections can separate from chromosomes to form circles that later reinsert themselves into the chromosomes at a different location. This disrupts the orderly sequence of genetic information and causes things to go haywire, as in, for example, the runaway growth that leads to cancer. This new study could provide important clues to the causes of other cancers, including adult cancers. The research group plans to conduct follow-up studies to investigate this idea.

Journal: “Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma,” appears in the December 16, 2019, issue of Nature Genetics

Expert Commentary: “We were able to show that certain types of circular DNA may lead to worse clinical outcomes,” Dr. Koche explained. “Testing for their presence may make it easier to predict the course of the disease.

“This challenges the conventional understanding of how these DNA circles affect the genome and contribute to cancer, especially childhood cancers,” Dr. Koche continued. “We were surprised at the extent to which the circular DNA is reintegrating into chromosomes and having profound effects on genetic function.

“Studying this process in the relatively quiet genomes of these pediatric tumors may help illuminate similar mechanisms that were previously missed in more complex adult cancers,” he added. “Given the recent interest in circular DNA in a variety of normal and disease contexts, the current study may have implications for a broad range of tumor types.”