Researchers explore the role of circular DNA in deadly childhood cancer

By Samantha Black, PhD, The Science Advisory Board staff writer

December 17, 2019 -- Researchers from Charité - University Medicine Berlin and the Memorial Sloan Kettering Cancer Center in New York combine genomic and transcriptomic approaches to describe the landscape of extrachromosomal circular DNA in neuroblastoma. The work was published in Nature Genetics on December 16.

These extrachromosomal circular DNA can contribute to cancer development in children. Neuroplastoma accounts for seven to ten percent of all childhood cancers with over 800 new cases each year in the United States alone. Extrachromosomal circular DNA can lead to oncogene amplification and is a powerful driver of intratumoral heterogeneity. The researchers proposed that DNA circularization could represent a genome-wide, driving mutagenic process with functional consequences beyond oncogene amplification.

Until recently, scientists have lacked the tools necessary to study extrachromosomal circular DNA. Based on their analysis the researchers were able to draw important conclusions regarding the development of the tumor. In the current research, DNA circularity was computationally inferred from genome-wide sequencing data (WGS). The researchers applied an algorithm using paired-end read orientation to detect circularity to WGS from 93 neuroblastomas paired with normal blood specimens. They applied modified circle sequencing method to endonuclease-treated gDNA to map circularized genomic regions. Sequence composition of circular DNA was analyzed using single-molecule real-time sequencing (SMRT-seq).

The analysis revealed the prevalence and diversity of circular DNA is much greater than previously thought. Each sample contained on average 5,000 circular DNA copies. Sequencing also revealed the process by which specific DNA segments separate from the chromosome to form circular DNA before reintegrating into the chromosome at different locations.

"This can potentially cause cancer if it results in the original sequence of genetic information being disrupted," explains the Emmy Noether Independent Junior Research Group's leader, Anton Henssen, who is also a researcher at the German Cancer Consortium (DKTK) in Berlin and a Berlin Institute of Health (BIH) Clinician Scientist. "The detailed processes involved had not previously been elucidated in this manner and provide insight into how even young cells, like those found in children, can transform into cancer cells."

The researchers determined that circular DNA is not restricted to oncogenes but also affects various coding and noncoding regions with unknown functional consequences. However, WGS confirms that extrachromosomal circular DNA does significantly contribute to oncogene overexpression, particularly MYCN (a gene associated with neuoblastoma). Even though DNA circularization is a major route to gene amplification, it appears insufficient alone (without combined amplification) to increase gene expression.

Given this observation, they hypothesized that circular DNA may have additional, cancer-relevant functions. Upon further investigation, the team found that circle-derived, tree-shaped rearrangement clusters are the result of chimeric circles and chromosomal circle integrations, thereby increasing the expression of proto-oncogenes.

"We were also able to show that certain types of circular DNA may accelerate neuroblastoma growth," explains Richard Koche, from Memorial Sloan Kettering Cancer Center. "Testing for their presence may, therefore, make it easier to predict the course of the disease. Additionally, 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. 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 and associated clinical outcomes."

This work represents a challenge to the current understanding of cancer genome remodeling. Further, extrachromosomally circularized DNA can actively contribute to genome remodeling with important functional and clinical consequences. The research groups plan to conduct a follow-up study to verify the diagnostic validity of circular DNA.


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