How circular DNA causes cancer in children
Every year, nearly half a million people in Germany are diagnosed with cancer. Only approximately 2,100 of these cancer patients are children under the age of 18. The fact that the majority of patients are old adults is due to the mechanisms contributing to cancer development. A range of exogenous factors, including tobacco smoke and radiation, can cause damage to cellular DNA. If this type of DNA damage is left to accumulate over many years, affected cells may lose control over cell division and growth – and a tumor develops.
Children, however, are not old enough to be affected by this mechanism of cancer development. What, then, is the reason for childhood cancers? A team of researchers, led by Dr. Anton Henssen of the Experimental and Clinical Research Center (ECRC,) an institution jointly operated by Charité and the Max Delbrück Center for Molecular Medicine (MDC), and of Charité’s Department of Pediatrics, Division of Oncology and Hematology, are a large step closer to finding an answer. Working alongside Dr. Richard Koche from the Memorial Sloan Kettering Cancer Center and other international partners, the researchers were able to show that rings of DNA can cause disruption of our cells’ genetic information, which can contribute to cancer development. The results are reported in Nature Genetics.
Scientists have known about these ring-shaped sections of DNA for decades. Found inside our cells, they do not form part of our normal genetic information, which is stored in the form of chromosomes. It is for this reason that they are referred to as extrachromosomal circular DNA. But even nowadays, scientists know relatively little about their function, mainly because they have lacked technologies for a more detailed analysis of circular DNA. Now, the researchers combined state-of-the-art sequencing techniques of the MDC/ BIH Genomics Platform led by Dr. Sascha Sauer with pioneering bioinformatics algorithms to perform the first-ever detailed mapping of circular DNA in neuroblastoma, a deadly childhood tumor. Based on their findings, the researchers were able to draw important conclusions regarding the development of this type of cancer.
Thousands of rings in every sample
Working with colleagues from the Barcelona Supercomputing Center, with the group of MDC researcher Dr. Roland Schwarz (“Evolutionary and cancer genomics”) tand with the BIH platform “Translational Bioinformatics” led by Dr. Dieter Beule, the researchers analyzed neuroblastoma tissue samples from a total of 93 children. Their analysis revealed that the prevalence and diversity of circular DNA is far greater than previously anticipated. According to the researchers’ findings, each tissue sample contained on average 5,000 circular DNA copies. DNA sequencing also revealed the process by which specific DNA sections separate from a chromosome to form circular DNA before reintegrating into the chromosome at a different location.
“This can potentially cause cancer if it results in the original sequence of genetic information being disrupted,” explains Henssen, who heads an Emmy Noether Independent Junior Research Group on Campus Buch and is also a researcher at the German Cancer Consortium (DKTK) in Berlin as well as a Berlin Institute of Health (BIH) Clinician Scientist. Henssen says: “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.”
“We were also able to show that certain types of circular DNA may accelerate neuroblastoma growth,” explains Koche. “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 which 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.”
The research groups plan to conduct a follow-up study to verify the diagnostic validity of circular DNA. “We also want to conduct more detailed research into the origins of circular DNA in order to better understand why it is that children develop cancer,” says Henssen.
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Richard Koche et al. (2019): „Extrachromosomal circular DNA drives oncogenic genome remodelling“, Nature Genetics, DOI: 10.1038/s41588-019-0547-z.