A poorly known type of circular DNA affects childhood cancer

Next steps involve the detailed analysis of these circular DNA in neuroblastoma patients to determine the levels of genomic damage and develop more efficient prevention and therapy protocols

A large number of studies in biomedicine have already demonstrated that the appearance of cancer is related to the progressive accumulation of defects in the genome, leading cells to grow without any control and generating tumors. Despite the incidence of cancer is higher among aged population, childhood cancer is also an important clinical and social burden. Among childhood-related tumors, Neuroblastoma is one of the most prevalent ones, causing up to 15% of child deaths in oncology. With the aim of uncover the mechanisms behind this tumor type and to generate new opportunities for therapies, an international collaborative effort including teams from the Barcelona Supercomputing Center, Charité – Faculty of Medicine in Berlin and the Memorial Sloan Kettering Cancer Center in Nueva York, have demonstrated that there is a relationship between a type of circular DNA, very rarely studied by scientists, and the biology of childhood cancer. These scientists have generated the first genetic map that includes circular DNA, and have answered questions that have remained unsolved for a long time. This study is published on Monday 16 December in Nature Genetics.

The accumulation of mutations in the genome and the progressive impairment of DNA repair mechanisms within cells, are the underlying mechanism behind the offset of tumors. Many external factors, such as smoking or UV light, harm our DNA, in a way that affected cells can lose control over their growth and become tumors. Efforts in research, targeting the understanding of the cellular processes involved in the offset and progression of tumors, have centered their attention on the changes taking place in the genome, that is, across all chromosomes. Despite these studies have provided (and are providing) important advances in the diagnosis and treatment of a large number of tumors, many important and central questions about the biology of tumors remain unsolved. In childhood cancer, and in particular in Neuroblastoma, one of the most prevalent tumors among infants, still many basic questions await answers, not only about the first genomic alterations that drive tumoral processes, but also about the factors that determine the evolution and aggressivity of the tumors. In this direction, an international team of scientists, including researchers of the Barcelona Supercomputing Center (BSC), David Torrents, Elias Rodriguez-Fos and Montserrat Puiggròs, together with other researchers of the Charité and Max-Delbrück-Center for Molecular Medicine in Berlin, and the Memorial Sloan Kettering Cancer Center in New York, have made an important scientific contribution by demonstrating the role of circular DNA in the development and progression of Neuroblastoma.

For decades, scientists have known of the existence of small fragments of DNA within the cells, independent of the chromosomal DNA, which confers the genome. Due to many technical challenges associated to the study of this circular DNA, it has been ignored by most molecular and biomedical studies, keeping its role in the basic biology of the cell unknown. In a study published today by the prestigious journal Nature Genetics, scientists have developed new laboratory and bioinformatic techniques that allow the isolation, sequencing and analysis of circular DNA. After applying these techniques to 93 Neuroblastoma samples and to different cell lines, scientists have been able to generate a highly detailed map of circular DNA (circulome) within these cells, counting an average of 5000 circles per sample. Furthermore, this study also describes a cyclic mechanism within Neuroblastoma cells, that starts with the formation of these circular DNA from the copy of chromosomal DNA, to end up reintegrating somewhere back in the genome, affecting different genes that are key for the normal functions of the cells. Finally, this study also demonstrates how patients with more genomic damage generated by these DNA rings are associated with more aggressive and lethal tumors. In this sense, Dr. Henssen, from the Charité and Max-Delbrück-Center for Molecular Medicine a researcher of the says: “The detailed processes involved had not previously been elucidated in this manner and provides insight into how even young cells, like those in children, can transform into cancer cells.”

“These results describe for the first time a map of circular DNA within Neuroblastoma, and opens the door to answering similar questions in other tumor types. All cellular processes behind cancer are very complex and their study requires different combined research strategies” says David Torrents, ICREA Research Professor and leader of the Computational Genomics group at the BSC. Next steps involve the detailed analysis of these circular DNA in neuroblastoma patients to determine the levels of genomic damage and develop more efficient prevention and therapy protocols.