Unveiling the secrets of DNA rings: Tracing their origins and impact in cancer growth

Researchers from Charité–Universitätsmedizin Berlin and the Max Delbrück Center have made significant progress in understanding the behavior of tumors through the study of DNA rings in neuroblastoma, a type of cancer. These DNA rings, known as extrachromosomal DNA (ecDNA), have long puzzled scientists, as they detach from the chromosomes and can influence tumor growth and drug resistance.

The international research team, led by Prof. Dr. Anton Henssen, has developed a novel technique to investigate the origin and impact of these DNA rings on a cellular level. By examining individual cells within the tumor, they can analyze the genetic code of the DNA rings and determine which genes are active. This approach allows them to quantify the presence of specific rings in the tumor cells and ascertain their relevance to cancer growth.

The researchers discovered that nearly one-third of tumors in both pediatric and adult patients contain DNA rings, which are typically associated with highly aggressive cancers. Additionally, the presence of ecDNA is often linked to the development of drug resistance. However, not all DNA rings have a detrimental effect on cancer growth, as some appear to be harmless.

The ability to distinguish between dangerous and harmless DNA rings and track their evolution within the tumor is crucial for identifying potential therapeutic approaches. Through their new technology, the research team aims to gain insights into the role of ecDNA in cancer and explore novel strategies for cancer treatment.

The findings of this study have been published in the journal Nature Genetics, marking a significant advancement in cancer research and providing a foundation for further investigations into the complex behavior of tumors.

Which DNA rings spur tumor growth?

In their study of cultured neuroblastoma cells, the researchers utilized their novel method to capture a comprehensive snapshot of DNA rings. Neuroblastoma is a highly malignant cancer that primarily affects young children. The investigation revealed substantial heterogeneity among cancer cells, with the number of DNA rings varying greatly from cell to cell—ranging from as few as 100 rings to as many as 2,000. Moreover, the DNA rings exhibited significant diversity in size, with the smallest containing just 30 genetic components and the largest encompassing over a million.

According to Rocío Chamorro González, the study’s first author, who is affiliated with the Department of Pediatric Oncology and Hematology at Charité and the ECRC, the larger DNA rings carry cancer genes derived from the cell’s own chromosomes. The ring structure grants these genes a degree of independence, enabling them to evade traditional genetic regulations. This newfound autonomy has profound implications that are only beginning to be comprehended. The study observed a prevalence of large DNA rings in numerous neuroblastoma cells, indicating their involvement in promoting cell growth. Conversely, the small rings were found in isolated instances, suggesting their limited relevance to cancer cells.

These findings shed light on the behavior of DNA rings within neuroblastoma cells, underscoring their potential impact on tumor development. By unraveling the complexities of these genetic structures, researchers can advance their understanding of cancer and potentially identify targeted approaches for treatment.

Evolution of an independent cancer gene

To unravel the origin and evolution of extrachromosomal DNA (ecDNA) within tumors, the research group conducted a meticulous examination of a pediatric neuroblastoma at the cellular level. Their analysis revealed that the MYCN gene, a well-known cancer gene, initially detached from its original chromosome and formed a ring-shaped ecDNA during the early stages of tumor growth in this particular case. Subsequently, two rings merged to create a larger one, which underwent further modifications by losing shorter and longer segments.

The researchers observed that the final ring, which appeared in a significant number of neuroblastoma cells, conferred a growth advantage. This indicates that the cancer gene not only gained independence through these processes but also underwent subsequent improvements to enhance its impact.

The ability to trace the evolutionary journey of ecDNA within a tumor was made possible by the newly developed method. Moving forward, the research team intends to employ the same technique to reconstruct the developmental stages in other instances of cancer. This approach will enable a better distinction between dangerous and harmless DNA rings.

The researchers envision a future where, based on the presence and characteristics of DNA rings, they can determine the aggressiveness of a tumor on an individual basis. This knowledge could then inform tailored treatment approaches. Thus, the next step for the research is to evaluate the predictive power of specific DNA rings and assess their potential as markers for guiding cancer therapy.

Overall, the findings of this study provide valuable insights into the evolutionary dynamics of DNA rings within tumors and offer the potential for more precise diagnostics and personalized treatment strategies in the future.

Source: Charité - Universitätsmedizin Berlin

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