2024-11-07 06:48:00
An international team of scientists has found small circular DNA particles in the cells of more than half of patients with certain types of cancer, including HER2+ breast cancer —one of the most aggressive — and glioblastoma in the brain. This free-floating genetic material has been identified since 1965but until 2017, it was considered rare and not significant.
But a major study, led by Spanish bioinformatician Oriol Pitch and British scientist Chris Baileyhas identified this circular DNA in 17% of nearly 15,000 cancer patients across 39 different types of tumors. “Its presence is associated with a worse survival rate for patients,” warns Pich, from the Francis Crick Institute in London.
The human cell’s genetic instructions are primarily contained within chromosomes. However, in 1965, scientists in the United States and the United Kingdom detected an enigmatic form of extrachromosomal circular DNA, much smaller than the DNA in chromosomes, in samples from tumor patients.
In 2017, dr. Paul Mischel’s team in the U.S. discovered that these tiny circular DNA particles encouraged cancer development. In 2022, an international consortium, led by Mischel, secured $25 million from the U.S. National Cancer Institute and Cancer Research UK to investigate this mysterious DNA further. Their latest findings were published on Wednesday in Natureone of the world’s leading scientific journals.
A person’s DNA is organized into around 20,000 segments, known as genes, each containing instructions for producing the proteins essential for life. In contrast, circular DNA molecules contain only a few genes, which are often linked to malignant tumors or the ability to evade the body’s immune defenses.
“Cancer does not have a single cause, it is multifactorial, so it is difficult to say that extrachromosomal circular DNA is the cause of cancer,” stresses the Barcelona-born scientist. “What we do know is that it is a driver of progression and a marker of poor prognosis. We know that, when there is abundant extrachromosomal circular DNA, the patient is worse off, it is correlated with a much more aggressive tumor.”
If a person has two copies of the same gene, one from their mother and one from their father, circular DNA can result in a hundred copies of a gene associated with cancer. “It’s like pouring petrol into the cell, everything goes at 500 kilometers per hour instead of the regulatory speed,” explains Pich, who has a PhD from the Barcelona Institute for Biomedical Research.
Spanish bioinformatician Oriol Pich and his British colleague Chris Bailey, at the Francis Crick Institute in London.Chris Bailey
Paul Mischel, co-author of the paper, believes that science is now entering a new phase. “This is a fundamental change in our understanding of a common and aggressive mechanism that promotes cancer,” Mischel, from Stanford University, said in a statement. In his opinion, the new results are “a turning point in how we view the onset and progression of cancer.”
Until less than a decade ago, it was thought that circular DNA only appeared in relevant quantities in 2% of tumors. The new work shows that its presence is widespread in the most aggressive cancers. Pich highlights that “in fact, the frequency of extrachromosomal circular DNA in metastases is higher than in primary tumors.” Metastasis is responsible for 90% of cancer deaths.
The international consortium, known as eDyNAmiC, has published another promising study in Nature. The researchers observed that blocking the activity of a protein called CHK1 leads to the death of tumor cells containing extrachromosomal circular DNA in laboratory settings. In mice with gastric cancer driven by circular DNA, blocking CHK1 resulted in tumor regression. The consortium is now testing an experimental treatment in human cancer patients.
Biochemist Juan Mendez studies DNA replication at the National Cancer Research Center in Madrid. “The scientific community has known for a long time that these molecules were there, but it seemed a very rare phenomenon,” he says. “In the last 10 years, with the development of new DNA sequencing and computational analysis techniques, interest has reignited, because we began to study the frequency of these molecules in cancer cells, and we have seen that the percentage is much higher,” continues the researcher, who applauds the capabilities of Oriol Pich’s laboratory, led by the British scientist Charles Swanton at the Francis Crick Institute.
Méndez, who did not participate in the new study, remains cautious about the findings. He believes that “cells with extrachromosomal circular DNA have advantages that facilitate tumor adaptation and resistance, such as a greater number of copies of oncogenes and immunomodulatory genes.” However, he adds: “It has not been sufficiently demonstrated that extrachromosomal circular DNA molecules are the originators of cancer.”
To prove this, he says complex genetic studies will be needed, involving thousands of people with pre-tumorous lesions transitioning into malignant tumors. This research will help determine whether the enigmatic circular DNA is a trigger for cancer or merely a consequence of it.
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**Interview with Oriol Pich: Unraveling the Role of Circular DNA in Cancer Progression**
**Interviewer**: Good morning, Oriol Pich! Thank you for joining us today to discuss your groundbreaking research on extrachromosomal circular DNA and its implications in cancer.
**Oriol Pich**: Good morning! It’s a pleasure to discuss our findings.
**Interviewer**: Your team found circular DNA particles in over half of patients with aggressive types of cancer like HER2+ breast cancer and glioblastoma. Can you explain why this discovery is significant?
**Oriol Pich**: Absolutely! While circular DNA was identified as early as 1965, it was long considered a rare phenomenon. Our study indicates that its presence correlates with poorer survival rates across a variety of tumors. This marks a significant shift in understanding how prevalent this type of DNA is in cancer progression.
**Interviewer**: You mentioned that while circular DNA isn’t the sole cause of cancer, it can be a driver of progression. Can you elaborate on this?
**Oriol Pich**: Certainly. Cancer is multifactorial, meaning that many factors contribute to its development. Circular DNA doesn’t cause cancer by itself, but we’ve seen that high levels of it are associated with more aggressive tumors. It essentially accelerates the growth of cancer cells.
**Interviewer**: How does circular DNA manipulate genetic information within cancer cells?
**Oriol Pich**: To put it simply, while normal human DNA contains around 20,000 genes, circular DNA can amplify certain genes—sometimes resulting in a hundred copies of a gene linked to tumor malignancy. This overabundance acts like pouring gasoline on a fire, speeding up the tumor’s growth significantly.
**Interviewer**: Your findings suggest that circular DNA is more frequent in metastatic tumors than in primary tumors. Why is this important?
**Oriol Pich**: Metastasis is responsible for 90% of cancer deaths. Our research indicates that circular DNA is not only prevalent in primary tumors but even more so in metastases. This could provide insights into why some cancers are more lethal than others and open new avenues for targeted therapies.
**Interviewer**: Paul Mischel described your research as a turning point in cancer understanding. What does this mean for future cancer treatments?
**Oriol Pich**: This acknowledgment reflects how we now recognize the importance of circular DNA as a common mechanism in cancer. Future treatments may focus on targeting the biological processes associated with this DNA, and we’re already testing experimental therapies that inhibit the activity of certain proteins linked to circular DNA in patients.
**Interviewer**: That sounds incredibly promising! What are the next steps for your research team?
**Oriol Pich**: We’re focusing on clinical trials to explore the effectiveness of new treatments aimed at blocking the activity of proteins like CHK1, which have shown potential in laboratory settings. Our goal is to translate these findings into real-world applications that can potentially improve patient outcomes.
**Interviewer**: Thank you, Oriol, for sharing these insights. It’s exciting to see how research is advancing our understanding of cancer!
**Oriol Pich**: Thank you for having me! I’m hopeful that our work will contribute to better diagnostic and therapeutic strategies for cancer patients.
