Mysterious circular DNA found in more than half of patients with certain types of cancer

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 1965, but until 2017, it was considered rare and not significant.

But a major study, led by Spanish bioinformatician Oriol Pich and British scientist Chris Bailey, has 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 Nature, one 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.

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 Méndez 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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