These circular fragments of DNA can increase tumour spread, boost the activity of cancer-driving genes and block the immune system from fighting back.

The new research is one of three papers published in Nature, from the eDyNAmiC Cancer Grand Challenges team, showing that ecDNA is linked to shorter patient survival and could represent a new treatment target.

Our DNA is usually stored within structures called chromosomes but, in cancer, tiny circles of rogue genetic material called ecDNA can exist outside of the chromosome. These runaway particles carry important cancer-driving genes and don’t follow the same rules as chromosomal DNA, allowing cancer cells to adapt quickly, evade treatments and grow uncontrollably.

The London research team analysed Genomics England data from nearly 15,000 people with one of 39 different types of cancer, finding that over 17% of the samples contained ecDNA, with the highest rates seen in sarcomas, glioblastoma and a type of breast cancer.

By profiling ecDNA genes, they found that many functioned to promote cancer-driving genes, and others modified the immune system by depleting immune T cells that would normally attack a tumour.

The team also identified ‘genetic flags’ in the main set of DNA, such as a marker for damage caused by smoking, which correlated with the presence of ecDNA.

By analysing the patient clinical data associated with the tumour samples, they found that ecDNA was associated with shorter survival across all cancer types. The researchers hope that identifying and targeting vulnerabilities in ecDNA could stop tumours from evolving and becoming resistant to treatment.

Their next steps are to determine which paths lead to the development of ecDNA and how this process can be targeted at the earliest stage.

Chris Bailey, first author and clinician scientist at the Crick and University College London Hospital, said:

These rogue pieces of DNA create even more genetic variation within a tumour, something that we know is associated with cancer spread and resistance to treatment.

If we could target ecDNA specifically, we might be able to boost response to standard cancer therapies. Our work has opened up new questions, such as how ecDNA forms in the first place, and when would be best to target it.

Charlie Swanton, Deputy Clinical Director and Head of the Cancer Evolution and Genome Instability lab at the Crick, medical oncologist at University College London Hospitals, Chair in Personalised Cancer Medicine at the UCL Cancer Institute, Chief Investigator for TRACERx, and senior author of the study, said: 

Our understanding of ecDNA is a step forward in building a complete picture of the complex biology of cancer. These circles of rogue DNA are a unique way for the tumour to hide from the immune system and evolve resistance to treatment. 

Now that we’ve now identified tumour types more likely to have ecDNA, we can work to target the ecDNA, with the aim of trying to improve response to cancer therapies.

How to take advantage of ecDNA’s vulnerabilities

Chris is part of Team eDyNAmiC, led by Paul Mischel at Stanford University.

Through Cancer Grand Challenges, team eDyNAmiC is funded by Cancer Research UK and the National Cancer Institute, with generous support to Cancer Research UK from Emerson Collective and The Kamini and Vindi Banga Family Trust.

Also published today in Nature, the Stanford researchers have characterised ecDNAs unique biological properties. It has an open structure to give easy access for cell machinery to read the DNA and produce proteins; some ecDNAs can be passed down to new cells together, breaking the usual rules of genetic inheritance; and it contains genes that only exist to promote the activity of other cancer genes.

ecDNA’s unique biology is clearly advantageous for the tumours but at the same time, presents a clear target. The Stanford researchers identified a drug, developed by biotechnology company Boundless Bio, that specifically kills ecDNA-containing cancer cells, by targeting a protein called CHK1, which helps ecDNA to copy its genetic information.

In tests with mice, the drug effectively reduced tumour growth and prevented resistance to another cancer drug. Boundless Bio is now continuing this research in humans.

eDyNAmiC team lead and Professor of Pathology at Stanford Medicine, Paul Mischel, said: 

We thought we understood the structure of cancer genomes, but in fact, something very important was missing. The discovery of extrachromosomal DNA, just how common it really is, and what it actually does, reveals a new layer of complexity in cancer evolution.

It not only facilitates rapid genetic changes but also highlights the cunning strategies cancer cells use to evade treatment, suppress the immune system, and survive. Understanding ecDNA is crucial for developing innovative therapies that can outsmart these relentless adversaries. We hope that these discoveries will yield benefit for patients with the most aggressive forms of cancer.

​​​​​​Read the three papers: origins and impact of ecDNA, the unique biology of ecDNA and the first ecDNA-targeting drug.