Researchers from the Francis Crick Institute and UCL, working with Genomics England, have shown that rogue genetic material called extrachromosomal DNA (ecDNA) can drive the survival of some of the most aggressive cancers.
The new research is one of three papers published in Nature, from the Cancer Research UK-funded 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 researhcers 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 UCLH, 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.
BRC-supported Charles Swanton, who is Deputy Clinical Director and Head of the Cancer Evolution and Genome Instability Laboratory 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.”
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