The patient samples showed that ecDNA can be a truncal driver of oesophageal cancer.
That had been hidden because, unlike chromosomal DNA, ecDNA isn’t split equally every time a cell copies its DNA and divides. In fact, the inheritance of this abnormal DNA is shockingly random.
One mother cell with 6 circles of ecDNA can split into one daughter cell with 12 and another with 0, one with 5 and one with 7, or any other combination. That means closely related cells can begin to look very different, very quickly. The trunk can hide among the branches.
More than that, because ecDNA can drop to undetectably low levels in some cells and then quickly start multiplying, every branch has the potential to become a trunk.
At that point, when the entire tumour can rapidly change its DNA composition, there’s not much sense in talking about trees at all.
One step ahead
This doesn’t change everything. Most cancers aren’t driven by ecDNA. But it’s a feature of many of the most aggressive and hard-to-treat tumours.
It might seem discouraging to find out that some of our most established ways of studying cancer can’t keep up with ecDNA, but Mischel is optimistic. The ground might be changing under us, but with every step forward we’re pushing back against cancer.
And this new ground could be the foundation for other breakthroughs, too. Evolutionary trees and chromosome-focused cancer maps are ways to deal with fires that are already raging, frameworks for studying things that have already been lost. Team eDyNAmiC have developed new tools that let us look forward instead.
Now we can see what ecDNA is doing and work out specific ways to stop it. And, as eDyNAmiC begin to focus on targeting ecDNAs with drugs, this new way of understanding cancer could become a way to intercept and prevent it, too.
“We’re really learning from patients,” says Mischel. “Thanks to them, our biological knowledge has jumped out ahead of our therapeutic toolkit – but the toolkit will be catching up.”
The samples eDyNAmiC used to track how ecDNA drives cancer were taken before doctors treated dysplastic Barrett’s oesophagus. That’s changed. Today, we’re much better at testing for Barrett’s oesophagus, and at stopping it becoming oesophageal cancer.
Want to find out more about our work to prevent and diagnose oesophageal cancer? Professor Rebecca Fitzgerald, a Cancer Research UK-funded researcher who took part in this study, recently featured on the BBC podcast Best Medicine, where she explained how her simple sponge-on-a-string test makes it easier to detect Barrett’s oesophagus.