“Rewrite the textbooks”: Circular RNA we make ourselves can trigger cancers

An unusual genetic quirk has been found as a cause of critical genetic mutations that could eventually lead to the onset of cancer and other diseases.

And it’s not something related to the outside world, nor perhaps inherited from one’s parents. Instead, it’s a problem that simply happens within the cells of all life – from humans to our animal, plant and fungal cousins, and even among single-celled organisms.

The culprit? A sticky form of ribonucleic acid – or RNA – the essential molecule that reads our DNA and begins the process of creating the proteins our body needs to function.

RNA normally exists as a single helix – a curly, singular strand of nitrogenous bases which transcribe and translate the genetic information encoded by DNA.

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Sometimes, two ends of these RNA strands bond together, forming a circular RNA (or ‘circRNA’) structure that can stick to – and sever – cellular DNA strands, alter their location within cells and fuse severed genetic fragments together.

A study published today in the highly respected oncological journal Cancer Cell has attributed cases of acute myeloid leukemia during infancy to the abundance of circRNA molecules in their neonatal blood tests, more so than children who did not go on to develop cancer.

The elevated presence of certain circRNA at about 100 times the baseline level, acts as a biomarker for cancer development.

“Circular RNA is a very sophisticated molecule,” says Professor Simon Conn, the head of Circular RNA research in Flinders University’s cancer laboratory, who is the senior author of the research.

In contrast to its typical, helical form, Conn describes circRNA as “superpowered” – an incredibly stable molecule with a long half-life, meaning it takes far longer to degrade. It also enables it to stubbornly bind with cell structures and particular segments of DNA.

When DNA is severed, the cell attempts to correct the error by reattaching fragments together. The involvement of circRNA can disrupt the process.

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“You’re getting breaks in the DNA at different spots throughout our genome and these are brought into closer proximity – genes that are not normally anywhere near each other actually become closer together,” Conn says.

“Then the repair actually involves sticking these two different genes together. That’s what actually drives the cancer itself.”

Not all circRNAs are cancer-causing, some have been found to have beneficial effects, and with hundreds of thousands of known circRNAs on record, it’s likely the vast majority are benign. But a subset of these genetic loops has the potential to cause disease.

That’s not just cancer either, some circRNA have been found in association with other disease-causing genetic mutations.  

Further research into why this happens is needed. Conn believes a bodily mechanism directs certain genes to produce circRNA – some don’t make it; others make substantial amounts. They describe the phenomenon as endogenous RNA-directed DNA damage – or ER3D – and expect it to now be considered among inherited and environmental causes of genetic mutation.

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“This phenomenon, we really believe has to actually result in textbooks being rewritten in terms of causes of mutations,” Conn says.

“It actually opens up a lot of potential for not only understanding how they arise, but then also intervening, and treating a range of diseases.”

It is hoped that identifying the presence of elevated circRNA as a cancer biomarker will enable precise molecule-targeting tests for individual human blood samples in clinical settings.

An extension of the research could also result in therapeutics that target the molecules – not dissimilar to antiviral treatments that dismantle pathogens like the SARS-CoV-2 virus.

“Strategies to destroy the RNA itself [could] be actually used as a treatment, to stop the cancer before it develops,” Conn says.

“But absolutely, we would need to know people had this high level [of circRNA] and that’s not very cheap. We wouldn’t necessarily suggest it would be a population screening type approach.”