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Temozolomide is the international standard of care for glioblastoma, a hard-to-treat brain tumour.

When fluids move around our body, molecules from nearby cells bathed in these fluids can get swept up and carried away. Researchers are betting that some of these molecules offer clues about disease.

Blood is one of the hottest fluids in research right now, particularly for cancer. This is because the blood offers a rich source of information that can be accessed in a relatively non-invasive way. Rogue cancer cells or tumour DNA can be fished from a patient’s blood to help doctors to learn more about the disease.

But to develop tests that detect molecules like tumour DNA, scientists need to know what to look for. And with around 9 to 12 pints of blood flowing around the average adult, rare pieces of tumour DNA can be hard to find.

That’s why our brain tumour scientists in Cambridge have turned to fishing for clues in another liquid that surrounds the brain and spinal cord, the cerebral spinal fluid (CSF). And in a new study, published in EMBO Molecular Medicine, they’ve uncovered signs of brain tumours in the CSF that could get them one step closer to developing a liquid biopsy for these diseases.

What is a liquid biopsy?

A test that analyses tumour DNA, cancer cells or other molecules fished from different liquid-based patient samples, such as the blood. These experimental tests can help doctors learn more about their patient’s cancer in a less invasive way.

Knowing where to look

“The main challenge for detecting any circulating tumour DNA is filtering the information in the blood circulation from all the other cells in the body that are also dying,” says Dr Florent Moulière, from the Cancer Research UK Cambridge Institute who co-led the study.

What is circulating tumour DNA?

Like healthy cells, tumour cells go through a cycle of growing, dividing and dying. When they die they spill out bits of broken DNA. These DNA fragments sometimes enter nearby bodily fluids, such as the blood or CSF, and float around freely.

The CSF, however, feeds directly into the brain and, depending on where the brain tumour is, can directly contact the tumour.

“In the brain the background noise from all the normal cells is much lower than that in the blood, because brain cells aren’t dividing at the same rate as cells in the rest of the body,” says Moulière.

So the CSF seemed like a good place to start the hunt for brain tumour DNA.

Fishing for brain tumour DNA

The team looked at CSF samples from 13 patients with aggressive brain tumours.

What we tried to do was identify patterns or marks within DNA that say: ‘This is from the tumour’.

– Richard Mair, co-lead author

They looked for fragments of tumour DNA floating free in the CSF.

Previous research suggests fragments released from tumours are smaller than those released by healthy cells, so they designed their lab tests to pick up these shorter sections. Detection was a success in the CSF samples of 5 patients, which has never been done before.

“Essentially what we tried to do was identify patterns or marks within DNA that say: ‘This is from the tumour’,” says Richard Mair, a neurosurgeon who co-led the study.

A larger catch

To make sure is was tumour DNA that they were picking up, Moulière and Mair also fished in the CSF for certain areas of repetition in a tumour’s genetic code.

Repetition in the genetic code of human cells is normal, but this is generally more common in tumour cells. These changes can mean large chunks of DNA are added or lost when tumour cells divide, making their DNA look different to healthy DNA.

Crucially, the team managed to spot these large DNA changes using a very cheap technique called shallow whole-genome sequencing.

“There have been a few papers looking into CSF liquid biopsies for brain tumours, but they use very complex and expensive techniques,” says Mair. “We’ve shown that the same things can be done cheaply in an easier way.”

A special case

This study shows that traces of brain tumour DNA can be detected in the CSF without the need for expensive techniques. But there was another interesting finding.

CSF samples might be able to reflect the entire repertoire of genetic changes found in brain tumours.

– Dr Florent Moulière, co-lead author

When a brain tumour patient has surgery, surgeons send several pieces of the tumour to the lab to work out how aggressive it is. But brain tumour cells can look different to one another, even within the same tumour.

“When you take sections of a tumour and test them you’re not getting an understanding of the genetic makeup of the whole tumour,” says Moulière, “just that section you’ve taken a biopsy of.”

Interestingly, they found the genetic changes in one patient’ surgery samples matched those in the CSF, but the CSF sample contained genetic changes that weren’t found in some of the tissue samples.

“This suggests that CSF samples might be able to reflect the entire repertoire of genetic changes found in brain tumours,” says Moulière.

Catching this genetic detail may give liquid biopsies the upper hand on invasive tissue samples and point to potential new routes to treatment.

“We don’t have the medications to do this yet, but one day we might be able to target precision therapies based on this genetic information,” says Mair.

Is a brain tumour blood test possible?

If tumour DNA can be detected in the CSF, Moulière says there’s no reason why the cheap technique couldn’t be adapted to work in the blood.

A liquid biopsy for people with brain tumours that would dramatically improve their quality of life.

– Richard Mair, co-lead author

“I see these patients all the time,” says Mair. “There are various applications for liquid biopsy for people with brain tumours that would dramatically improve their quality of life.”

For one, a brain tumour DNA-detecting blood test would mean patients could have quick and regular check-ups to make sure their treatment is working.

“There are also certain cancers of the brain where the best treatment isn’t necessarily surgery,” says Mair. “This could be because the tumour is too widespread or involved in regions of the brain that are too delicate to operate on.”

Some brain tumours are also better treated with chemotherapy and radiotherapy. “If we could identify a genomic marker that indicates this it could save them a risky surgical procedure,” he says.

More to do

The current technique can only pick up tumour DNA if the tumour contacts the fluid surrounding the brain. The signal is all or nothing and potentially explains why tumour DNA was only detected in 5 out of 13 patients.

“It’s very important to improve this analysis so we can then start to move this method towards working with blood,” says Moulière.

But for now, these results mark a promising start towards better ways to monitor brain tumours and show, that when looking for brain tumour DNA, our scientists are casting their nets in the right direction.

Gabi

Reference

Moulière , F & Mair, R et al. (2018) Detection of cell‐free DNA fragmentation and copy number alterations in cerebrospinal fluid from glioma patients. EMBO Molecular Medicine DOI 10.15252/emmm.201809323

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