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Piecing together the mosaic: how genetic research is revealing new connections

by Kat Arney | Analysis

4 March 2016

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By untangling the genetic roots of ECCL - a 'mosaic' disorder - scientists are finding new clues for tackling brain tumours.

Open a molecular biology textbook and you’ll see web-like diagrams of blobs and arrows spidering across the pages. These complex circuits represent biological messages sent inside the cells of our bodies – known as signalling pathways – which tell them to grow, divide, specialise and even die.

Like fiddling with the parts of an electronic circuit, changes in the behaviour of the molecules in these pathways can have profound effects on our cells, including leading to cancer.

Yet for even the most dedicated researchers who spend their lives studying the circuitry in our cells, these neat pathways can seem a bit detached from real life. But now Professor Mark O’Driscoll  – who heads a Cancer Research UK-funded team at the University of Sussex – and his colleagues have made an unexpected and potentially life-saving connection between the misfiring molecular circuits behind an unusual genetic syndrome and a rare type of brain tumour.

Introducing ECCL

“I’ve studied these biological pathways for years and sometimes they can seem a little abstract,” he told us, “but when you can pin changes in them to conditions in real people, it’s so important.”

In this case, the people affected are children with a disease called Encephalocraniocutaneous Lipomatosis, or ECCL for short (also sometimes known as Haberland’s Syndrome). They develop fatty lumps – non-cancerous tumours known as lipomas – on their heads, faces, eyes and elsewhere, and can have brain problems such as epilepsy and learning difficulties. In some cases the condition can prove fatal – for example, if a lump presses against the spinal cord or brain and can’t be removed through an operation.

Pilocytic astrocytoma

Pilocytic astrocytoma (the white blob in this x-ray image) can be difficult to treat, especially if it’s deep inside the brain. Image via Wikimedia Commons, public domain.

What’s more, children with ECCL are also much more likely to develop a type of brain tumour known as pilocytic astrocytoma. And although these rare cancers tend to be slow-growing, they can be difficult to treat, especially if they’re in part of the brain that’s hard for a surgeon to get at.

Until now, it’s been difficult to uncover the genetic culprit lying at the syndrome’s root. Unlike many genetic syndromes that can be traced down through families, so are relatively easy to pin down to a single faulty gene, ECCL doesn’t follow this kind of pattern. It turns up unpredictably, without a really clear hereditary pattern, and previous studies have drawn a blank on a genetic cause.

The biggest problem has been the fact that the condition is what’s known as ‘mosaic’, meaning that the gene fault causing the fatty lumps to grow isn’t found in every cell of the body, but only in a subset. This unusual situation comes about very early on during development, when a baby is little more than a few cells growing in the womb. For some reason, a single one of these cells develops a mistake in a gene which propagates to all its descendants, wherever they might be in the body.

In time, these faulty cells can develop into the fatty growths and other problems seen in children with ECCL, although their effects are diluted by all the genetically healthy cells around them. And because the gene fault isn’t present in all the cells of the body it can be difficult to track it down, even with the latest gene reading (or ‘sequencing’) technology.

But the findings of a new study by an international collaborative team– including Professor O’Driscoll – which have been published in this month’s American Journal of Human Genetics, finally solves the mystery.

Not in the blood

“It started at a scientific conference when the leader of a Canadian group looking for rare disease genes – Kym Boycott – was chatting to a colleague from Seattle – Bill Dobyns,” O’Driscoll recalls.

As the conversation flowed, the researchers realised they were both hunting for the gene faults responsible for ECCL. But rather than compete, they decided to team up.

One of the problems that both teams faced was linked to ECCL’s mosaic nature – it meant that despite using the very latest sequencing tools, when the researchers looked at DNA in blood samples from affected children they kept coming up with nothing.

This was frustrating – even though the genetic fault driving the condition only affects a small proportion of cells in the body, the scientists still expected to find tell-tale genetic clues in the bloodstream. (It’s the same principle underpinning new ‘liquid biopsy’ techniques being developed to monitor cancer).

It was only when they were able to look for gene faults in tissue taken from the patients’ lipomas that they finally spotted the culprit. Using an incredibly sensitive technique that can analyse individual strands of DNA, they discovered that tissue samples from five unrelated children with ECCL all had a fault in a gene called FGFR1 – more formally known as Fibroblast Growth Factor Receptor 1.

Then when they trawled through the huge databases of gene faults found in cancer (created by mass cancer DNA sequencing projects such as TCGA and ICGC) the scientists noticed the very same faults in FGFR1 turning up in samples from pilocytic astrocytoma tumours – the very brain tumours that ECCL patients are at increased risk of developing – as well as other diseases such as breast cancer.

So far, so intriguing. But what does this gene actually do?

From genes to pathways

It’s here that Professor O’Driscoll and his team in Sussex come in. He’d worked separately with Boycott and Dobyns on previous projects investigating the effects of faulty genes in rare conditions, using his expertise to trace the signalling networks involved.

The FGFR1 gene encodes a type of molecule known as a growth factor receptor, responsible for receiving signals that come into cells – in the form of little chemicals called growth factors – and passing them on, telling the cell to grow and divide.

So it was a natural next step to get O’Driscoll involved in working out what FGFR1 was doing in ECCL – it’s exactly this kind of signalling pathway that O’Driscoll is an expert in studying, through his work looking at how cells respond to damage to their DNA. Although receiving growth messages and alerting cells to DNA damage might sound like very different processes, they both use similar molecular ‘relay races’ – signalling pathways – to send this vital information.

Thanks to collaborations with teams in the US, Australia, Europe and China, Mark and his team were lucky enough to have access to cells from ECCL patients’ lipomas that they could grow in plastic dishes in the lab. By looking in depth at how certain molecules change in the ECCL cells compared to healthy cells, they realised that something was very wrong with FGFR1.

“When we looked at the signalling pathways, they’re constantly turned on. It’s as if the volume button is jammed on 10, and it’s turned up all the time.”

When they looked more closely at the precise FGFR1 gene faults in each patient, they discovered that they were all ‘gain-of-function’ – a term scientists use to describe receptors that are jammed on, even in the absence of their usual messages. As O’Driscoll explained, one key experiment proved that it was this gain in activity that was driving the cells to grow out of control and form lipomas in the children with ECCL.

“It’s very simple,” he explains. “To see the difference, all we do is get cells growing in a rich broth with lots of serum, which contains growth factors. Then we remove the serum, wash the cells vigorously and leave them.”

Healthy cells can’t cope with this, so they stop growing and eventually die. But not the ECCL ones. “They don’t care. Their signalling is still turned on and they just keep going – it’s amazing.”

From pathways to drugs

Finding a gain–of-function mutation in a signalling molecule is a huge boon to cancer drug developers (unlike the so-called ‘undruggable’ targets we’ve written about recently). If an overactive rogue gene is driving cells to multiply out of control – whether it’s the fatty lumps of ECCL or a pilocytic astrocytoma – then developing a targeted drug that blocks it should stop them in their tracks.

And because faults in FGFR1 and related genes are already known in more common diseases such as breast cancer, drugs that block it – such as one called lucitanib – are already in clinical trials for some types of tumour. No one yet knows whether the drug could be useful for treating ECCL or pilocytic astrocytoma, but researchers are now on the case.

There are some potential stumbling blocks – notably the suggestion that the particular faults in FGFR1 found in pilocytic astrocytoma might mean these tumours aren’t sensitive to lucitanib. But there’s always the option of developing and testing new drugs that might be more effective, or combining it with other treatments that enhance its effectiveness.

The power of genetics

Although there’s some way to go to turn these findings into effective treatments for patients, the study highlights some important points – as well as intriguing directions for future research.

For example, there are some ECCL patients who don’t seem to carry any faults in FGFR1 – so what’s causing their condition? Furthermore, the team discovered that some cells in normal-looking skin from these children can have a faulty version of FGFR1, but they don’t form lumps. Why? At the moment, the researchers don’t know, but they’re working hard to find out.

There’s a broader perspective too. Back in 2014, we wrote about how our researchers at The Institute of Cancer Research discovered an important link between a rare genetic condition known as Stone Man syndrome – where muscle cells transform into bone – and the childhood brain cancer DIPG by trawling through sequencing data.

This new study from Professor O’Driscoll and his colleagues is yet another example of an unusual connection between a rare genetic disease and brain tumours, highlighting the importance of delving deep into the genome to find new approaches to tackling these cancers.

“It’s fundamentally pinned on the new genetic technology,” he tells us. “That’s where the insights are coming from. And people are now realising these pathways in rare syndromes are so important for cancer. I didn’t set out to work on this stuff, but through my Cancer Research UK-funded work we have the tools, we know the tests, and we can do the experiments for any signalling pathway.”

Ultimately, Mark hopes that his work will form part of the bigger pathway that leads to more effective treatments for people with pilocytic astrocytoma, ECCL or the misfortune to have both. And it’s thinking about these patients that keeps him and his colleagues focused on their work.

“We have pictures of these kids in the office. The parents are desperate and highly motivated to find out what’s going on, and to know whether their children can be helped. It’s people-oriented rather than abstract signal transduction, and that’s so important.”



Bennett et al., Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis, The American Journal of Human Genetics (2016)