Finding the genes that drive childhood brain tumours: Professor Chris Jones

Professor Chris Jones is leading world-class research at The Institute of Cancer Research in London. His team is focused on finding the genes that drive the development of childhood brain tumours. 

Chris is passionate this is an area of research ripe with new opportunities, and with major goals in reach that could bring much needed clinical impact to paediatric brain cancer. Here he tells us about his career path, his highlights and his hopes for the future.

“I was drawn to the area of brain tumour research over a decade ago. I had originally been studying breast cancer for my postdoc, and then moved into research on Wilms’ tumour, a childhood kidney cancer. But I became aware that very few people were studying childhood brain tumours and yet there were certain types where all children affected were dying. I was drawn into the research area by this very clear unmet clinical need.

Gliomas are the most common type of brain tumour, formed from the progenerators of glial cells, which normally support and protect nerve cells. In childhood, high-grade gliomas are simply devastating, with no effective cure. 

Funding from CRUK’s project grants enabled us to start to understand the biology of the disease. We first explored single genetic markers, then in 2012, we applied for a CRUK Genomics Initiative Grant. This was funding for whole genome sequencing. I pitched specifically for sequencing of a subtype of glioma called diffuse intrinsic pontine glioma, or DIPG. This is a rare and devastating type of tumour that forms in the middle part of the brainstem and so is incredibly difficult to treat. It occurs almost exclusively in children, and all children affected die within a couple of years.

At the time we knew nothing about the genetics of DIPG at all. The location of the tumour had meant surgery was impossible and diagnosis only achieved by imaging, so there had simply been no tumour material to study. Then two new approaches arose. In the US, open rapid autopsy protocols were developed, so parents could consent to tumours being removed specifically for research purposes. Around the same time, a French group pioneered the reintroduction of safe stereotactic biopsies – using MRI to guide the biopsy needle to carefully sample the tumour. So for the first time we could collect the rare tumour material, enabling us to pitch to CRUK to do the first extensive whole genome sequencing of this glioma.

A landmark moment

The results of this research were a real landmark moment. In 2014 four companion papers were published in Nature Genetics, which really defined the landscape of glioma. Thanks to the CRUK Genomics Initiative Grant we suddenly had all this rich new information.  This was one of the highlights of my career so far.

In terms of the biology, the results were fascinating. Samples of this type of tumour look the same down the microscope, but the genomics revealed a whole hidden world of differences. We also identified genes unique to paediatric high-grade glioma, not present in the adult disease. Some of the findings had direct clinical impact — we could biopsy patients to identify the genetic subtype of their disease, and use this to guide different treatment strategies. 

A major discovery in the 2014 papers was a mutation in a gene called ACVR1. This mutation is not seen in any other type of cancer – it’s unique to DIPG. But interestingly the exact same mutation is found in another rare but drastically different disease, termed FOP. FOP is a devastating condition, sometimes called Stone Man Syndrome, in which muscle damage turns to bone. It seems if the faulty ACVR1 gene is affected in all cells from birth, it causes FOP, but if it occurs in the precursors to glial cells in the brain, it can cause DIPG. This strange shared genetics between the two rare diseases means that research into drugs to treat FOP might also be important for treating DIPG.

Read more about the connection between DIPG and FOP in our Science Blog

Diversity

We have now just published a new paper in Cancer Cell that makes further major revelations about glioma. This was an extraordinary international collaborative effort to achieve a sample size of over 1,000 tumours, including many new cases as well as published data. A real feat in itself for such a rare disease.

Given how rare glioma in children is, we really have to work together and pool resources. We’re all united by this aim to beat this dreadful disease.

Down the microscope, all high-grade gliomas look the same, but our results have shown that this isn’t just one disease. There are around 10 different subtypes that are all remarkably different at the genetic level. It has been amazing to uncover how different and diverse a group it is. That under this same umbrella classification of ‘high-grade glioma’ there’s such a diverse set of diseases. They have different genetics, affect different ages, different parts of the brain, and have different clinical outcomes.

As well as the different subtypes, we’ve also shown a remarkable heterogeneity within tumours. So within the cancer from any one patient there are numerous different cell types. This helps explain why so many therapies have failed. It’s not one population of cells, but many, many different types.  

In 2016 we won CRUK Programme Award funding to map how heterogeneous these individual tumours are. We are trying to isolate and characterise the different sub-populations of tumour cells, and work out how they interact with each other. This will feed directly into new drugs being developed. If we can understand how the different populations of cells interact, we can work on blocking these pathways in some way, to give new strategies for treatment.

We are making real inroads into uncovering the genetics of this rare but devastating brain cancer, but there are major goals ahead in now translating that to the clinic and survival rates. It’s a field where there are real opportunities, and as a research community it’s an incredibly collaborative field. Given how rare glioma in children is, we really have to work together and pool resources. We’re all united by this aim to beat this dreadful disease.

The unmet clinical need that drew me into brain cancer research is still my primary motivation. Each step of research taking us closer to improve survival for these children.”