Expert opinion: Professor Charlie Swanton – plotting a route through cancer evolution

Nearly two years ago a team of our scientists began a crucial journey to reveal new insights into cancer genetics.

Along the way they helped to re-define how we view cancer’s evolutionary map.

Led by Professor Charlie Swanton, the team described in intricate detail how the genetic changes within kidney tumours are hugely diverse.

In fact, no two samples from the same tumour in the same patient were genetically identical.

This phenomenon, known as intratumour heterogeneity, shares striking similarities with the laws of evolution set out by Charles Darwin over 150 years ago.

We covered the research when it came out, and with two new papers the team are beginning to flesh out the issue of intratumour heterogeneity, offering new insights into how to tackle it.

To help navigate their latest research and to provide an idea of what comes next, we caught up with Professor Swanton in his office at our London Research Institute.

Cancer Research UK: Can you summarise some of the key issues your research focuses on?

Professor Swanton: As I see it there are three big challenges we face.

Firstly, finding molecules – so called biomarkers – that can accurately predict how a person’s cancer will progress or how they will respond to treatment is really tough.

Secondly, advanced cancers can become resistant to the treatments we use.

And thirdly, once the disease has spread to other parts of the body it is particularly difficult to treat.

Now the key question is why?

If tumours always evolved in a consistent, step-by-step way – resulting in all cells within the tumour being identical – then in theory, curing that tumour should be relatively straightforward.

Each cell would be killed off by a drug designed to target the key genetic changes driving that tumour.

But we don’t see that in the majority of advanced cancers that have spread around the body.

Now, a number of labs – including my own – working over the last five years or so have found increasing evidence that tumours evolve in a branched fashion, resulting in what we call intratumour heterogeneity.

Cancer Research UK: So does intratumour heterogeneity offer some explanations for the challenges you’ve mentioned?

Professor Swanton: If you imagine the tumour is a tree, the first wave of genetic changes that initiate the tumour would be found in the trunk.

As the tumour grows and the cells acquire new genetic changes we see that it becomes more diverse and groups of cells with different genetic changes now form the many branches of the tree.

Our work has really been looking at how diverse tumours are, with a particular focus on kidney cancer and lung cancer.

In kidney cancer we see that about two thirds of genetic changes are not shared across all the tumour biopsies we have looked at.

We think this might begin to explain some of the difficulties researchers have faced when looking for biomarkers and finding truly curative drugs.

Cancer Research UK: What are your latest findings?

Professor Swanton: For kidney cancer we upped the number of tumours we’ve analysed. We’ve now read – or sequenced – the DNA code from multiple biopsies taken from 10 different tumours.

This is no easy feat, but it’s confirmed that branched evolution occurs in all tumours – it is the norm rather than the exception in these types of kidney cancer.

We also saw strong evidence for something called ‘parallel evolution.’

Cancer Research UK: Can you tell us a little more about that?

Professor Swanton: This is truly fascinating. In the case of different species, parallel evolution is when two distinct species that share a common ancestor evolve a similar trait.

Old and new world porcupines are a great example of this. Their ancestors were separated when their home continents broke apart, yet the old and new world porcupines have evolved strikingly similar spines.

In kidney cancer, we see the same molecules becoming faulty in multiple patients, but the faults arise due to different changes within these molecules which are present in distinct regions of the tumour.

If you look at the numbers, the probability of this happening by chance is very, very small.

It’s fascinating and seems to show that one way or other these kidney cancers are inactivating the same handful of molecules.

If we can understand more about this and find out what the early events are in the tumour then we might be able to predict the cancer’s next evolutionary move.

That’s the hope – it’s very exciting as it shows us there is actually order in these chaotic tumours.

Cancer Research UK: Are there any other patterns emerging?

Professor Swanton: Our lab is very interested in understanding how diversity within tumours occurs.

And something that’s caught our attention recently is a process called ‘genome doubling’.

This is where all the genetic information within the cell becomes duplicated inappropriately, meaning a cell is left with double the normal amount of DNA.

To study this we use bowel cancer cells grown in the lab.

The majority of these cells contain the correct amount of DNA, but around one or two per cent have double the normal amount.

When we separated these two groups of cells and grew them independently in the lab we found that the cells with the doubled DNA were able to tolerate this added genetic burden and continue to grow.

Next, we followed the cells under the microscope and looked at what happened when they made a mistake when dividing up their DNA during cell division.

If the cells with the correct amount of DNA made an error, they stopped dividing or died.

The cells with double the amount of DNA were perfectly happy to divide and grow when errors were made.

This tells us there must be a tolerance mechanism that allows genome doubling to occur and be maintained.

Finding this mechanism is our next challenge, we think this may hold a key to blocking one form of cancer progression.

We also think that genome doubling could be helping cancers evolve.

The longer we grew the cells in the lab the more genetically diverse they became.

It’s really fascinating as you actually see genome doubling in up to 60 per cent of solid tumours and 20 per cent of kidney cancers.

That’s why we focus on finding the things that actually drive diversity. If we don’t understand what causes the diversity, tackling it is going to be very difficult.

Cancer Research UK: Could this influence how we develop new drugs?

Professor Swanton: We believe that if we can identify and target the genetic faults that lie within the trunk of these tumour trees then this could be a more effective way of beating the disease.

If we can also monitor changes in the tumour branches over time then we hope to better understand how different cancers can become resistant to treatments.

That’s exactly what we are trying to achieve with the TRACERx project looking at lung cancer.

We want to assess the entire evolutionary trajectory of these tumours.

Based on what we know from our research on kidney cancer, the genetic changes that drive these tumours appear in different patterns.

And they occur at different times during tumour evolution as well.

This is something we need to be aware of when thinking about drug development.

If we block one genetic driver there may be another one ready to take its place.

Cancer Research UK: What’s next for your lab and the field?

Professor Swanton: In terms of the field, one area I am watching with great interest is immunotherapy – the idea of harnessing the body’s own immune system to fight cancer.

And one theory starting to emerge is that genetic diversity could provide more opportunities for the immune system to spot a tumour once it’s been re-energised by immunotherapy treatments.

Essentially, diversity could be the Achilles heel of the tumour, which would be a fascinating development.

In our lab we are starting to look at a broader range of tumours, analysing more and more genetic code from tumours at various stages so we can build up the best map of tumour diversity possible.

We are trying to answer important questions about how many samples or biopsies we need to give us a comprehensive idea of the evolutionary stage a patient’s tumour has reached and the impact of tumour heterogeneity on the immune system.

As we continue our sequencing approach we are starting to see more and more signposts in the road that are shared across different tumours.

If we can find reliable ways to spot these signposts in patients then we think they could indicate the route a tumour is taking along its evolutionary journey and potentially find new ways to stop it.

Interview conducted by Nick Peel

Professor Swanton’s advanced sequencing work in kidney cancer received funding from our Catalyst Club.

References:

• Gerlinger M., et al. (2014). Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing, Nature Genetics, 46 (3) 225-233. DOI: 10.1038/ng.2891
• Dewhurst S.M., et al. (2014). Tolerance of Whole-Genome Doubling Propagates Chromosomal Instability and Accelerates Cancer Genome Evolution, Cancer Discovery, 4 (2) 175-185. DOI: 10.1158/2159-8290.CD-13-0285