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This entry is part 5 of 10 in the series Grand Challenge

In October 2015 we launched the Cancer Research UK Grand Challenge – a £100m scheme to tackle seven of the biggest challenges in understanding and treating cancer. 

And in an ongoing series of posts we’re exploring each of the seven Grand Challenge questions set by a panel of the world’s leading cancer experts. The third of our Grand Challenge topics asks: can we prevent cancer by studying ‘scars’ in its DNA?

If you’ve read the news recently, you may have stumbled across an ongoing debate about whether cancer is caused by ‘bad luck’, or by the choices we make during our lives.

The reality, of course, is that it’s both. But the answer to the simple question ‘what causes cancer?’ depends on who you ask.

Researchers from a branch of science called epidemiology, who study disease trends across whole populations, would point to things like smoking or obesity – because their studies have shown that some cancers are more common among people who smoke or are obese.

And we now know that as many as four in ten cancers are linked to what epidemiologists collectively call ‘exposures’ – either well-known things like chemical carcinogens in tobacco smoke, or more complex processes  like ‘a poor diet’, which is much less well understood.

But if you ask the laboratory-based biologists, who study cells’ inner mysteries, they’d probably talk about things like DNA, genes and mutations. From this point of view, cancer is caused when the genetic programming in our cells gets corrupted.

Clearly both answers are true. And thanks to decades of research, we know a fair bit about how the machinery inside our cells can go catastrophically wrong, and that things in our environment – so-called carcinogens – can make this more likely.

But there are some crucial missing pieces in this jigsaw puzzle.

On the one hand, we simply don’t know exactly how some of these things cause cancer – particularly ‘lifestyle’ factors like obesity or excess alcohol consumption (although we do have decent theories for some of them).

On the other, large studies looking at countless thousands of patients’ tumour DNA have started to find scores of patterns – the scars left on our genomes as cancer develops. And with a few notable exceptions, most of them are of unknown origin.

So the third of our Grand Challenges is to try to make significant headway in uncovering vital new links between the processes in our cells and the way our environment affects them – both to better understand how cancers arise and, crucially, to prevent them in the first place.

Grand Challenge 3 gif1

‘Reverse epidemiology’

As Harvard Medical School’s Professor Ed Harlow – a member of our Grand Challenge Advisory Panel – tells us: “Epidemiology typically starts by looking for patterns in the distribution of tumours – where they occur in the population – and then uses those patterns to do detective work to figure out what might be the cause.”

This conventional approach has resulted in some “spectacular” findings, he says, identifying many of the important causes of cancer, such as smoking or UV radiation.

“But over the last few decades – and particularly the last couple of years – we’ve see the appearance of another type of approach, that focuses first on the characteristics of tumours themselves, and uses those as a clue to search for what the cause might be.”

“So the idea that you might be able to find new carcinogens by this method caught the Grand Challenge panel’s attention. We thought, ‘oh yeah, we’ve got to do that’.”

And Harlow thinks the approach has the potential to transform how cancer development is understood.

We thought, ‘oh yeah, we’ve got to do that’.

– Professor Ed Harlow

To show how powerful it can be, he recalls the story of aristolochic acid, a powerful cancer-causing chemical found in certain plants – including those used in certain traditional Chinese medicines.

In 2012, researchers studying a rare form of bladder cancer found a suspicious pattern of mutations in tumours from those who’d taken these medicines – effectively a fingerprint of the damage the chemical in them had wreaked inside the patient’s cells.

But the researchers subsequently found the exact same fingerprint in the DNA of some patients’ liver cancers too – a form of the disease not previously linked to aristolochic acid exposure, and giving renewed urgency to efforts to enforce bans of medicines containing it.

So identifying these patterns can lead to clear ways to prevent cancer. Can we find more?

Work in progress

One of the labs making big inroads is the Wellcome Trust’s Sanger Institute in Cambridge, UK. As researchers around the world have begun to publish reams of cancer DNA data, a team at the Sanger led by Dr Serena Nik-Zainal has been combing them for underlying patterns.

They started back in 2012 by looking in breast cancer, “a cancer type known not to have clear environmental associations,” she says. “We wanted to see whether we could make sense of the vast mountain of mutation information that we would get from large numbers of samples.”

“We were heartened by unearthing 5 signatures in this single cancer type alone.”

This led to further studies, in more types of cancer. “We’ve now identified 30 signatures in around 40 different cancer types. Some are associated with environmental exposures like UV radiation or aristolochic acid. Others are associated with problems inside cells, like defective DNA repair pathways, or the action of certain enzymes.”

But the vast majority, she says, are of completely unknown origin.

Professor Laurence Pearl, from the Genome Damage and Stability Centre at the University of Sussex, and one of Cancer Research UK’s leading experts in understanding how cells repair damaged DNA,  has been keenly following the Sanger team’s progress.

“You look at some of the patterns Serena’s team have discovered and think, oh, that’s clearly caused by faults in one or other of the processes we’ve known about for some time,” he says.

“But for others, we’ve all been scratching our heads trying to think what failure – or sequence of failures – could cause them. Understanding what’s going on has eluded us to date.”

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A broad coalition

As well as the obvious strategy of playing ‘match the pattern to the carcinogen’, the Grand Challenge panel is hoping to see these sorts of efforts scaled up considerably, and broadened in scope – Harlow says he’s keen to look beyond mistakes in the sequence of ‘letters’ in the cancer’s DNA, for even wider patterns in how entire chromosomes or even cell types are organised.

“There’s a general call in this Challenge to say ‘look for new patterns,’ patterns that are inherited from tumour cell to tumour cell,” says Harlow. “If they are unique, or different – or even just found much more commonly in certain types of tumours – then that must mean that there’s some reason. Let’s go back and see what it is.”

So while looking simply for the action of carcinogenic chemicals is a “clear, relatively easily understandable first step,” Harlow thinks it might also lead to things we don’t understand at all at the moment.

And this, he says, will need expertise from a whole range of different scientific traditions.

Laurence Pearl (via wiki commons

It’s very, very difficult, but certainly not impossible – Prof Laurence Pearl  Credit: Wikimedia Commons via CC-BY-SA 3.0

“Starting at the beginning, if you identify a carcinogen [by analysing DNA patterns] you’d want to know the steps between exposure and actual changes in the DNA.

“So you’d need biochemists, cell biologists and systems biologists to be part of that discovery process, to try and learn what that pathway is. Then, if you’re thinking about mechanisms of prevention, you might bring in whole other types of scientific expertise too.”

And ‘traditional’ epidemiology has a vital role to play too: “Having people who think about the actual incidence of disease might be an interesting group to add to mix too, to point out places where it would be more interesting to look,” he says.

Pearl and Nik-Zainal agree. “You need a team with the capability to track how these changes emerge in tumours over time,” says Pearl. “It needs a really broad set of skills – not just geneticists, although you need them too. It’ll be a fascinating challenge. It’s very, very difficult, but certainly not impossible.”

This combination of cross-disciplinary experts “would permit systematic, large-scale studies that could propel the understanding of signatures further and faster,” says Nik-Zainal.

But there’s also a geographic angle to this. Different regions of the world are affected by different types of cancer – and this is likely due to differences in lifestyle, environment, and genetics. So Harlow is keen to stress that the Challenge needs international input too.

“The broader you build your database of cancer DNA sequences, the greater chance you have to find patterns of interest. So more groups, and more information, gives you a much broader starting point, but it also changes the kinds of exposure and the kinds of cancer-causing events that might be picked up,” he says.

The Patient Perspective

I don’t have a science background, but I do know from my life experience that the best way to handle difficult situations is to ensure, as best you can, that they don’t arise in the first place. It’s a simplistic view, but it would be fantastic if we could this with cancer. For me, the attraction of the Grand Challenge is that it is most definitely not “business as usual.” At the session I went to in Edinburgh it was noticeable that even some very seasoned and well-published researchers were finding it challenging to think ‘big’ and remind themselves that this is not a routine grant-funding exercise. In my book, preventing cancer is the biggest challenge of all and the one with the biggest potential in terms of positive outcome, not just for patients, but for society as a whole. This is an exciting prospect, which means that, if the challenges are met, patient benefit should be on a very large scale.

– Peter, Grand Challenge patient panel member

Prevention is better

The ultimate aim of the Challenge, says Harlow, is to try to find ways to prevent people from developing cancer – whether it’s by identifying rare, potent carcinogens, or a better, deeper understanding of how our lives affect our genomes.

“There are ‘knowns’ that we could get from this that are very valuable, but the chances of uncovering something even more powerful, but unknown, seems to me to make this a very exciting opportunity.

“There are all sorts of things about how we live our lives that we don’t understand in great molecular detail yet. And I can imagine there could be something out there that we could find that would be eye-opening and completely astonishing to all of us.

“And I don’t know whether that will happen – but it certainly should be something we should aim for.”

– Henry

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