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Cambridge University’s Sir Bruce Ponder on cancer risk and our genetic hand of cards

Sir Bruce Ponder was founder director of the CRUK Cambridge Institute. Picture: Keith Heppell
Sir Bruce Ponder was founder director of the CRUK Cambridge Institute. Picture: Keith Heppell

The founding director of Cancer Research UK Cambridge Institute has spent decades exploring our inherited susceptibility

Our genes have an influence on our risk of developing cancer
Our genes have an influence on our risk of developing cancer

At conception, you are dealt a genetic hand of cards by your parents.

Among other factors, it influences your risk of developing cancer - and it is this predisposition that Sir Bruce Ponder has been exploring for decades of his distinguished career.

"The inherited genetics that most people are familiar with is, for breast cancer, the 'Angelina Jolie gene',says Sir Bruce."Genes like BRCA1 and 2 are rare in the population but they have quite a strong effect.

"They are inherited, so you'll get multiple cases of breast cancer or ovarian cancer in the family."

The Hollywood actress announced in May 2013 that she had elected to have a double mastectomy to reduce her risk of breast cancer.

Doctors estimated that she had an 87 per cent chance of developing the disease, having inherited the faulty BRCA1 gene from her mother, who died of ovarian cancer at just 56.

In March 2015, she went public with the news that she had also chosen to have her ovaries and fallopian tubes removed to reduce the risk of ovarian cancer, which she had a 50 per cent chance of developing.

About one in 1,000 women inherit a faulty BRCA1 gene from their parents, considerably increasing their predisposition to cancer.

They account for about one in 20 breast cancer cases, and about 20 per cent of overall inherited susceptibility.

Sir Bruce Ponder has spent decades exploring our genetic predisposition to cancer. Picture: Keith Heppell
Sir Bruce Ponder has spent decades exploring our genetic predisposition to cancer. Picture: Keith Heppell

Sir Bruce, the emeritus professor of oncology at the University of Cambridge and founding director of the Cancer Research UK Cambridge Institute, is particularly interested in 'polygenic variation', which makes up the remaining 80 per cent of our susceptibility.

"This is the normal variation with the population,he explains."For example, the shape of your face is made up by the combined effect of normal variation of several hundred genes. That's why there is family resemblance.

"Our genes are subject through the history of the population to mutation. Some of these mutations are deleterious and some make no difference at all. Some very subtly alter the way the gene is working or how it's controlled.

"The variation that can affect the shape of your face, or your height, also affects your susceptibility to disease - whether that's cancer, diabetes, asthma, blood pressure or whatever."

He adds:"It's hard to pick this out in terms of a strong family history because it's in the background, so you don't get the patterns you get with the BRCA genes.

"But overall, in terms of breast cancer risk, they probably make quite an important contribution."

Sir Bruce's group has previously estimated, using assumptions about the polygenic background in breast cancer, that as many as half of breast cancers occur in the 12 per cent of women dealt the worst"hand of cards- variation of genes - at conception.

"Finding these genes and understanding how they work together is potentially important because it could identify the group of women at greater risk of breast cancer - and we are working on lung cancer too now,says Sir Bruce.

"You could potentially target screening programmes or prevention to them. If you understood how these genes work, that might help you lower the risk by nudging them back to a less risky form."

Sir Bruce Ponder is emeritus professor of oncology at Cambridge. Picture: Keith Heppell
Sir Bruce Ponder is emeritus professor of oncology at Cambridge. Picture: Keith Heppell

However, it is no small task to find the genes that control this risk.

"We collected blood samples from several thousand women with breast cancer and several thousand women from the same population of roughly the same age who didn't have breast cancer and then we went through as many of these variants as we could,explains Sir Bruce."We asked which of these variants are significantly more common in the women who had breast cancer than the women who didn't.

"It's a laborious search and you need a large sample because the effect is quite small.

"Like most things in scientific research, it became possible when the technology developed, so we could analyse these genetic variations across the whole genome and it was practical and affordable to do so with thousands of people."

In 2007, Sir Bruce's group published the identification of the first five of the variants for breast cancer, derived from studying samples from 2,000 people across East Anglia.

"Then we put together a worldwide collaboration with almost all the labs around the world engaged in the same research,he recalls."We pooled our results and we got tens of thousands of women with breast cancer and tens of thousands for control. It's now up to something like 150,000. So we've got very much more reliable results.

"The number of common genetic variants in the population which are associated with breast cancer has gone up to between 150 and 200."

Now Sir Bruce is working on how these variants combine to influence risk.

"Each one may be present in 10 or 20 per cent of women but only has a tiny effect on breast cancer risk,he says."You may have tens or hundreds of variants combining to influence risk."

Sir Bruce Ponder at CRUK Cambridge Institute on Cambridge Biomedical Campus. Picture: Keith Heppell
Sir Bruce Ponder at CRUK Cambridge Institute on Cambridge Biomedical Campus. Picture: Keith Heppell

Sir Bruce's research found the majority of variants initially identified influenced the signalling of the oestrogen, which made sense as higher lifetime exposure to the hormone is known to increase breast cancer risk.

"Drugs like Tamoxifen, which are used to reduce the risk of breast cancer, impact on the same signalling pathways, reducing the strength of the oestrogen signalling,says Sir Bruce.

A key question for the researchers is whether the large number of variants mean that many cellular mechanisms are involved - which would be difficult to target with drugs - or converge on a smaller number of common mechanisms.

"If you've got 100 of these genomic loci, how do they work together? We are still exploring this,says Sir Bruce.

"The evidence we've got so far is they don't all converge on the same mechanism but nor do they impact in 100 different ways. It may be that they cluster together - a third will act on one mechanism and a third will act on another.

"The question is the level at which you look at it. We looked at breast cancer at rather a high level. We found the inherited variants were affecting the strength of the oestrogen signalling within the cell, which affects the activity of a lot of genes. But you could go downstream of those genes and look at what they are doing - they are sending signals down to detailed mechanisms in different parts of the cell.

"I prefer to stay one level up because I think if you want to influence this by reducing risk you would want to aim at the rather higher level like oestrogen signalling."

Women enter the national breast cancer screening programme at the age of 47.

"It's a risk threshold defined by age,says Sir Bruce."But in fact there will be women of 55 or 60 with a good hand of genes who won't be above the average risk threshold of a 47-year-old, and women of 40 who have a bad hand who will have already reached the threshold."

In principle, you could use knowledge about genetic predisposition to target early screening towards those at most risk. Testing a quarter of a million places in the genome via a simple blood test and a microchip costs just a few pounds today.

"I'm now looking at people who smoke cigarettes and, in particular, those who stop but are still at risk of lung cancer,says Sir Bruce."Trying to find out who is at most risk is much more difficult because we have very little idea of the genetic variants that underlie lung cancer. We are in completely unmapped territory."

But then the scale of the challenge never stopped him beforeナ

Setting up Cancer Research UK's Cambridge Institute - and the future of cancer research

When Sir Bruce Ponder took on the role of professor of oncology at the University of Cambridge in the mid-1990s, he spotted a massive opportunity for researchers in the city to work together.

"We had a cancer department but it wasn't very big,says Sir Bruce."But in Cambridge we had two advantages for cancer research. We are geographically in the centre of East Anglia with a fairly stable population and there aren't lots of other big hospitals around. If you want to do research you need patients and tissue samples. But the main point was we were sitting in the middle of a city with the strongest biomedical research in Europe, even at that point - and undeniably now.

"What was missing was the link between the clinic and the people doing cancer research and those not just in biology but chemistry, physics, mathematics and engineering and all the other stuff we had in Cambridge."

Strengthening the clinical department, then building a nucleus for research on the Addenbrooke's site that could attract a multi-disciplinary group of scientists, Sir Bruce became the founding director of what is now called Cancer Research UK's Cambridge Institute, which opened in 2007.

"Having the institute made a huge difference,he says."There was a big investment by Cancer Research UK and we could appoint more smart scientists.

"From that we've been able to build links across Cambridge and build the Cambridge Cancer Centre - one of the major cancer centres in the UK, for CRUK.

"We anticipated by a year or two the government setting up a cancer network around the country."

Now emeritus professor of oncology at Cambridge and emeritus professor at Jesus College, he was knighted in 2008 for his services to medicine and won a Lifetime Achievement Award from Cancer Research UK in 2013.

He sits on the scientific advisory board of Owlstone Medical, the exciting Cambridge Science Park firm creating a breathalyser for the early diagnosis of cancer and other diseases.

What does he seeing as the next major step for cancer medicine?

"The advances in cancer research over the last two decades are extremely impressive but we've still got an awful long way to go,he says.

"All the attention at the moment is on precision medicine and that's great. But the analysis so far is 'Here is the cancer, we take a bit out, do genomics on it, find a mutation and that helps us choose which drug to use'.

"But the next leap in understanding is what's going on in the cancer cell. What effect a particular mutation has on a cancer cell is very dependent on the context - the surroundings of the cell and the other genetic changes within it.

"Most cancer cells are associated with inflammation and immune responses of the surrounding tissue, which send signals to the cell. That and the background genetics - the small variations in each individual - are influencing how the cancer is going to behave. Our predictions are going to become sharper."

Targeting these processes, which lie outside the cell, could possibly get around the issue of cells becoming resistant to cancer drugs, he predicts.

"One of the things Cancer Research UK will be giving an emphasis to is the cancer cell in the tissue,he says."If I had to bet on something to invest in the next 10 years, I'd bet on that."

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