Polygenic susceptibility: What might it tell us?

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Published: 14 Nov 2013
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Sir Bruce Ponder - University of Cambridge, UK

Prof Ponder talks to ecancertv at the UK's National Cancer Research Institute ( NCRI ) 2013 meeting where he received the Lifetime Achievement award.

Prof Ponder's first major success in genetics was the linkage of medullary thyroid cancer to chromosome 10, which led to a test for genetic susceptibility to this rare disease.

In the late 1980s he moved on to study breast cancer; the international consortium he established  in breast cancer genetics led directly to the discovery of BRCA1 and BRCA2.

Later still he was involved in the first genome-wide association scans (GWAS).

Results from these, however, have been disappointing: for example, even with GWAS we have been able to explain less than 20% of the genetic variation in breast cancer risk.

Ponder ended his plenary lecture by suggesting that combining genes into networks might help explain some of this missing heritability of breast cancer.

NCRI 2013

Polygenic susceptibility: What might it tell us?

Sir Bruce Ponder - University of Cambridge, UK


Talking about my early career, my intention was to say how my career had worked itself out, lots of luck and chance in it but the lessons that I learned from that which I hoped might be of interest to some of the younger people in the audience who are starting out now and particularly the clinicians because I think clinicians find themselves on a sort of career escalator and it’s quite hard for them to step off and yet if people stay too much in the conventional line then we’re going to miss out on people with new ideas, actually.

What would be your advice to young clinical scientists?

My advice would be decide what it is that you really want to do, what you think is important, then you have to be honest with yourself and decide whether you’re good enough to do whatever it is and then go for it. I can tell you in my years as institute director and trying to give advice to young people, it’s much easier to advise somebody who comes along and says, ‘I would like to do this,’ and then you can have a conversation with them about it and help them think about it. You don’t make up their mind for them but you can have a dialogue. If they come and say, ‘What shall I do next?’ it puts a huge responsibility on you and you can’t really answer for them. So be positive is my advice.

What do you consider the most promising area for young clinicians?

I think the most promising area is the area you’re really interested in. I wouldn’t choose one over another, it’s what grabs you. In my case I trained as a medical oncologist but I decided that in the days, it’s a long time ago, that drug development and medical oncology was terribly empirical and I wanted to be much more science based and I thought developmental biology was the science that might unlock some of the ways into cancer for us. So I went into developmental biology, very unconventional but it turned out OK.

Can you tell us about the science you covered in your talk?

I covered two bits of the science in my early career; one was an attempt to look at cancer as a disease where there’s a breakdown of tissue organisation. To put it briefly, the central problem of biology is how do you go from a fertilised egg to a mature organism? And one can look at cancer in some senses as a case when the rules of tissue organisation break down. So I was interested in trying to understand better the clonal organisation of an epithelium from which a cancer arises and then being able to look at how the organisation breaks down as the cancer develops. As it turns out I was twenty years too early and we didn’t really have the technologies to do it but I think that was an interesting idea and the lesson, of course, for the young scientists was if you get to a point where you can’t progress, even though I had several papers in Nature about it, it wasn’t unsuccessful but it was a failure in the sense I couldn’t go forward. So you have to stop. And then the other area that I talked about was genetics and I was very interested in the genetic basis of cancer and that as a way in to understanding how cancers develop back in the late ‘70s. But, again at that time, we didn’t have restriction enzyme polymorphisms, we didn’t have any of the tools so I couldn’t take it forward. But three or four years later that technology came in and I saw the chance to start mapping the genes in some of the cancer families that I saw in the clinic. So I talked about my research career in that and we started with the uncommon genes with very strong effects, multiple endocrine neoplasia syndrome and BRCA1, BRCA2, but in recent years we’re starting to tackle the polygenic component of inheritance, not rare genes with strong effects but the combined effects of hundreds of different variants and I talked about that too.

Where is this leading us next?

I don’t know where it’s going to lead us because it’s an extremely difficult problem but what’s happened is that the first cancer GWAS was published in breast cancer by us about six years ago and we found a few of these variants that are involved in susceptibility to breast cancer but progress in finding more of these variants and understanding what they do has been slow. The reason is that these variants have quite small effects and so it’s difficult to find them and then what people have been doing is taking them one by one, and there are dozens of them, and trying to work out what each one of them does and that’s very labour intensive and it’s slow. So the proposition I’m putting forward, but I don’t know whether we’ll succeed, is that in fact these variants are having their effect in combination, it’s that combination of the hand of bad genes that you have that determines your susceptibility so we should try to get a handle on the combined effect. And my proposal is that they probably have their effect, these variants, and it’s expressed through the patterns of gene expression in the cell so we should be looking at gene expression networks and how those are altered by the predisposing variants and that may give us an integrated way into mechanism. I showed a couple of very preliminary data slides which I think are quite optimistic that this direction may work but there’s years to go.

Will cancer control be a reality?

Not as a blanket, no. We have quite effective cancer control already. If you stick scopes up people’s backsides you’re pretty effective at controlling colon cancer, you don’t need high tech, so there are going to be different solutions to different cancers. But if your question is when will understanding of the polygenic basis of susceptibility give us markers of risk and then targets which we can use for prevention, very hard to suggest. Science over the last twenty years has always moved faster than one expected but this is a terribly complex problem. I would say ten or twenty years; if I live to see it I’ll be quite pleased, let’s put it that way.

What are you going to do next?

I’m still Director of the Cancer Centre at Cambridge and Head of the Oncology Department so I still have two reasonably substantial jobs. I’m going to see whether they can’t find somebody to take those over from me and I want to go back to doing my research; I’ve got a small research group. The research in polygenic susceptibility and its mechanism is risky, speculative, that’s rather suitable for an old guy like me because if I fail it doesn’t matter, I can just go off and play golf or take photographs. So I’m going to have a go at it and see how far I get and if it works then I hope to be able to hand it over to some successors to take it forward. If it doesn’t work, well at least I will have found out usefully that there’s one alley that doesn’t need exploring further.