Genetic susceptibility to cancer

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Published: 17 Aug 2010
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Dr Allan Balmain - UCSF, San Francisco, USA
Dr Balmain speaks to about his work identifying individuals who are highly susceptible to cancer. Dr Balmain discusses what information is used to determine cancer susceptibility in mice and suggests how he believes this research will be put to use.

EACR 21, 26—29 June 2010, Oslo

Interview with Dr Allan Balmain (UCSF, San Francisco, USA)

Genetic susceptibility to cancer

The main focus of the research we do is genetics of susceptibility to cancer. So, as you know, there is a tremendous variation in the individual susceptibility of different people for developing cancers and we’re trying to find the genes and the so-called genetic variants that render one individual highly susceptible while others are highly resistant. So there’s a bell-shaped curve where a proportion of the population is very highly susceptible and others are highly resistant. The whole idea is to try to identify the susceptible individuals because, if you can do that, then the emphasis on prevention, on screening could be focussed more accurately on the people who need it most, the people who are most likely to develop tumours. At the moment we don’t have any ways to do that.

How long before this could be standard procedure?

It’s still a long way away but one of the approaches we take is to use mouse models of cancer, so mice develop cancers in exactly the same way as humans do, obviously with some differences, but the overall genetics of the process is rather similar. Whereas it’s difficult to study human populations in detail because of the heterogeneity, this can be minimised in mouse populations and we have some strains and species of mice that are highly resistant to cancer; they’re genetically resistant, they’re born resistant and we can breed those animals with other strains that are highly susceptible and then begin to tease out the genes, the patterns, the combinations of genes that make one strain susceptible and the other one resistant. This has proven to be very fruitful, it remains to be seen how many of the genes that we find and the combinations that we find will actually turn out to be relevant in humans. A few of them have turned out to be relevant but the overall picture isn’t clear yet and won’t be clear, I don’t think, for quite some time.

A test for everyone telling you what you’re going to get?

Clearly that’s where all the speculation is about exactly that kind of thing and, as I’m sure you know, there are companies who claim to be able to do that – you send them a cheek swab in an envelope and they claim to be able to assess your probability of developing cancers of one kind or another. At the moment I’d say it’s nonsense, we just don’t have enough information to be able to predict who is actually going to be susceptible and who is resistant, regardless of what the companies say. It’s such a complex business and what we have learned from the human genome projects and the mouse genome projects is that it’s not just one or a small number of genes that control susceptibility to the major cancers, it’s dozens or hundreds or even thousands of genes working together in complex patterns. At the moment the methods the human geneticists are using are really to go through all of these genes one by one and try to find the variant that causes an increase in susceptibility. So it’s a very painstaking process and it’s probably not ultimately going to be the right way to do it; we need to find other computational methods to find these complex patterns because these things work in groups. Finding the groups is not easy, we need to develop new computational approaches to be able to do this. I think it will be done but it’s still quite some way away.

What were the conclusions of your talk at EACR 21?

The standard way to look for the genes that cause susceptibility is to take DNA; you take a blood sample from a thousand patients and a thousand controls. You make the DNA from those blood samples, so you’re essentially looking in normal DNA for a sign, an indication, of which individual is susceptible and which one is resistant. The kinds of studies we’ve been doing, these are more integrated so-called systems types of approaches where we use as much information as we can from the patient, and in our case these are mouse patients. But instead of just taking the blood and looking at normal DNA, we actually take a small sample of the normal tissue like, in our case, skin or we can take small samples of other tissues and look, not just at the DNA but at the RNA, at the expression of the genes; we can look at proteins, we can also look at phenotypes in these mice. In other words in a heterogeneous population of mice some are big, some are small, some are fat, some are thin and just in the same way as obesity is associated with cancer susceptibility in humans, it’s the same in mice. So we can use these phenotypes together with the patterns of gene expression, together with the DNA, all of that information together to find these patterns that may be predictable. So these kinds of systems approaches are what I’ll be talking about and what we’ve been trying to develop for quite a few years now.