The Festival of Genomics and Biodata is just around the corner, and we’ve had the opportunity to sit down with some of our expert speakers to get a sneak peek into what they’ll be discussing, and why they think you should come along to the event.
In today’s interview, we speak to Ros Eeles (Professor and Group Leader, Institute of Cancer Research) about the role of both rare and common varitation in cancer, the implications of this for screening and diagnostics, and the importance of ensuring diversity in research.
Register for the Festival of Genomics and Biodata here.
Please note transcript has been edited for brevity and clarity.
FLG: Hi everybody. Today we’re joined by Ros Eeles from The Institute of Cancer Research. Ros is joining us in January at The Festival of Genomics and Biodata, and we’re really excited to have a bit of time with her today to get a sneak peek at what she’ll be talking about. Ros, can you kick us off by telling us a bit about yourself and your career?
Ros: Yes, thank you. It’s a pleasure to be here. I’m Professor of Oncogenetics at The Institute of Cancer Research. I’ve also got an Honorary Consultant contract at The Royal Marsden NHS Foundation Trust. I’m a clinical oncologist, but also have a specialist interest in adult cancer genetics, and so I both see patients, and also do translational research. I’m a clinician scientist, and most of our research program focuses on trying to find genetic alterations that are inherited that increase the risk of disease, particularly prostate cancer.
FLG: Lovely. Your work focuses on understanding both rare and common variation – could you explain what the difference is between those and their influence on health, and why it’s so important that we understand both?
Ros: Indeed; in prostate cancer, there is a mix of both rare and common variants that predispose to increased risk of the disease. The rarer variants are so-called because they are less common; a lot of them are present in less than one in 100 of the population. They tend to increase cancer risk by at least two-fold, for some of them up to even 10-fold, which are really quite high levels of risk. And common variation tends to occur in more than 1% of the population. These are usually SNPs, which are millions of genetic variants in each genome. Most of them are single letter changes in the genome you’ve inherited from your parents, and each one has a very small effect on disease risk, but because they act together, their risks are log additive or multiplicative, and they can result, again, in quite large relative risks.
FLG: It’s really interesting, and of course, a lot of that work will then apply to screening methods. Can you explain why it’s so important that we develop better screening methods for cancer, and also for other diseases? Because early detection, I imagine, can have quite an effect on the patient’s outcomes?
Ros: Indeed. We know that if you detect cancers earlier, often they may be easier to treat or you may need less treatment. For example, you may need less extensive surgery. You may not need, for example, adjuvant chemotherapy or other adjuvant treatments. And the other thing is that there’s a better survival. So, if the cancer is smaller because you’ve detected it earlier, then you’re much more likely to have a better survival in many of the cancer cases. For example, in prostate cancer, that’s definitely the case. If it’s detected earlier, there’s definitely better survival rates.
So, it’s excellent to be able to find it earlier, but if you can identify people that might be more at risk of getting the disease, then you could focus the intensity of your screening in those individuals. For example, for rare variants, where we know that there’s an increased risk of prostate cancer, some of the rare variants might confer a five-to-eight-fold relative risk of the disease. Then, although those variants might be relatively rare in the population, but for the individual concerned, the risk is high. And then for the common variants, because these are common in the general population, they have implications for population risk stratification. Their associated risk is in a normal risk distribution. I often say, if you imagine we had 100 men lined up in a field, they have a normal risk distribution, say, of their height. And for prostate cancer risk from common variants, we see the same normal risk distribution. In days gone by, before we had profiling for the common variants, we couldn’t pick out who was the man at the highest level of risk versus the man at the lowest level of risk. But now we can do that and say in 100 men, the man who is number 100 on the right hand side of the field, at the top level of risk, has about an 11-fold risk compared with the average of the population. So, these are quite considerable risks from the common variant profiles, they could be as high or even slightly higher than the risk from the rare variants. So, common variants might be very important for population level risk stratification, and for rare variants, you want to find that individual who is at higher risk.
FLG: That’s really interesting to me. I think often when you hear about this, you would assume that perhaps rare variants would be much more risky. Obviously, when we’re talking about variants, something that many people will have heard of is BRCA mutations. Those are commonly heard about in the context of breast and ovarian cancer, but they also influence prostate cancer. Could you explain the mechanism behind that?
Ros: We know that the BRCA1 alteration, which was the first breast cancer gene that was known to increase risk of breast and ovarian cancer, does increase prostate cancer risk by about 1.8 to, at the most, three-fold in some studies. But the one that’s probably of higher risk and causes particularly aggressive disease is BRCA2, when it has disease causing genetic alterations. All these are pathogenic alterations, I should say, we’re not talking about variants of uncertain significance. With the BRCA2 alterations, they increase the risk about six- to eight-fold.
FLG: While we’re talking about prostate cancer, it’s the most common male cancer, but its incidence is higher in men of African ancestry. Why do we see that disparity, and how do these genetic factors contribute to that difference? Going on from that, how can we address those issues in research?
Ros: Men of African ancestry have twice the risk of men of European ancestry. We’re talking about by the age of 80, the risk would be one in eight if you’re European, and one in four if you’re of African ancestry. The risk in Europeans is one in six by the time you’re 90. We now know that some of the contribution to the increased risk is due to certain common variants, but some of them are unique to the African population. The ones which are unique to people of African ancestry have a higher per allele odds ratio than the variants that you see in Europeans.
And then, how do we address this problem? First of all, I think one does have to reach out to the communities. We’ve been doing a lot of work on how to reach out to community groups. At this point, I’d like to say a huge thank you to the men of African ancestry who run these community groups, a lot of them are working closely with us. To put it in context, when we first started our targeted screening study in men of African ancestry, this was some years ago, in the first year, we had about two men who signed up to take part in the research. As a result of going into the community groups, we now have over 200 in those studies. So, it’s made a huge difference, the outreach work that they have done to help lead us into talking to the community groups.
FLG: Outreach is so vital, and there is an emphasis at the moment on improving the genomic data that we have from diverse communities and individuals of diverse ancestries. But what other steps should be taken to ensure that the outputs of that research and its benefits are more inclusive of under-represented populations?
Ros: I think there are two things that we should do. One is to make sure, as you say, that the research includes individuals from those groups. For example, in our research at the moment, we are engaging now with men of African ancestry, but we have much less engagement with men of Asian ancestry. In the recent multi-ethnic study that we did, which was published in Nature Genetics last December, we do now have an increased proportion of Asian participants in that data set. But I think in Britain we still need to increase that, and we might need different approaches for different community groups. It may be that in men of African ancestry, we need to go into community groups through links into those groups. Maybe in men of Asian ancestry, we need to go to, say, religious or community leaders. We don’t yet know whether that’s going to be the most optimal way to reach those groups, so we’re going to ask them if they could help us and tell us how we could do that.
FLG: That’s a crucial point, isn’t it? Asking people and figuring out what they would benefit from. It’s much more important, I imagine, than deciding for people on their behalf. That’s really important. Now, looking ahead, what would you say are the next big breakthroughs in cancer genetics that you’re excited about, and what do you think the landscape of cancer prevention and treatment will look like?
Ros: One of our biggest challenges at the moment is what we call the ‘dark matter’. We know that probably just over half of the genetic predisposition to prostate cancer, we have now found. About 7% of it is rare variants, about 43% of it, roughly, is common variants. But the rest of it, just under half, is unknown, and we don’t yet know whether these are private mutations in each family, for example. That might be one possibility. Another possibility is that we just need bigger studies to find the common variants. We have, through fairly big studies, tried to find those, so we think it’s probably not that problem. Another possibility is there’s another type of genetic variation, and there’s a lot of interest in modification of the genome. So, it could, in theory, be methylation. If you’re trying to find modification of the genome, could that in theory be inherited through controlling areas in the genome? Such control, for example methylation modification, could potentially inform interaction with the environment. That would be a very, very exciting way forward, because potentially that is an area for prevention.
FLG: That does sound really exciting. I think with something like cancer in particular, it impacts so many people that everybody really should be very interested in hearing about these potential future research avenues. It does sound like there’s a lot of really important work going on. How do you see the role of personalized medicine evolving, particularly for individuals with high risk genetic variants?
Ros: The first thing is, can we identify people at higher risk? There’s a lot of interest now in how you might do genetic testing in populations. There are a few studies going on, for example one of my colleagues, Ranjit Manchanda, is looking more at population-based testing. Also for example, we’ve got a new i4i NIHR grant now looking at saliva testing, and how you might do testing in the general population to try and find people at increased risk of prostate cancer. One way forward might be more extensive testing, so you can actually find those individuals who are at higher risk. Then you could offer earlier screening. But the other thing about precision medicine is, if somebody then was found to have cancer, you might be able to tailor your treatment based on the genomic profile, not only of the person themselves, but the profile of the tumor. And then you could use some targeted treatments.
FLG: That sounds quite exciting, and obviously you’ve discussed that your research focuses a lot on prostate cancer. But can your findings translate into other types of cancer, or even other diseases entirely?
Ros: Yes. And indeed, I think this is one area where I’ve had to upskill in recent years. I now work a lot with people who don’t do cancer genetics, because if you are going to do more widespread genetic testing, say, for alterations that might increase prostate cancer risk, as part of that you may find other variants that are associated with other diseases. That means you then must work in teams. We’ve had to start working with cardiac geneticists, people who are interested in carrier testing, for example, family planning, and also colleagues who work in pharmacogenomics, because there are variants that might alter how you prescribe drugs. A lot of that will go into general practice, because a general practitioner has to look at all types of care and the holistic care of the person. So, part of the work is very applicable to testing for other diseases,
FLG: Sounds like teamwork in collaboration is one of the most important parts of it. As I mentioned earlier, you’re coming along to The Festival of Genomics and Biodata in January to discuss your work, and we’re really excited to have you there. Can you tell us what you’re looking forward to at The Festival, and why did you agree to speak?
Ros: I’m very honoured to be asked to speak because I think it’s a fantastic Festival. The other thing is that it tells you what’s going on in genomics. At the moment, it’s a very, very exciting time, it’s really revolutionizing medicine. It’s a bit like in previous days where physicians learned how the body worked, and they described that in the 16th century. I think this is the new revolution in medicine, and that’s why The Festival of Genomics is such a great event, because we’re learning about cutting edge findings and it is an opportunity to have interaction between different groups and different researchers and the public.
FLG: What do you think the audience can gain from attending the event?
Ros: I think personally, I would be very interested in what’s going on at the cutting edge and the new advances. But I think from the point of view of the patients and the public, they can also find out what we’re doing, and what the latest advances are.
FLG: Great. Well, thank you, and we’re really looking forward to seeing you in January. Thank you again for making the time to speak with us today.
Ros: Thank you. I’m really looking forward to it.
Register for the Festival of Genomics and Biodata here.
