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With one in two of us receiving a cancer diagnosis at some point during our lives, it has never been more important to improve the outcomes for people affected by cancer.
This cancer research podcast is brought to you by The University of Manchester in partnership with the Manchester Cancer Research Centre (MCRC). In each episode, our cancer researchers discuss the innovations, discoveries and projects that are changing the landscape of early detection.
Sally Best
Hello. You are listening to One in Two, a Manchester Cancer Research podcast brought to you by the University of Manchester and the Manchester Cancer Research Centre. With 1 in 2 of us receiving a cancer diagnosis at some point in our lifetime, it has never been more important for our research to improve the outcomes for people affected by cancer. I'm your host, Sally best, and throughout this series, I'll be speaking with Manchester Cancer researchers about their innovations, discoveries and projects that are changing the landscape of cancer detection and treatment.
In this special episode we speak to David Wedge, professor of cancer genomics and data science about breast cancer in Black African women. We discuss cancer genomics and what we understand ethnicity to be in the context of cancer genomics.
Oh, this is so exciting. We've got David Wedge in today.
David Wedge
Thank you. Pleased to be here.
Sally Best
How are you doing?
David Wedge
I�m very good. Thank you.
Sally Best
Mr.. Worldwide. We�re here in the new studio David.
David Wedge
Yeah.
Sally Best
Do you feel very special? Yeah. You're the first person to have ever stepped foot in here and recorded in here with me. I feel like a kid with a new toy at Christmas. And Christmas has already been. And I've got. We've got a new, kind of camera view, and people can see more of us now. So you guys get to see that my new jumpers on. I don't know if it's a bit too Christmasy, but I quite like it. So anyway, thank you for joining us. You're doing okay?
David Wedge
Yes. I'm good, thank you.
Sally Best
Coping with your Christmas. Okay.
David Wedge
Yes. Thanks.
Sally Best
Yeah, yeah. For our listeners, were in January 2024, if you're listening, ten years in the future and David will still be storming ahead. But anyway, it's so great to have you here. and I mean, could you just kind of start by telling me a little bit about you, what you do? in terms of, like, the work, your work background and, you know.
David Wedge
Yeah. So, I work in, in cancer genomics and I can say a little bit about that. So, so when we talk about, genomics, we're talking about DNA. So you have DNA in all of your cells, and we, we study that that DNA. Yeah. the difference between genomics and genetics, which, a lot of the listeners will have heard of is genetics is usually focussed on kind of individual genes. And looking at the function of individual genes, whereas when we're looking at genomics, we're looking at all of the genes. So we have, all of us have 20,000 genes within, within all of our cells. And we look at them all together. So we usually do whole genome sequencing. So we look at all of the genes in the cells and, and look at how they, how they interact and work together to cause cancer. so I've been working in, in cancer genomics for, 12 years. and, I just find it find it really, really fascinating seeing, how cancer finds this way of, growing really, you know, faster than other cells, of a, you know, not dying. And the, the way they do that is largely through, altering their genes because that that alters the whole function of, of the cells.
Sally Best
And what was your path into genomics?
David Wedge
so it's actually not been at all linear.
Sally Best
That's great. We don�t like linear path. I mean, no simplicity allowed here.
David Wedge
How long have you got?
Sally Best
well, yeah. Give us a synopsis, David is all I'll ask for.
David Wedge
So, so my undergraduate degree, my first degree was actually in chemistry. First degree. which I did at Oxford. I never actually worked in chemistry, though. After, after I completed my degree, I actually went into teaching. so I was teaching, primary school, kids for, for seven years. I got a bit fed up with, with, with teaching. because, well, I think I was, I was, I was a good teacher, and I enjoyed teaching. but I kind of got a bit fed up with being told what to do by the government, you know, like. Always kind of testing the children and. Yeah. Which I really didn't enjoy, at all. so I went back to, to university, I did, I did a masters in software development. I then went on to do a, a PhD in kind of artificial intelligence. It was kind of maths, maths and computing. and that actually wasn't in, genomics at all. It was actually I was trying to predict how much water would come over sea walls. and I was using this kind of machine learning artificial neural networks methods for trying to predict how much water would come over sea walls. after that, I did a series of research post postdoctoral research posts, and I was working, actually in Manchester, looking at metabolomics, which is that kind of small, small molecules glued onto proteomics that's looking at the proteins. and then I moved on to genomics. So that's looking at the, at the DNA side. I did various different, projects looking at different aspects of biology. and then from, from there, I then kind of kind of got stuck because I though actually this is what I want to do. Yeah. I thought, I just think, genomics is, is, is fascinating. And so I've kind of got stuck in that area and I've been working in, in cancer genomics for, ever since.
Sally Best
You've been all over the shop. I love it, you can tell everybody that careers are not for life.
David Wedge
Yeah. No, no, absolutely. I think, you know, if if you see something else that you're interested in then then yeah, go for it. You know, it's that there's no there's no point staying, you know, stuck in a job if you're not, if you're not enjoying it and you can see something else that you would rather do, then yeah.
David Wedge
Yeah. Go for it.
Sally Best
Good message for the day. And you've said before that you don't actually, I know back then it was O-levels. You don't have any qualification past O-levels of biology.
David Wedge
No. That's right. So I gave up biology.
Sally Best
Shame on you, David.
David Wedge
I did, chemistry and physics, A-levels and maths and English actually. I mean, the reason that I, that I went for chemistry rather than biology was because when I, when I really like about chemistry is the underlying, molecular model. So you do all these experiments and you get all of that, you generate all of this data.
but there's also this underlying explanatory model, which is all based on, on your atoms and molecules. And so you're, you're using that model to explain all of the observable phenomena. And at the time that I was doing, O level biology, which is, which is some time ago, we didn't really have that, that model in, in biology. Yeah. But I, since I think since with, with the advent of genomics, I think that that is the, the underlying model and genomics can explain, not everything but it can explain, really a large amount of, of the observable biology. So I think biology is now at the stage that chemistry was kind of 40 years ago, where they do now have that this explanatory model. And for me, because I'm essentially, I'm a computational scientists. What I do is I, I analyse the data. And so for me, having that, that underlying explanatory model means that I can use my skills because I can analyse all of this genomic data. and I think I'm putting my skills to, to good use. in biology. Yeah. With this genomic model.
Sally Best
Yeah. So if you had your time now, would you do biology?
David Wedge
Yes. Yeah. Maybe I'd actually go into biology.
Sally Best
Trying to convert you, it�s the best subject. Ever. Sorry, I sound a bit biased. and so from your kind of line of work, what have you, what's been your overall view of how, what have you learned about how different cancers evolve? Yeah. So, so when we talk about, evolution in cancer, it's our focus is quite different. How you might, you might normally think about evolution. So when we talk about evolution, you think of Darwinian evolution. It's about how species, you'll have a lot of, individuals who are members of a species and they will, acquire mutations which allow them to, to, to change their behaviour. Those will be selected over time. And, and eventually you get emergence of a new species. because you've got, you've got, enough mutations that they actually become differentiated from, the previous ancestor. And when we look at cancer, we're not going not looking at evolution of individuals. We're actually looking at the evolution of cells in individual cells. So when we look at a cancer, what we see is that actually, a cancer isn't just that, a homogeneous mass. Actually, if you look at the individual cells, every cell within a cancer is different. So each cell will, will have acquired, a number of, of mutations that are only seen in that cell. some of those, some of those cells might acquire an advantage.
David Wedge
They might get a mutation in a gene, which means that they can grow a bit faster than the, the cells, around it. And then so that will give rise to, to lots of, daughter cells and granddaughter cells. And it might outgrow, the other cells within the tumour. and so that's why we have evolution. It's because we have mutations that are occurring in the cells generating lots of extraneity, lots of different cells, and then they're competing with each other. And that's leading to evolution. I guess we kind of look at the evolution in three phases. So the first thing we look at is why do normal healthy cells become cancer. And I mean the simple answer is, is mutations that are the mutations occurring all the time in normal and in cancer cells. if and yeah, if you're unlucky, then one of those mutations might, affect, a gene that causes cancer. So there are some like very well known genes, like, BRCA one, BRCA two, which cause, breast cancer. Yeah. So you might be unlucky because one of your normal cells might acquire, a mutation, which, which causes that cell to become cancerous. And then because it's divided, that cell will divide, give rise to two daughter cells, they'll keep dividing. Then you may get a growing cancer. One of the interesting things that we found when looking at looking at that, that how certain normal cells become cancer, is that, you have lots of these small mutations. They just be single base pair, mutations. You see them in normal and in cancer cells. But what really seems to distinguish cancer from normal cells is actually these large scale rearrangements. So as well as having single base pair mutations you can get these massive rearrangements in cancer. And in fact we nearly always say large scale structural rearrangements in cancer. But we, we rarely see them in normal cells. So it looks like in terms of their evolutionary process, that is the key events that really, enables normal cells to become cancer. the, the other phases of evolution that we look at are kind of how tumours become more aggressive and how they're able to grow larger and that is different when we look at different tumour types. So if you look at the genes that are mutated in breast cancer, then they'll be quite different to the genes that we see mutated in leukaemia or liver cancer or whatever. You know, there. And every cancer actually has different drivers. But what they all have in common is that they all evolve over time and they all have lots of heterogeneity. So when you look when we look at the cancer cells, that they're always, we always see lots of differences between the different cells. And I suppose the third and final phase revolution that we look at is the transition from the primary, organ to metastatic site. So cancers, as they, as they grow, sometimes you'll have some cells that, that acquire the, the ability to, to break off from the primary tumour, go into the bloodstream or the lymph system, and they can spread to, to other sites.
And again, that's an evolutionary process. We could look at that genomically we can identify what are the mutations that are enabling cells to become metastatic. But I think in, in, in that, situation, we're also very interested in the, the normal cells that are around the tumour because if you think about metastasis, you've got, a cell that is in the primary organ. what, what it, what it and what happens when it metastasises is that it has to go into a completely different environment because that's to break away from the, the primary, site, go into the blood, survive in the blood, lodge itself in some distant sites and then grow in that distant site. And because that's going to be a different tissue or a different organ, it's going to be a very different environment. So when we're thinking about metastasis, as well as looking at the tumour genomics, we need to actually think about the microenvironment. So this the surrounding normal cells and what they're doing. So effectively we've got a kind of coevolution process where we're looking at how the how the normal cells around the tumour respond to the cancer cells and how the cancer cells, the cancer cell responds to the, to the surrounding normal cells. Yeah. So in a lot of our studies, we're now, looking not just at the, at the, the evolution of the cancer, but we're also very interested in, in how the, the surrounding normal tissue responds to, that cancer cell and that there are things like, like the immune, the immune cell response. So, yeah, know your body is supposed to, detect the cancer cells and eliminate them. but sometimes it doesn't work so effectively. Yeah. So we are, increasingly in recent years, starting to look at, look beyond the, the cancer genomics to look at the, the microenvironment as well.
Sally Best
Yeah. So there's a lot of complexity to what you're doing here. and in terms of like we know that, you know, we each have our kind of individual footprint in terms of the genome. And there's differences between each of our genomes and that they vary, kind of in context between, say, races or, you know, kind of different families within different continents or and I'm just wondering what, how race comes into this and what the context, what you would understand race to be in the context of genomics evolution. Because I know in, you know, in some ways, like my understanding would be biologically, you know, race is kind of a slightly tricky thing to define now just because of like, continental drift and, migration patterns and things like that. So I'm just wondering what it is in terms of genomics.
David Wedge
Yeah. So, so you're right there, there is a lot of complexity in terms of, of race, and how that is, that is defined. so, you know, you can draw out the, the kind of the, the, you know, how people are, related. Yeah. but actually, that is actually more complex than it is in, in cancer. So, yeah, I was just talking about the evolution in cancer. Yeah. In cancer, essentially, you have one cell which gives rise to, to two daughter cells, and those daughter cells will inherit all of their, the variants, all of the mutations that are in the parent cell. Yeah. and when you're looking at humans, that actually isn't true basically because each individual has two parents. Yeah. and you will inherit kind of half of your, approximately half of your DNA from your mother and half of your DNA from your, from your father. And so that means that actually it's not so simple to just draw out, a tree, with that kind of phylogenetic relationship showing the, the relationship between individuals. and so you obviously you'll have people who, yeah, maybe may have, that, that all of their DNA that comes from, particular locations, you might have somebody, and yeah, all of their ancestors, have been, European. They. Yeah, they, they've grown up in Europe and they are, you know, will be quite closely related genetically. but you also, you know, obviously, a lot of us, a mixed race, including myself. So I'm, about 50% European and 50% Asian. and so obviously that that that is a challenge in terms of, you know, drawing out the phylogeny. Yeah. Wait, wait, where do I come from? Because here I actually have DNA, which comes from two different branches of the, of the, of the tree. If you're thinking about the tree of, of all human life, so it's actually much more complicated thinking about the, the, the genetic relationship between individuals than it is thinking about the, the genetic relationship between individual cancer cells.
so, you know, with, with that caveat, we can look at individuals, we can identify all of their, the variants within their genome. And typically each individual will have several million kind of about 3 million or, or more than that. variants within that genome, we can look at how many of those variants they share with other individuals. and so we can get a kind of, effectively it's kind of distance metric. So we're saying how far away is this individual from another, individual? If we do that, then we can see that we have groups of people who have who have less distance between them, between themselves than they do with people in another group. Yeah. So, so we can define genetically, groups of people who have broadly similar, genetics. and that is because they will have broadly similar ancestry. So they might have they might share some, some ancestor. So if you go back, you know, some generation, then you will find that those people who have similar genetics likely share, some of their ancestors. Yeah. so it is complicated and it's not as simple as drawing out, a tree and saying, these people go in this place on the tree. Yeah, people go somewhere else. But we can, calculate kind of broad metrics that will tell us how similar people are.
Sally Best
Yeah. Okay. So I was going to say I was trying to holistically think about kind of race the other day. And you have, you know, what you would kind of title as social races. And then when it comes to actual kind of biological race, thinking about migration patterns and understanding. So if I was born in France, would that make me French or because my parents are English?
Am I still English? Yeah, but it's quite nice that you've got that broader view of saying, okay, well, we can define people within a category whereby they fit within this group because they are a certain percent related.
David Wedge
Yeah. So, so I guess because, you know, when we're working within cancer genomics, we will usually kind of look primarily at the genetic kind of definition of, of race rather than kind of more social definitions of ethnicity. Yeah. but that, that is complicated. Yeah. so if, if we, for example, if we sequenced, a set of, cancer patients of black cancer patients in, in Nigeria say. Yeah. And then we sequenced, a cohort of white patients in the UK. And then we see some differences between those two cohorts. Then we would see the genetics so we can see it there, there are genetic differences between those two groups. But we don't know if it's the genetic differences that explain the, the differences in the behaviour of the cancer.
So yeah, if, if, you know, if the one set of of cancers behaved more aggressively than the other, we wouldn't know if that was because of the genetics or if it is because of, environmental effects. So we can't completely ignore those environmental, effects or behavioural effects. You know, people might, might, you know, have a different diet or, you know, might, might, might make different, life choices which are associated with, the aggressiveness of the cancers. Yeah. so ideally what, what we'd like to do is to study, people of different, races, but also in different locations. Yeah. so, and then we can, hopefully separate out the environmental effects and the genetic effects.
Sally Best
Yeah. So it's kind of like a nature versus nurture
David Wedge
Absolutely.
Sally Best
Interesting I love it. Yeah. Thank you. And I think it's a good thing to remember about because I kind of thought about it this way. But the kind of genetic race versus social ethnicity. And it's nice to be able to put them in two discrete categories for this conversation, because otherwise, well, we go around in absolute circles. so you're involved in the International Genomes Consortium, very fancy title. Tell me about it. What does it involve? How did you get involved?
David Wedge
Yeah. so the International Cancer Genome Consortium was first started in, I think around 2008, something like that, 2006. So, so it's been around for, for a while. Yeah. And their aim was to, to collect, samples from 25,000 cancers. And this is across all different, tumour types so into different tissues. So they, they actually I think collected samples I think 38 different tumour types. and then they wanted to do DNA sequencing of samples from those cancers. there are different types of sequencing that you can do. So I mostly work with whole genome sequencing where you sequence every, the whole of the DNA, every base within the DNA. but sometimes people just sequence there, the regions that are, that are actually coding for, for genes, and proteins, sometimes people just do targeted sequencing of genes that are known to be, known to cause cancer. so within that 25,000, set of samples, they didn't have whole genome sequencing from all of their the samples. So there was a kind of a sub group within, within that, that set and that were working with, almost 3000 cancers that had been whole genome sequenced. and they were analysed by, by a group called the Pan Cancer Analysis of Whole Genomes. So that's, PCAWG, so we call it PCAWG is kind of, how we normally,
Sally Best
Science acronyms never end
David Wedge
And I was asked in, I think it's about 2013 if I would lead one of the working groups that was analysing, the data, within, PCAWG. and so had these different working groups that were looking at different aspects of, cancer genomics. And I was leading, one of the working groups that was looking at cancer evolution and heterogeneity, together with Peter Van Lu and Paul Spellman. So there were, there were three of us, leading that, that consortium.
Sally Best
So just quickly the heterogeneity, is the difference between.
David Wedge
So I said when I'm saying heterogeneity here, I'm talking about heterogeneity within the tumour.
Sally Best
Okay.
David Wedge
and I see we have lots of heterogeneity between individuals and between vectors.
But here we were looking at the intra tumour okay. So there so the heterogeneity between individual cells within the cancers.
Sally Best
Yeah. Okay. yeah. Cool. Sorry to interrupt. You just clarify slightly.
David Wedge
Yeah. So yeah, we ran that project for it was 5 or 6 years because we had such a large amount of data that said, that's how long it took to analyse the data. And then we, we published, two papers in 2020 and 2021. from, from those, those studies, in which we, we reported kind of the evolutionary patterns that we observed in all of the 38 different, tumour types. Yeah. one thing that was, so, so I think that the great strength of that consortium was that it was international. They work in lots of different countries. one of the, don�t want to say deficiencies, but one of the kind of the, the gaps, in that consortium, was that it wasn't, truly global. So it was international. but actually, most of the most of the, the studies, that made up the ICGC were in Europe and North America. there were smaller number in Asia, but there were actually no projects, in Africa. Yeah. so it wasn't really, truly a global study. so we found out, enormous amount of information about, about cancers, in, in, in richer countries. but we, we, we, we weren't able to discover very much about how cancer works in, in those other countries, particularly in Africa.
Sally Best
Yeah. And I guess that's a pattern that was pretty common, throughout research history and things. And it's sad, but, it's nice to see that this kind of international progression is coming to kind of throughput now, and with Mr worldwide over here. We're obviously making great steps. And, so just kind of going back to the, the point of race and this point of Africa. So we kind of see breast cancer. We spoke about it in season one with Gareth Evans so long ago. We were talking about Gareth earlier. and we talked to him about PROCAS and it was like, looking at the risk assessment. So he was talking about things like BRCA and, hereditary, genes and things that would increase your risk of developing breast cancer over your lifetime.
and it was really interesting to hear that. and within that, I guess, comes the question of kind of different races and different risks. And we know that. And so as a black African women, the risk of developing breast cancer is more than that in kind of you white Caucasian women. But also the, the as you've said, the compilation of data that we have available to us is mainly of those Caucasian women.
David Wedge
Yeah.
Sally Best
yeah. So I mean, firstly it's to ask, you know, why is that? Why is that data mainly Caucasian? And secondly, you know, what more do we know about those differences between black women and Caucasian? Black African women sorry. And Caucasian women.
David Wedge
Yeah. so I mean, I think a lot of the, a lot of the reasons are, economic. Yeah. so, like in the, in the UK, we're very fortunate because, the UK government and, and charities such as CRUK do put a lot of money into, cancer research. And yeah, similarly, in, in countries like, like the US, there is a lot of money going into scientific research and generally because the, because the funding is coming from, governments or charities within, within those countries, it's kind of understandable. They, they want to be fund projects within, within the, their own countries. Yeah. And so historically, the majority of funding has been spent within, those, those rich countries, who tend to have, people who, who are of, European or Asian ancestry and there's been, you know, relatively, small amounts of funding, that have gone into, Africa and into South America as well, actually. why that matters is because, if we look at the, the genetics, lets say, you can, you can, you know, classify people genetically based on their, that the similarity or the difference between their, between their genomes. And so people, who are living in Africa and who are have African ancestry are likely to have a set of variants that it that, yeah, often similar between individuals, individuals, of African ancestry. And then if you look at people of European ancestry, you know, similarly they will they are likely to to share, a lot of their, a lot of their mutations, a lot of their variants, within their, their genomes. But when you compare across different races, we see that there's, there's much lower overlap in terms of the variants. So, you know, they have developed these risk prediction tools that will, predict how likely, you know, for example, women are to, to develop, breast cancer or to develop, aggressive, breast cancer, but those are primarily being developed, using the genomes from, white women in rich countries. and that is the reality. but that means that they are actually not, not effective as risk prediction tools and they're not really able to, to predict well, the probability that a black woman, will develop, breast cancer.
Sally Best
Yeah. And I guess it's quite limiting as well, not only here but worldwide. I mean, we've got such a kind of diverse diaspora here, you know, I don't know the figures at all, but I think because of that, you can understand that there might be, you know, a lack of precision. so the treatments that you can allocate because of that, that data base doesn't hold enough data.
David Wedge
No. That's right, I mean In the UK, when, when, when, doctors are doing these trials, that they're, they're completely blind. So they'll, they'll take all comers and anybody who is willing to, to take part in a trial, yeah. Can do but because the, you know, that the numbers of, of people that we have, you know, in the UK, you know, of, of non-European ancestry, well, well, you know, obviously be lower than they are for, for people of European ancestry. Yeah. we just don't have the numbers typically, from, from studies that are carried out just in the UK and that's why so I and now and contributing to a number of collaborations, in, in Africa and also in, in countries in Asia, to collect samples from, from patients, in those countries because, because we can get data from patients of different, different ancestries. and also we can look at the environmental effects, in those, in those other countries.
Sally Best
Yeah. Okay. So I mean, yeah, we've kind of and I understand a lot of the work that you do in your, in prostate and oesophageal, but you have said talk about breast. and yeah. So I mean reading up about breast cancer is quite shocking actually. Like the disparities between kind of yeah, breast cancer in Caucasian women, breast cancer in black African women. and I think, is it kind of that difference is still you know, if it's, black African women that are in, kind of high economically developed countries also have, a differentiation in the aggressiveness of Caucasian women in those high economically developed countries. Is that right?
David Wedge
Yes, yes. I mean, at that that is, very interesting observation actually. So, so the studies that have been done, in Africa, they have shown that there is a higher prevalence, particularly of the more aggressive types of, of breast cancer, in Africa. But when we come to, to, richer, richer countries such as the UK and the US, I mean, we we've actually removed a lot of the confounders when we do that. You know, we're, we're looking at patients who have grown up in the, in this in the same country who will be exposed to the similar environmental, factors. but we still see, a significant difference in, the prevalence of aggressive breast cancers between, black UK women and white women, white UK women and a similar observation being made in the US.
Sally Best
So from that you can infer that you can remove all environmental impact on that. that there's some underlying genetics there.
David Wedge
So, we think so. I mean, I mean, a bit of care needs to be seen. You can because you still have factors, such as, such as class. So yeah, there's the interactions between different social factors.
Sally Best
Oh yeah that�s a really good point.
David Wedge
Yeah. At race there will be an interaction with kind of socio-economic factors. Yeah. but it does look like the, the underlying genetics or ancestry. certainly do play a large part in, in causing that, that difference in, in aggressiveness of breast cancer
Sally Best
And it's a difficult job for you because there are so many cofactors. that are contributing to differences. So your modelling must be very blooming complex to say the least. so can you tell me about the research that you're doing in Nigeria? Just give me a bit of an overview of that.
David Wedge
Yes.
Sally Best
So interesting. Yeah, I've read about it.
David Wedge
yeah. So, so, so, I was contacted, I think 5 or 6 years ago, by a researcher Funmi Olopade. so she, she is, she works at the University of Chicago. but she carries out most of her, her research, in Nigeria. and she, she contacted me because she, I think she'd seen some, some of the work that we've done, previously looking at looking at evolution of cancers, including, breast cancer. and she asked me if I, if I wanted to be involved in, in, in some of the analysis of the data that she was generating. so she, at that time had collected, samples from 100, women with breast cancer, in Nigeria. And she wanted us to analyse the genomes of those cancers and compare them with, a cohort from, from the US of actually African American women, but also, white women, in the US, so we, we took the data, we, we analysed it through our pipeline. So we have kind of computational pipelines that will run various analyses, on the data. And we were looking for kind of signatures that might tell us something about how, the tumours, might evolve differently. in the Nigerian women, compared to the, to the US women, the black and the white, US women essentially that, that was, that was what we did and we still actually working with, with Funmi and she's now, built up her cohort. So several hundred women we are continuing to analyse those samples.
Sally Best
So just to clarify, they were all black African.
David Wedge
That's right.
Sally Best
Yes, yes. yeah. Because obviously it's quite interesting. You've got the distinguished like we have kind of black American, black Afro-Caribbean, there's a lot of, kind of. Yeah, different sets of data that I can understand that you'd, you'd have to collect. what were the confounding differences that you saw in terms of the kind of aggressiveness of the cancer?
Sally Best
And what was it what was different about the cancer that these kind of black African women that were presenting with them that you'd seen previously in white Caucasian women?
David Wedge
Yeah. So, so I mean, we were primarily focussed on the, on the, the, the genomics. Yeah. And when, when I say that, we were, we were actually we weren't looking at the inherited, status. So, so yeah, we know obviously that the, the black women, you know, have different ancestry may will have a different, inherited genome that they will have inherited from their parents. we actually weren't looking at that. What we were looking at was the, what we call this the somatic mutation. So these will be the, the mutations that have occurred within, a patient's body during their lifetime. Yeah. so in cancer, you know, we can see all of these mutations. So typically, a breast cancer would have around 5000 mutations, in some, some cancers have more and some have less, but around 5000 mutations that have occurred just within the cancer cells.
And we could also see, the kind of large scale rearrangements. And I was talking about earlier. So we were, we were looking at their, the somatic, you can say pattern. within the Nigerian women, African American women and the, the white women in the US, what we, what we what we found that was, surprising, was that we saw a high rate of mutation in this gene, called GATA3 and, GATA3 has previously been seen in, breast cancer in, in white women in the UK. But what was surprising in, in Nigeria was first that we saw it had a much higher prevalence in that group than we've seen in, in another in other cohort. So for example, in the, in the UK and the US, but also we saw that the GATA3 mutations were occurring across all the different subtypes. So, so within breast cancer, there's been a lot of work, done that's identified that, that not all breast cancers are the same, that we can separate them into different, subtypes. And they're often called, hormonal subtypes, because we'll look at the, so for example, we'll look at oestrogen receptor, and see the, the expression of, of that that receptor so we can separate breast cancers into ER positive. And ER negative tumours.
Sally Best
So that's oestrogen receptor. That's positive. Yeah.
David Wedge
and we also look at, look at some other some other genes such as HER2. So we can have HER2 positive HER2 negative tumours. so previously GATA3 has been reported to primarily occur in I think HER2 negative tumours. Okay. but when we looked at Nigeria we saw actually very similar prevalence of GATA3 mutations in the HER2 positive and the HER2 negative tumours. So it looks like something very different is going on. Yeah. In terms of the genetics, the somatic genetics of breast cancer in Nigerian women vs US women okay.
Sally Best
And is interesting to break it down. So you have your germline which is your inherited and then your somatic which is what changes after you are kind of a foetus basically.
David Wedge
Yes. Exactly. And I mean I suppose because, because I tend to think about things through an evolutionary perspective. That, that it probably isn't surprising if there's actually an interaction between the germline, the inherited genetics and your somatic genomics. Yeah. Because those mutations are occurring kind of on the background of the inherited genome. So all of your all of your cells have your inherited variation, your germline variation. And then when it, when a mutation comes along in the cancer that's occurring on, on top of the, the pre-existing mutations. Yeah. So actually where we're not really surprised if there's a, there's a link, an interaction between the germline genetics and the somatic genome. Yes.
Sally Best
But it's all very complex. So just to simplify it for our listeners slightly, what you're saying is that between when you were looking at the cohorts holistically, between the white Caucasian and the black Afro, black African women what you saw in the genome, and you were studying the somatic, kind of cell line, which is what you, develop after you have been conceived. So it's not inherited is that you saw, kind of a higher prevalence of some of the tumour driver genes, which is like the way that you'd define them.
David Wedge
Yes.
Sally Best
Okay. And was that, less genomic stability? Was there more genomic instability within that cohort?
David Wedge
Yeah. So we did see that. So, so first we see there was a not that key driver gene. So we had GATA3. We also had a lot of our tumours that had mutations in TP53, which is a very well-known driver gene. Yeah. Which causes a lot of genomic, instability. and so we if we separated the tumours into those that had GATA3 mutations and those that had TP53 mutations, then we saw more genomic instability in, in the, the tumours that had TP53 mutations. But actually when we looked at the cohort as a whole, they generally had more genomic instability than the, than the, the breast cancers in, in whites, US women.
Sally Best
Okay. And what does genomic instability mean. The kind of the level of the genome.
David Wedge
Yes. So genomic instability is to do with how the cancer DNA, is different from your normal healthy DNA. So when we when we look at the, the, the DNA, we're looking at the mutations that are occurring in the cancer. But we always actually look at the blood. We'll look at a blood sample as well. So when, when we collect a sample from a patient's tumour and we will also take a blood sample and we'll look at the DNA in the blood, and then we'll look at the DNA in the, in the tumour. We'll see what's different. And what we see, is that we have lots of these, these small mutations, single nucleotide events. We got as one, one base pair in the genome that's changed. But we also have lots of these large scale rearrangements. So when we talk about genomic instability what we what we're mainly talking about is those large scale rearrangements. So not just the single point mutations but these massive rearrangements. And they can affect a large part of the genome. So just having one rearrangement could affect lots of different genes.
Sally Best
Okay.
David Wedge
So those, those can have a much stronger effect, on the cells than just having, a single point mutation.
Sally Best
So can that increase the aggressiveness of the tumour then.
David Wedge
Yes. Yes it can. Yeah. so it can increase the aggressiveness of the tumour because, because having these, these rearrangements can affect lots of different genes. And if you have a lot of genomic instability, it means that you are the cells are requiring lots of lots of changes to the genome at every cell division. So every time, a cell divides and gives rise to two daughter cells, you'll have more and more genomic instability. So they evolve, much faster. and you also risk generating because you're generating lots of heterogeneity. That kind of gives the, the raw material that evolution can act on. So if you've got lots of different cells that all have different, mutations, then some of them may not benefit the tumour at all. And actually some of those cells might die because they're not they're not benefited at all by the by the genomic instability. But then if you happen to get one cell that has acquired, the functionality to, to actually make it, more, more competitive, maybe to divide faster or to be less likely to, to die, then that will, yeah, continue to grow faster, will give rise to, to more, more daughter cells. And that's why we get evolution and we get cancers kind of progressively become more and more aggressive. Yeah. as they grow interesting.
Sally Best
So basically, what we've kind of summarised is that we can't negate the interaction of, environmental factors, socioeconomic factors, sort of things like diet, but what we have here from this study is a grounding in the fact that the interplay of the kind of the genome and these different, genetics and expressions of different genes is contributing to the fact that black African women present with breast cancer earlier and at a later stage, that is more aggressive.
David Wedge
Yes. Yes, we think so. We think that there is a genetic contribution to that aggressiveness.
Sally Best
Yeah. Got it. So interesting. And I'll link the paper for everybody because I've had obviously a bit of a read of it, as is required. But it's really interesting the, the research that you've, you've gone into and I guess my next question would be like, what are the next stages of that? You've done this kind of what was it two initial studies that you've done, 1 in 2018 was at the was the first one that you were involved in this one and then there was one before?
David Wedge
so, there were some previous studies, from, from that cohort that were published before I, before I joined
So I, I only have my name on one page for them. But we are we are, we are, we are still working with that cohort and it keeps getting larger and larger. And we are so we're, we're now doing, we're, we're continuing to do the whole genome sequencing to look at the DNA. And we're also now expanding the analysis.
So we're doing other things. So we're looking at the RNA and the proteins within the tumours are also now doing multiple sampling. So, so in some cases were able to get quite large samples from, from the tumours. And particularly if the, if the, if the women have undergone surgery to remove the remove the cancer, then we can actually get a really large chunk of the tumour. And then we could take small biopsies from, from that tumour. And then we can actually sequence lots of different regions of the tumour. So that gives us a lot more information about the, the heterogeneity and the evolution that's occurring within those tumours. So we're kind of going further and getting more resolution in terms of looking at the heterogeneity in evolution in the tumours.
Sally Best
Interesting. And I mean, I wouldn't be surprised if people were listening and thinking, well, it's all very well and good that we know about these differences between two cohorts. and in terms of genetics, but what is the application of that in a clinical setting and kind of a medicinal medical setting?
David Wedge
Yeah. So I mean, I think that I think the starting point for me is that is that we do need to, generate more, more knowledge. because until very recently, there were no whole genome studies in Africa. So I think this, this paper with the way we talked about was actually the first paper, to report whole genome sequencing of any cohort of cancer patients, in Africa. And so I think the first step is just to generate that knowledge. We need to know how cancers work, how they evolve, in African women or in black women in Africa and in and in other countries. I think that now we are starting to get that knowledge and we can kind of see there are some, some, kind of insights into how we might, might be able to treat, those patients, with kind of different, slightly different, ways to how we might treat, white women in the UK. the I guess one of the hints is, is around the, the genomic instability that we've talked about. so there are treatments that are particularly effective, on, on tumours that are genomically unstable. So there are things that we call, Parp inhibitors. That's a drug that can be given that is particularly effective on, on tumours that have this genomic instability. I think radio therapy tends to be, somewhat more effective on tumours that are genomically unstable. Yeah. so, you know, there are treatments that we know of that that may be more effective, on, on these particular types of tumours. but we haven't really yet explored or it hasn't really been explored in particularly in Africa. So I think those would be the next steps would be to see, if we can, kind of tune, tune treatments more towards individual people's cancers. And one of the factors that I think we could be taking into account, when we're looking at looking at individuals, is is their, their ancestral, background, their, their race.
Sally Best
Amazing. So, yeah, that's what you're talking about there is precision medicine as a whole. and understanding that if you can kind of. Yeah, get somebody down to understanding what their genome is, then you would hope that in the future precision medicines can be applied. That would kind of. Yeah. Precisely. personalised medicine. Yeah. Within that. Yeah.
David Wedge
Yeah. Exactly, exactly. And I think, I think, you know, race is just one, one of the, one of the factors that could be taken into account. Yeah. I mean, ultimately we're not aiming just to, just to tailor treatment towards one particular group of people, but we are really aiming for personalised treatment. I think that that this is just one, one aspect.
Sally Best
Of. Yeah. So striving towards like health equity then.
David Wedge
Yeah, absolutely.
Sally Best
So interesting because I guess as well, the way that medicines have been devised within, say, the UK would have been based on a Caucasian background. And Caucasian clinical trials. So then you can kind of see that how people slip through the hoops, because the treatment that is applied as a kind of a blanket, within the UK that is based on those data sets, will then apply to these other cohorts.
So it's so interesting to kind of think about the minutia of it and then where your work is going to feed and, and hopefully be implemented in healthcare systems as well.
David Wedge
Yeah, absolutely. I think it is a question of equity and of inclusion. We are also doing other studies, in other countries. So we're looking at, at prostate cancer in South Africa, looking at oesophageal cancer in Kenya. And we also we also have some studies looking at breast cancer, in Asia. so we've got a paper, that we're, we're about to submit to. The journals, breast cancer in Hong Kong. And we also just started, work with collaborators in, in Malaysia looking at breast cancer and ovarian cancer, in Malaysia. so, yeah, and we we're really trying to broaden our answer to, as many, as many different, different regions and as many different, ethnicities as we can.
Sally Best
Oh, that's absolutely incredible. I don't know all that, you really are Mr worldwide you and the team. that's great to hear. And I think, yeah, it's really humbling to know about these projects that are going on outside of Europe and this kind of Eurocentric, sphere that we sometimes end up living in. What are your hopes for the future of genomics research as a whole?
David Wedge
Yeah. So, I mean, I think in terms of the global genomics where we're certainly going in in the right direction. you know, yeah, I've talked a bit about, about my research, but it's I think, you know, lots of people now, do doing research, much broader research covering, people of different races, and of different, social classes as well. I think that's another important, differentiator. we're also moving beyond the genome, and starting to look much more at the, the interaction between, the cancer cells in their and the tumour microenvironment. and there are, there are lots of new, new techniques that, that are coming out now that that allow you to look much more at the, the kind of spatial distribution. So, so most of what we've done, until recently has been taking, a piece of tissue, kind of chopping it all up and then sequencing it. But there are now a lot of novel techniques that, that can carry out sequencing without kind of chopping up all the, all the tissue. So you can actually see the kind of spatial arrangements, you can see, how individual tumour cells are interacting with, with other tumour cells and with the, their, their, environments. And so we're doing a lot of work now, in that space. So moving beyond the, the genomics and looking at the more the interaction between the, the tumour cells and the environment. So I think that those are the areas that I think, you know, I'm working on. I think a lot of other people are a very interested in as well.
Sally Best
Interesting. And at the start of the podcast, you talked about your slightly, slightly transitory career jumps. Do you feel fulfilled in what you're doing now?
David Wedge
so I, I, I don't plan on moving anywhere else. I think, I think, I'm going to be staying with, with cancer genomics or omics. So, so we're now looking at proteomics and transcriptomics as well as the, the genomics. but now I don't think I'm going to be going, going anywhere else.
Sally Best
Now, that's what I was trying to ask. But in a really polite PC way, it's basically, David, don't go anywhere. well, thank you so much. So you've kind of talked to us, about, yeah. What we understand as race within genomics, the difference between genomics and genetics, the importance of internationalisation, your research projects and breast cancer. And I know you've mentioned a few others, and, we've got breast cancer in Hong Kong. and then you've mentioned kind of prostate and oesophageal and I'd love to grab you and talk to you about them all, at some point, we all, fortunately don't have enough time to go through your portfolio. and, yeah, we've talked about your hopes for the future, and it's been great. absolutely lovely discussion with you. So honestly, thank you so much for taking a time away from, you know, computer software. Really appreciate it. You definitely need a break from that once in a while. and yeah, thank you ever so much for just sitting and talking with me and, letting our audience hear about everything that you do.
David Wedge
Thank you.
Sally Best
I think it's been great. and guys, I'll link all of the stuff because there's kind of a few papers that you might be interested in, and I'm sure David, we can link. software and everything. but yeah, thank you guys for listening to our very special episode with Mr. Worldwide. and yeah, we'll speak to you next time.
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