We are all made up of code. 3000 million letters of code to be exact.  

These codes make up genes within our DNA and are responsible for how cells in our body grow and multiply. 

But what happens when something in that code goes wrong?  

Welcome to another episode of That Cancer Conversation, a podcast from Cancer Research UK which brings together the science and the stories behind cancer, with me Sophie Wedekind. 

In this episode, we’re unpacking the human genome and looking at how inherited gene mutations can increase our risk of getting cancer.  

Mike 

Well, genetics is really the study of DNA and mutations. Mutations are changes in DNA sequence. We know that DNA is a long sequence of letters of code. We have about 3000 million of them in the human genome, and a mutation is a change of one of those letters of genetic code. We believe as a principle that all cancers in some form or another are due to changes in DNA. 

Sophie 

That’s Professor Mike Stratton, former director of the Wellcome Sanger Institute and a pioneer in cancer genetics.  

Mike 

Now, those changes in DNA could be changes that are inherited between a parent and their offspring, or they could be changes in DNA that are introduced during the course of a lifetime, these changes are happening in every single cell of our body during our lives. Our DNA is constantly in the process of being mutated and changed. And if the wrong set of mutations happen to occur in a single cell, then that cell could be put along the path to becoming cancer. 

Sophie 

Changes in our DNA are called mutations. You can think of it like printing an instruction manual. If the words are changed or an instruction is missing it might affect your actions. And it’s the same for our cells. If there’s a mutation it can change the way a cell acts, which could have negative effects.  

Cancer itself can’t be passed down from parents to children. And genetic changes in cancers cells also can’t be passed down. But a genetic change that increases the risk of cancer can be passed down if it is present in a parent’s egg or sperm cells. 

The idea of cancer passing down within families goes back a long way. As far back as 1866, when French surgeon Pierre Paul Broca noticed the history of breast cancer in his wife’s family which included 10 women with breast cancer over three generations.   

Mike 

I was always interested in biology and in discovering new things about the living world. And really that was the reason I went into medicine, I think because I thought that would be a way of, you know, reaching those aspirations. So I trained as a doctor and becoming a pathologist meant that I was looking down the microscope and I was seeing, actually, the biology of human disease, really upfront every day of the week. I was lucky enough, really, to be alive at a moment of an extraordinarily important discovery. 

So I was a young pathologist working but wanting to start my research career. And the discovery that was made was the discovery of the first mutation, actually of any sort in a cancer. And this was really a change of just one letter of code, literally just one out of the 3000 million in the human genome, in a particular gene. And the remarkable thing about that single letter of code change was that it enabled the conversion of a normal cell into a cancer cell on its own, just that one letter of code change. 

And it was the extraordinary simplicity and clarity of that discovery that literally, one mutation in DNA could convert a normal cell into a cancer cell. And when I was looking down at cancer tissues, I could see their nuclei, which is where the DNA is located. And the nuclei of the cancer cells were very abnormal. They were often too big, too irregular, all sorts of big, peculiar abnormalities. And that spoke to me that, yes, there probably are a huge number more abnormalities of DNA in the average cancer cell. And wouldn’t it be extraordinary if we could know about them all, and from that, find out how cancers were created so and basically that is what I have done throughout my career in one form or another, finding the changes In DNA that contribute to the causation of cancer. 

Sophie 

It’s been 30 years since the discovery of one of the most famous cancer genes, the Breast Cancer gene, or more commonly known to you and me as BRCA.  

In 1948, British researcher Sir David Smithers published a paper that looked at the family trees of more than 450 people with breast cancer and showed that breast cancer can occasionally run in families.    

It couldn’t be just a coincidence, there had to be something happening on a genetic level. And so the search began. Researchers around the world were competing to be the first to discover the gene that was causing these breast cancers. 

And by the early 1990s, researchers had narrowed it down to a specific chromosome, called chromosome 17. BRCA1 was found. But that wasn’t the end of finding the breast cancer gene mutation. Mike and his team believed there was another. 

Mike 

So the human genome is made up of 22 chromosomes, and x and y, and the first step in finding genes like BRCA1 and BRCA2 is working out where they are in the human genome. And for BRCA1, this was worked out as being on chromosome 17. So this was when I started researching in the area, and we evaluated the samples that we had from breast cancer families that the Institute of Cancer Research. And indeed it looked to us as if certain of those families were likely to be due to BRCA1 on chromosome 17, but there was some evidence that some families did not seem to be due to that gene. And so that was the beginnings of some hint that there could be another breast cancer gene in existence. The evidence at that time was not very strong, because there could be all sorts of reasons why a particular family might appear not to be due to BRCA1 so. But it was enough for us and for me to start following that particular line of research. 

Now the first thing that one has to do is to find, in order to do that, is to find families that might be with breast cancer that might be informative in this regard, and there were many families at the Institute of Cancer Research on our books that had breast cancer. But because of the nature of the way we lived in the latter part of the 20th century, many of these families were quite small. In other words, with five six individuals, maybe three or four of whom were affected by breast cancer. That’s terrible for those families. But in terms of doing the genetics and discovery, those families are not very powerful. So the first thing that we did was to contact clinicians working in a part of the world where we thought the families might be bigger, not that there would be more breast cancer families, but that the families were bigger. And so we contacted all the oncologists in Dublin, and one of those oncologists, Peter Daly, wrote back to me and said, Yes, he had a family that seemed that had many cases of breast cancer, and this family had many typical features of such families, in that the breast cancers were often diagnosed at a quite a young age, between 40 and 50, and there was a higher frequency of individuals with bilateral breast cancer and there was also ovarian cancer in the family. So we began to work together with Peter Daly to study that one family, and the first thing that we did was to test whether the gene that was underlying that family was BRCA1 on chromosome 17. And to do that, we had to analyse what are called DNA markers on chromosome 17. The gene had not yet been identified and not been discovered. It was only where it was, and it became clear fairly quickly that that family, that Irish family, seemed unlikely to be due to BRCA1.  

So over the next couple of years, together with Peter and the family. We extended the family. In other words, we asked family members for their personal history. We took samples from them, we asked them about the wider family. We contacted further members of the family, and as a result, we built up this family into what was and we describe it for ourselves in the terms of a pedigree drawing that we have on a computer. And the printout of that pedigree drawing was about 20 meters long by the time we finished. 

The more samples we got, the more it became clear that this was unlikely to be due to BRCA1. So that was the prompt for us to start looking for BRCA2. And the way that you do, that we have, it was in the first part of these. All this sort of work is again, to find out where in the human genome, BRCA2 might be. And to do that, we divide the genome into about 200 pieces, and in the middle of each of those, we have what’s called a DNA marker, and we typed that DNA marker on as many samples from each family as we can. So that’s what we did with that Irish family. We typed about 200 DNA markers across the whole of the genome on many samples from that family, and the answer what we got was a null. We just couldn’t find it. 

Sophie 

They had to go back to the drawing board. Mike and his team discussed and finally reached a conclusion, the best thing to do was to do it all over again. But there was hope, the family had since grown, so there were more samples to analyse and on top of that technology in the field had vastly improved. 

Mike 

So we got again about 200 markers, but this time they were easier to type, and we went round the whole of the genome again. And this time I remember very clearly, you know, the afternoon one of the people working with me came in waving an x ray film, because that’s how we were able to see the results, and said, Have a look at this. And it was very clear from that the data that was represented on that X ray film that BRCA2 was on chromosome 13. But more importantly, or equally importantly, it was the final evidence that BRCA2 had to exist. So that was the discovery of where it was in the human genome, and it was really empowered by that single Irish family. 

So that’s the first part of the of the process of identifying a cancer susceptibility gene. But then the second part is, you now know where it is in the genome you have, but in that region they can be 10s of different genes. So it’s which one of those genes in that region is the actual cancer susceptibility gene. Here is where you know the story takes an additional twist, the work that we had been doing had been in collaboration with many people around the world, sending us material from many families. It was generally a very collaborative field. However, a key collaborator was in Salt Lake City, and this collaborator had set up a company that wanted in order to identify breast cancer genes. 

Sophie 

However, that collaboration soon became a competition, with various disagreements between the company and the team. But luckily for Mike and his team, the Wellcome Sanger Institute were in current discussion at the time to sequence the whole human genome.  

Mike 

And we contacted them to ask them whether they would help us and supply some of these in the region of chromosome 13 that we knew BRCA today. And they were, they were very happy to do so. So the collaboration with the Sanger Institute started in that way, and they provided us the actual pieces of DNA that were in those in that region on chromosome 13. What they also did was they offered us to sequence the whole of that region and to sequence it to high quality. And as a result, that piece of multiple millions of bases of letters of code of. DNA on chromosome 13 was the first piece of the human genome that was sequenced to finishing quality because the Sanger Institute used it as a an exemplar of what the whole human genome would subsequently look like, and in doing so, provided us very high quality information about the particular region of the image, BRCA. Two lay what they also did, because the Sanger Institute is committed to open what was to open, release help data was that they put it out on the internet. So although we had access to it, so did our competitors. And so the collaboration came together. Now we were it was important to have many, as many families that seemed like they were due to BRCA two as possible, because the anticipation was that each family might have a different mutation in the gene, and the more mutations in the gene that we had, the more likely it was that when we first landed in the gene, we might see one of those mutations. And it’s the finding of that mutation that would tell us, would indicate to us that that was the gene. And so it became a, you know, again, a very collaborative effort, albeit a race with our competitors, and we assembled the genes that were in that region, and one by one, we looked through them using the DNA from these breast cancer families, until we found and I remember this morning very well as well a postdoc working with Richard Worcester, he said, Well, have a look at this. And what we saw was a very, very, very messy piece of sequenced DNA. And the reason it was messy is relevant because, and the reason it’s messy is because, actually, when you sequence a piece of DNA from a human being, you’re sequencing two copies. You’re sequencing them mother’s copy and you’re sequencing the father’s copy at the same time, and you have to look at them at the same time again on an x ray film. But if there is a certain type of mutation which is only present in one copy, that copy gets shifted, and the sequences get overlaid, and they look very messy. So the messiness of those sequences was a real clue, but we had to spend the morning teasing apart what these two messy overlying sequences were, and when we did that, we saw that there was a mutation, a deletion, of six letters of DNA sequence, which was exactly the sort of thing that we had been looking for. And we would need confirmation. But at that moment, we were pretty sure that we’d landed in BRCA2 and had thus discovered it. 

Sophie 

It was a huge milestone in the field of cancer research. From that point, clinicians were able to refer families with extensive history of breast cancer for genetic testing to see if they had the BRCA gene mutations. 

Everyone has BRCA genes. Normally, BRCA1 and BRCA2 genes stop cells in our body from growing and dividing out of control. But the mutation in these genes means that cells can grow out of control. That’s why people who inherit these faulty versions have an increased risk of developing not only breast cancer, but also ovarian, prostate and in some cases pancreatic cancer.  

The history and data of families kickstarted the journey to find the breast cancer gene mutations. Without them the BRCA2 gene mutation might have never been found, saving the lives of many families to come. One of those families is Maria, her sister Chrissy, and their mother, all who have the BRCA2 gene mutation. I sat down with them to discuss having the gene mutation and the impact it’s had on them.  

Just a little disclaimer to avoid any confusion, in the interview when we’re talking about being positive for BRCA or the BRCA gene, what we’re really discussing is the BRCA gene mutation, because we all have BRCA1 and BRCA2 genes, but it’s the mutations which give people a higher cancer risk. 

Sophie 

So we’re talking about BRCA and the BRCA gene, and you’ve had an extensive history of breast cancer within your family. I wondered, like, it was that a constant conversation you had before you even heard about BRCA? Like, did you – do you talk about it often that kind of coincidence of breast cancer within the family? 

Maria and Chrissy’s Mum 

I lost two of my sisters at an early age. They were 37 and 38 years old when we lost them to breast cancer, and there was already we’d lost my grandmother to the disease as well, and a sibling of hers. And obviously, there was a quite a bit in the family, and I’d started to, you know, we all, as a family, thought, well, you know, how come? How come? It was such a lot, you know, within the family. And slowly, as the years went by, I found out about the BRCA gene, and I asked to be tested. My GP was amazing. He referred me and everything, and I was seen by a consultant myself. I used to go regularly, and I kept asking about the BRCA gene. Unfortunately, in his wisdom, he decided to tell me that I’d missed the gene. Now, you know, I said to him, in all due respect, how do you know I haven’t had any tests done? Obviously, I don’t know. I’m not a doctor. I didn’t know. But how do you know? His answer to me was, well, you’re older than your siblings were where they were diagnosed. It led to me being diagnosed with cancer myself before I could access the gene. And the rest, as I say, is history. But we have, we’ve been talking about it, yeah, you know, trying, tried my hardest, to get the gene. As I said, the GPs were amazing. They did refer me, but my consultant, fine 

Chrissy 

yes how long ago with that?  

Maria and Chrissy’s Mum 

That was oh gosh, we lost my sisters, the one in ’83 and the other one in ’87 but it was a few years after that. You know, we heard of the gene, and I tried to try to get it done. 

Sophie 

And Maria and Chrissy, did you find it difficult to get tested for the BRCA gene mutation, or was it easier for you guys? 

Chrissy 

Well, so with what my Mum said about when she first went I mean, that was a good few years ago, it had obviously been found and been discussed and stuff, but I think maybe it’s probably over 10 years ago that was, 

Maria and Chrissy’s Mum 

oh god yes, it was a long time ago. 

Chrissy 

So it wasn’t that well known. But I think now, obviously research and everything’s come on so much and we subsequently, when my mum was diagnosed, people knew about it a lot more. So then when we came to get tested, it was following on from my mum finding out, yeah, she does have the BRCA2 gene. So it was quite from that point, from my mom actually being tested. It was quite easy. 

Maria 

It was straightforward, all of the family went to the doctors. We received a letter saying that there was someone in the family that had the BRCA gene so then we were eligible straight away for early screening and the blood test to see if we were BRCA. And luckily, so it was the year that mom was diagnosed and got the BRCA got told she had the BRCA gene that I went straight to the doctor, because it was always in the back of all of our minds with the family history. That is it me next, and luckily, I went for any screening, and it was me next, but because of the BRCA gene and all the research and everything that’s happened, that they found it straight away, and I’m here now because of that, yeah, so we’re so thankful to The all the research, all the work that’s been done. 

Chrissy 

Well, yeah, because it was off the back of mom finding out that she was positive that you, like you said, because you were over 30 at the time, went in. But yeah, did, and they found it because you didn’t have any neither. 

Maria 

I had no symptoms. I was well, there was no lump that I could feel so it was all thanks to mum. 

Sophie 

Yeah I think that’s yeah, really important point that, you know, having genetic testing, it kind of you don’t have to wait for the symptoms to come about, which can be really late for a lot of people, and getting that earlier diagnosis. What, how did you guys, you know, feel when you got that confirmation? Did you feel like you had a bit more power ahead in terms of choosing your next steps? 

Maria 

Yes, it was definitely a positive thing, because it’s always in the back of your mind. Yeah. But, and you’re not eligible to have screening when you’re young, but as soon as I know you’ve got the gene, then everything changes. And yeah, like you said, we’ve got more control. 

Chrissy 

And I think it was almost obviously, like so many terrible things had happened in the family. It was almost like giving a reason to it. It wasn’t just, you know, just completely random, like there was a reason for why we’d, like, lost so many people in the family. And, I mean, like Maria said, I think it’s for us, it’s been a positive thing, being able to have that knowledge and that information to then be able to kind of take it into our own hands and decide what, what we’re going to do and which way to go. 

Sophie 

And you had preventative surgery, is that right? 

Chrissy 

Yeah, I did. So I, when my mom was diagnosed, I wasn’t 30 yet. And then they, if you do have the BRCA gene either offer you yearly screening from when you turn 30, or you can have a preventative mastectomy when, obviously we found out that we did have it in the family. I’d already pretty much made up my mind if I if I had the BRCA gene, I already knew straight off, I think because I’d had it in my mind, because obviously my aunties were so young, and then my mom and my sister were diagnosed so close, I thought, if I’ve got the gene I like, I want them gone, like, I don’t want that worry. And they said to us, there was, like, an 88% chance that I would get breast cancer at some point in my life. And I just thought, I don’t, I don’t like, those are, like I said, I’d see my mom and my sister be diagnosed so close together. So yeah, because, like I said, I wasn’t 30, I couldn’t have screening, but I just said to the consultants I’d seen, I just wanted to be put forward for a preventative mastectomy, and that I had that when I was 29. Yeah, but like I said, I’d, I’d already made up my mind what I wanted to do, like I had the chance, I was lucky enough to have the chance to do something about it and kind of pre-empt it. And yeah, so it was, it was kind of as difficult as it was. It was an easy decision for me personally to make. 

Sophie 

And I guess, how have you felt as a family, kind of moving on from that, like moving forward? Do you still feel like it’s something you think about? 

Maria 

Well, we’ve got lots of nephews and nieces and people that can’t be tested yet, so it’s in the back of our minds, because their parents have got the gene, like my brother and he’s got his two children. So you think there’s a 50/50 chance that they could have it as well. So it is on your mind, and you do worry about it, but again, things have come on so much since my aunties died, and things will come on more by the time my nephews and nieces get to the age where they can be tested. But knowledge is power, so we’ll be prepared for what the future holds. 

Sophie 

When you hear it’s been 30 years since the discovery of BRCA, what kind of thoughts and feelings come up for you guys? 

Maria and Chrissy’s Mum 

I mean I…when my sisters were diagnosed, I was helping their nursing. You know, they needed help and seeing what they went through with the medication, with the treatment they were getting, and seeing the treatment that myself and my daughter received for our cancer, it’s so different. I could see such a difference, even though I wasn’t medical having nursed my sisters and then helped nurse my daughter and she and me, the difference is astronomical, really. So, oh, you know, so thankful to the research that’s going on. 

Maria 

And I mean, me and Mum both had cancer, and had we not known we had the gene, we wouldn’t have got a double mastectomy. It would have just been the one, and that would have been worrying. So it’s good that we knew about the gene so we could make that choice. And have had bilateral mastectomies.  

Chrissy 

Like Maria said, it kind of because it was, it was always something we all thought about, because obviously family history that you did just kind of think, oh, okay, is it going to happen to me? And because of obviously, it’s been 30 years, there’s been so much research that’s gone into it. We aren’t just kind of lucky. We as well, it’s a bad situation, but we’re lucky. 

Maria and Chrissy’s Mum 

We are lucky. Because for me, if we didn’t, if we didn’t know we had the BRCA gene. Maybe Maria wouldn’t be here today, because, as she said, she had no inkling it to think, no lung, no symptoms. So when she would have got to the point where she did have symptoms, then it might have been too late. (It) was because she got tested. When she was tested, just a routine mammogram, and that’s what did it, you know? And it was because, like, the gene, the BRCA gene, had I tested negative to the BRCA gene, Maria wouldn’t have been allowed testing at the age she was and, you know, so yeah, one the grateful word is, yeah, yeah. I’m so grateful that you know of all the research and knowing about the BRCA gene, it’s just it’s not the best thing to have, or to know that you’ve got, but 

Maria 

We’re in a special club.  

All 

(laugh) 

Sophie 

Yeah that’s a nice way to put it. I think, yeah, it is that weird situation where it’s like, it’s kind of the a question you never wanted to ask, but you’re kind of happy you have an answer for. 

All 

Yeah. 

Maria 

Yeah,100%. 

Maria and Chrissy’s Mum 

I mean, we’ve got quite a few other family members. I know we’re not allowed to say their names, but as we’ve got another six nieces, that had preparation, uh preventative surgery, because they went on to have the gene test done after us, found to have the BRCA gene, and they’ve decided, and they’ve had the operations as well, preventative so, 

Maria 

So it saves lives as well, knowing that you have it. 

Sophie 

Yeah, and you guys talk quite a lot, I think as a family about it. For some people, they may not feel like they can talk about it within their families, even though it impacts a family. You know, did talking to each other really help in those processes and in those moments that were difficult for you guys? 

Maria and Chrissy’s Mum 

Yeah 

Chrissy 

Yeah, yeah, I think so I definitely. I mean, like, like, you said, I’ve spoken to other people who have been impacted of the family, but they, they kind of don’t, they don’t talk about it. Or someone in the family doesn’t want to get tested, so they don’t. And for me, that seems alien, because we are so open, and we do discuss it, and we’ve all been kind of very open from the beginning and from when my mum was diagnosed. So yeah, I think definitely (it) does help. 

Sophie 

The discovery of BRCA mutations has not only helped with cancer diagnosis but has also helped with cancer treatments too. Like PARP inhibitors, they’re a type of targeted cancer drug that was funded by Cancer Research UK.  

They work by blocking the protein PARP, which is found in our cells and helps them to repair themselves when damaged. Cancer cells with BRCA gene mutations already have a poor repair system, so blocking PARP with a PARP inhibitor drug means that the cells can’t repair themselves anymore and will result in them dying. Essentially killing the cancer cells. 

Now BRCA gene mutations are not the only inheritable gene faults, there are more that have been discovered since linked to cancers like melanoma and colorectal cancer. But cancers caused by inherited mutations are still quite rare, with only 5-10% causing these types of cancers.  

But every discovery matters. It changes people’s lives like Maria and her family’s and it can  lead to even bigger breakthroughs, like the next cancer treatment drug. 30 years on from the first discovery of BRCA, we’ve made huge strides in the field of cancer research. But there’s still so much more to discover.

We hoped you enjoyed this episode of That Cancer Conversation, and if you’d like to listen to more episodes you can find us on Apple podcasts, Spotify or wherever you get your podcasts.  

That Cancer Conversation is produced by the digital news team at Cancer Research UK.  Thanks for listening and talk to you next time!