#190      27 min 26 sec
Germline confidential: Hunting down genes linked to breast cancer

Genetics researchers Prof Melissa Southey and Prof David Goldgar discuss the enterprise of tracking down genes that make one susceptible to breast cancer. With science host Dr Shane Huntington.

"Some people, unfortunately, have mutation or a variation in the genetic code in some genes that increase their susceptibility to cancer." -- Prof Melissa Southey




Prof Melissa Southey
Professor Melissa Southey

Professor Melissa Southey (PhD, Grad Dip Law, FHGSA, FFSc (RCPA)) is Head of the Genetic Epidemiology Laboratory in the Department of Pathology at The University of Melbourne. Her research focuses on population-based studies of the genetic epidemiology of breast, pediatric, prostate and colorectal cancer. Only a small proportion of these cancers can be explained by what is currently known about their causes. The factors responsible for the majority of early-onset cancers arising in individuals with a strong family history are yet to be identified. Melissa utilizes international and local cancer research resources to identify genetic factors of relevance to clinical genetics services. Recent emphasis and activities have been focused on identifying additional cancer susceptibility genes via the application of new genetic technology (massively parallel sequencing) and studies of the molecular determinants of mammographic density (a strong risk factor for breast cancer). These population-based studies provide definitive information about cancer susceptibility genes and have recently identified further susceptibility genes that impact on clinical genetics services worldwide. New findings have immediate and significant impact on the clinical management of all individuals and families with early-onset and multiple-cases of cancer and may provide additional target information for future treatment strategies and drug development.

Publications

Southey Lab - Cancer Genomics

Melbourne Medical School, University of Melbourne

Prof David Goldgar
Professor David Goldgar

Prof David Goldgar has worked in the field of Cancer Genetics/Genetic Epidemiology for nearly 30 years. He began his career in cancer genetics at the University of Utah and was involved in linkage and positional cloning of the BRCA1 and BRCA2 genes. From 1996-2005 he was head of the Genetic Epidemiology Unit of at the International Agency for Research in Cancer in Lyon, France where he learned to appreciate good food and wine and initiated a number of international collaborative projects on breast cancer genetics, most notably the IBCCS prospective study of BRCA1 and BRCA2 mutation carriers. Since his return to Utah, he has been actively involved in assessment of unclassified sequence variants in disease genes. In particular he has been very active in assessing genetic evidence and how the genetic evidence can be used to calibrate functional and in silico analyses within the constructs of a multifactorial model. He is a co-founder and chair of the steering committee of the international ENIGMA consortium initiated to address the problem of VUSs, and has been a member of the steering committee of the BIC database since its formation in 1995. Most recently he has been working on experimental designs for exome-sequencing studies and has initiated an exome-sequencing study of high-risk breast cancer families.

Publications

Huntsman Cancer Insititute, University of Utah

Credits

Host: Dr Shane Huntington
Producers: Eric van Bemmel, Kelvin Param
Audio Engineer: Gavin Nebauer
Episode Research: Dr Dyani Lewis
Voiceover: Nerissa Hannink
Series Creators: Kelvin Param & Eric van Bemmel 

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VOICEOVER
Welcome to Up Close, the research talk show from the University of Melbourne, Australia.

SHANE HUNTINGTON
I'm Shane Huntington. Thanks for joining us. The battle against breast cancer has come a long way over the last few decades. And we now have a solid understanding of why some people are susceptible to this form of cancer. Nevertheless, the picture is far from complete, and we are not yet in a position to prevent malignant breast neoplasm - as breast cancer is medically known - from occurring.In the early 1990s two genes that make people susceptible to breast cancer were discovered, leading to improved screening. Unfortunately, these two are not the only genes that cause the problem. Today on Up Close we speak to two researchers who are continuing the effort to identify additional genes responsible for breast cancer: Professor Melissa Southey from the Department of Pathology at the University of Melbourne, who has appeared on this program before; and, joining us via Skype, Professor David Goldgar from the Department of Oncological Sciences at the Huntsman Cancer Institute in the University of Utah's School of Medicine.Welcome to Up Close, Melissa and David.

MELISSA SOUTHEY
Thank you, Shane.

DAVID GOLDGAR
Thank you, Shane.

SHANE HUNTINGTON
David, I might start with you. We've all heard a lot about breast cancer, but can you give us an idea of how common it is, how many people it affects?

DAVID GOLDGAR
Well, the generally accepted figure is anywhere from one in 12 to one in eight women will develop breast cancer in her lifetime. It's more common in western developed countries, although incidence rates are increasing throughout the world as countries become more developed and start adapting some of our bad habits, you might say: bad dietary habits, bad lifestyle habits. So in countries where breast cancer used to be quite rare it's now becoming more common. 

SHANE HUNTINGTON
You mentioned the stats around women. What about men? Are they also having the same issue?

DAVID GOLDGAR
Well, male breast cancer is rare. For every 100 women diagnosed with breast cancer there might be one man. So you can see it's quite a bit less common. Still, for people who carry genetic susceptibility, the increased risk of male breast cancer can be even higher than that for females.

SHANE HUNTINGTON
And David, what's happening to the body when someone develops breast cancer? Why can it end up being fatal?

DAVID GOLDGAR
I should probably let Melissa answer that, but the reason people die from breast cancer is due to metastases. That is bits of the cancer go through the bloodstream and lodge in other parts of the body where you really can't do as much about it - in the brain or in the liver. Many women who die from breast cancer die from these metastases rather than from the original tumour.

MELISSA SOUTHEY
I think that was pretty good, David. The metastases replace tissue that's essential for life, often in the brain; the bone as well, also very common in breast cancer metastasis. So a woman living with metastatic disease is often not enjoying a very high quality of life. Once metastasised the woman's life expectancy is significantly reduced.

SHANE HUNTINGTON
Can you explain for me this metastasis process? What's going on there? You're obviously starting with a problem in the breast, but what's the function that's occurring to get to that point?

MELISSA SOUTHEY
Well, a large number of events need to take place, but a cancer that's growing in one place is often very content to stay there. That's not such a disastrous situation. Surgery can be very effective in breast cancers that are very localised in the breast.But after many different genetic and molecular events some cells in some women are able to obtain the ability to leave the tumour and enter the bloodstream or enter another part of the body and move to a part of the body, like the brain, and establish itself as a secondary cancer. 

SHANE HUNTINGTON
Is the life expectancy of the person determined by whether or not that process has started? Do you have to catch the cancer before that spread occurs?

MELISSA SOUTHEY
It's a really interesting question. Again, it's slightly outside the context of our expertise, but understanding whether a breast cancer has metastasised is actually a very difficult thing. Evidence of metastasis in the brain is sometimes very hard to detect. Of course, we think that breast cancers can exist as isolated cells in a blood system for a very long time. Detecting them is actually very challenging. So understanding, after a primary biopsy, whether the whole cancer has been removed from a breast is actually a very difficult thing to determine. 

SHANE HUNTINGTON
Melissa, when we speak about a person having a gene for breast cancer - which is often the statement that you'll hear...

MELISSA SOUTHEY
Yes.

SHANE HUNTINGTON
This sounds like it's a bit erroneous, the way it's stated. What do we mean by this?

MELISSA SOUTHEY
Well, that's the common language, I suppose. I mean we all have all the genes - that's what makes us human - but some people, unfortunately, have mutation or a variation in the genetic code in some genes that increase their susceptibility to cancer. So I guess the more correct thing is a mutation in a gene rather than the gene.

SHANE HUNTINGTON
David, in the intro I mentioned that some of the genes have already been discovered that give you this susceptibility. You're involved with some of the very well known early work on the BRCA1 and 2 gene in the early 1990s. Can you give us an idea of what was happening around that time and how you went about making those discoveries?

DAVID GOLDGAR
Well, things were much more difficult in some ways in those days. In other ways they were a bit easier because the genes that you spoke about - BRCA1 and BRCA2 - mutations in those genes are more common than in - particularly the gene that is the subject of our most recent paper. And in Utah we had the advantage of having a large genealogical resource that was linked to the Utah Cancer Registry, and several other regional cancer registries, which allowed us to identify very large breast and ovarian cancer families that allowed us to narrow the region where we thought the BRCA1 or BRCA2 gene must lie, and allowing us to then use molecular methods to identify the specific gene; because 15, 20 years ago, when these genes were being identified, we didn't have the whole human genome sequence and many of the resources and high throughput sequencing that we do today.So, in some ways, it was more challenging, from the technological point of view, but then the nature of those genes made it a bit easier, and the existence of very large families that allowed us to narrow down the region where these genes must be.

SHANE HUNTINGTON
David, in terms of the early work you did was it commonly understood at that point that it would be a particular gene or several genes that was causing this problem? Or was that, in itself, a new way of thinking about cancer?

DAVID GOLDGAR
I think that the notion that breast cancer, in particular, could be inherited, as well as other types of cancer, was fairly well established. In fact, there was a famous description of a family with early onset breast cancer, published in, I think, 1865 or 1885 - I can't quite remember - in France. That was really the first example of someone deciding their cancer could be genetic in origin.Most recently - it was really in the 1970s, I think, that the study of familial cancer - through the work of pioneers such as Henry Lynch, Mary-Claire King and my mentor, Mark Skolnick, studying large cancer prone families and then using some of the - at that time - new genetic molecular techniques to actually go after some of those genes.Really, it was a observation of people who saw these families and described the syndrome that we now know as due to BRCA1 or BRCA2. BRCA1 and BRCA2 were not known in that time, so they were novel genes that we wouldn't have necessarily expected to be breast cancer genes. We knew that they were the right genes because we identified some of these high risk families to have genetic changes in those genes that would be likely to disrupt their function.

SHANE HUNTINGTON
This is Up Close, coming to you from the University of Melbourne, Australia. I'm Shane Huntington. In this episode we're talking about susceptibility genes for breast cancer with molecular geneticist, Melissa Southey, and statistical geneticist, David Goldgar. Melissa, how many of the susceptibility genes do we know about now? What do they normally do in the body when they're not giving us cancer?

MELISSA SOUTHEY
Well, the number's a little bit hard to determine. It depends a little bit how you count them. I guess we're approaching 10 - the two primary genes that David's just described. There are a couple of other genes that we have known via their association with other syndromes and other situations, like p53, which was described via Li-Fraumeni Syndrome in paediatric oncology, essentially. We now know it has an association with early onset breast cancer; the same with p10. Other genes have been described to have very rare mutations that are associated with breast cancer risk that have been found by candidate gene approaches since the description of BRCA1 and 2 - and a few more to the number, but none of them account for very many families with multiple cases of breast cancer. So even today, with our recent discovery, we know that the majority of families with multiple cases of breast cancer we don't know the underlying genetic explanation. 

SHANE HUNTINGTON
What do these genes normally do?

MELISSA SOUTHEY
Almost exclusively they are involved in DNA repair. So they're the sorts of genes that have a function once DNA damage occurs, that they move into place and repair errors; which, I guess, is very logical when you're thinking about cancer. It's a genetic disease. People with faults in these genes don't have the normal capacity to repair their DNA, so DNA damage exists persists in exists in next generations of cells. 

SHANE HUNTINGTON
David mentioned earlier that there was a correlation between lifestyle and the incidence of breast cancer. How does that lack of a repair mechanism link in to that lifestyle shift and what we're seeing in terms of the statistics in the developed world?

MELISSA SOUTHEY
Well that's an interesting one. I guess many of us are still trying to tie those two things together. I think obesity would be one you're probably alluding to, David, with breast cancer?

DAVID GOLDGAR
Yes, a general high calorie intake diet.

MELISSA SOUTHEY
I mean general pressures on biological systems, I guess, is always going to put pressure on DNA repair, but the actual relationship between the two, I think, needs much further description and characterisation.

SHANE HUNTINGTON
Are all of these genes that we now are aware of used in the genetic screening and testing procedures that we find?

MELISSA SOUTHEY
No. At least in Australia today - in 2012 - really, genes that are handled in a clinical setting are BRCA1 and BRCA2. Some families would have some counselling to do with p53, depending on their very specific family situation but, really, our clinical services are focusing on BRCA1 and 2. There really is a huge effort at the moment to understand how to use the information from the other genetic information that we know about in clinical practice, but it's really not clear to us exactly how to do that yet. For some it's because the mutations don't seem to be associated with such high risk; so how to understand them in the context of advising a woman about her behaviour is very difficult. For some of them it's because the mutations are very rare and the actual practicalities of testing a large number of women for something that's very rare - the health economics of that are very challenging to address. So the reasons are a little bit different, but it all adds up to a bit of a challenge.

SHANE HUNTINGTON
You and David - along with a number of international colleagues - have just discovered another susceptibility gene. Tell us all about this finding.

MELISSA SOUTHEY
Well, it really started in similar ways to the way David described the work for BRCA1 and 2. After that work there were a large number of families that had been collected in research resources that we knew had multiple cases of breast cancer and we knew were not due to mutations in BRCA1 and 2.And we, in Melbourne, had collected these families since the very early 1990s. There were collections around the world that were older than that that had these most extraordinary families in them that the evidence would have - looking at the pedigree - there was something very genetic about the predisposition to cancer in them, but we didn't have an explanation.So we were able to use some of these families in our research and apply new genetic technology. One of the big steps that's happened since the work that David described, where he, I think, was pouring acrylamide gels and running isotope in these to do DNA sequencing; and was sequencing hundreds of base pairs at a time.

DAVID GOLDGAR
Yes.

MELISSA SOUTHEY
We're now in an environment where we can actually sequence the entire human genome in single instrument runs. We didn't actually do that. We did what was known as exome sequencing. So we pulled out from the human DNA the part of the DNA that codes the protein. This made the proportion of DNA much smaller, but still very large. There's about 40,000 genes in a human genome. So we analysed these all at once - in one go - in one instrument.We were able to look at families - at their entire exome - rather than just looking at candidate genes or regions that had been identified via our linkage analysis. 

SHANE HUNTINGTON
David, you've been in this game for quite a while now. You've seen this transformation in technology. Is it your expectation that we're still going to find a large number of genes that we haven’t already identified that will be linked to breast cancer, as these recent ones have?

DAVID GOLDGAR
Yes, I think that will happen because we do have this new sequencing technology that will allow us to perform these studies in ways that we couldn't have done even five years ago. And we know that there are still many, many families who we believe to have a genetic cause, if you will, of their breast cancer that are not explained by any of the 10 or 15 known genes. I suspect that what's going to happen - from our own studies, our own collaborative work that we're doing, looking at these families, as well as other groups around the world - there will be a number of additional genes that will be discovered that are - that mutations in these genes are very rare, so they each won't account for very much. It will almost come to the situation where there may be families that have their own private mutation in a particular gene that is, essentially, unknown in anyone else. That's going to be more of a challenge to prove - that that is a breast cancer related gene - because, for example, in our study that's published in March 2012, we were able to identify a number of other families in addition to the original observation that had mutations in the same gene, which led us to, essentially, be able to prove, statistically, that this gene was related to breast cancer. That will become more and more difficult.That being said, I think there will be - in the next two to three years - at least an equal number of genes to those that are known now that will be discovered using similar methods to our own.

SHANE HUNTINGTON
David, just following on from that, given the personalised nature of some of this work, is it likely that these new gene discoveries will end up being used in screening tests?

DAVID GOLDGAR
By screening, you mean in the same way that, right now, we screen for mutations in BRCA1 and 2?

SHANE HUNTINGTON
Yes.

DAVID GOLDGAR
I think that will happen. The new sequencing technologies are now making the transition from purely research purposes to clinical use. What I imagine will happen is that all the genes that we know about for breast cancer susceptibility, or even cancer susceptibility, will be done in one go using these new technologies, so that a woman with a family history of breast cancer, for example, will come into the clinic and then we will test at one time all known breast cancer susceptibility genes; because that's now going to be economically feasible. Right now, it's making that transition from research to clinical application.

SHANE HUNTINGTON
I'm Shane Huntington. My guests today are molecular geneticist, Melissa Southey, and statistical geneticist, David Goldgar. We're talking about susceptibility genes for breast cancer here on Up Close, coming to you from the University of Melbourne, Australia. Melissa, what do we know about this new gene that you've discovered this year, 2012, which I understand you've called XRCC2?

MELISSA SOUTHEY
Actually, we didn't call it that. Unlike BRCA1 and 2, when David found them they were genes that weren’t known prior to them finding them. Actually, XRCC2 is quite a well known gene. It has a very well defined function in DNA repair. It has been well characterised. There are lovely mouse models that demonstrate its biological activity, which is actually very helpful to us. Immediately we found something that we knew had a relevant biological explanation for it being involved in breast cancer predisposition. So we found this gene via a study of a very unique family. We chose it because it had several features in it that were suggestive to us that it had an underlying genetic explanation for the cancer predisposition. It was funny: at the beginning of the conversation we talked about male breast cancer. This family had a male breast cancer case that was diagnosed at the age of 29. I think there were 15 cases of male breast cancer diagnosed in the state of Victoria, which has a population of about four and a half million. Most of them are in men in their 60s or 70s. To have a case diagnosed at 29 is really remarkable and really puts up a flag about this might be something to do with an underlying genetic predisposition. The sister of this man was also affected with breast cancer at a very young age, as was his mother, as was his first cousin; so he had a very rich pedigree. We applied exome sequencing and we very quickly found a mutation in XRCC2.And as David quite nicely described, once you find this sort of mutation in one family, it's actually not clear what to do with it. It could be a mutation that has everything to do with breast cancer in this family or nothing to do with it. It might be only to do with this family and not with others. And it wasn't until we had this quite study changing conversation with one of our colleagues in The Netherlands, who was applying the same technology to similar families in the Netherlands - I spoke to him one evening, Melbourne time - which was morning in The Netherlands. I told him about what we'd found. By the time I woke up the next morning he'd sent me back a pedigree from his own study that had found a mutation in the same gene in a family with quite a remarkable family history of breast cancer. Putting these two together was really a very significant finding and launched us into looking at this gene in a very large number of other breast cancer families where - as David described - we found quite a lot of other families with mutations in this gene; and were able to prove, statistically, that it was associated with breast cancer risk.

SHANE HUNTINGTON
Melissa, when we look at this particular gene how does it compare to the other genes that we know are susceptibility genes for breast cancer? Are there big distinguishing features for this gene?

MELISSA SOUTHEY
Well, one is actually a physical difference. XRCC2 is almost the smallest gene that I know. It actually helped facilitate this work. The genomic distance it covers is very, very small. It has three coding exons. In comparison to some of the other genes - I don’t know - 1000 times bigger.ATM - which is another gene that we haven’t mentioned specifically, but is involved in breast cancer - has 64 coding exons. So, from a technical point of view, it's actually very easy to screen.

SHANE HUNTINGTON
I'm going to have to ask you to explain to me what a coding exon is and what it does.

MELISSA SOUTHEY
The part of the gene that's responsible for making the protein. So it has the code that makes the protein what the protein is. So, from a genomic point of view, they're actually very different, but from a functional point of view they have some great similarities. They're both involved in DNA repair. Although BRCA1 and 2 and other breast cancer genes are much bigger and probably have other functions in addition to the DNA repair, XRCC2 actually works with them in a group of proteins that works to repair DNA in certain circumstances; so it has great biological similarities.

SHANE HUNTINGTON
David, we know that there is the inheritance element to these types of cancer. Can you tell us what's happening with regards to these genes being passed on from our parents? Why are we receiving these faulty genes, if you will, that end up causing cancer throughout an entire family?

DAVID GOLDGAR
Yes. What typically happens - at least, in the genes that we know about - there will have been a random mutation - a DNA change in a sperm cell or an egg cell - that will then be transmitted to a child, an offspring. Then, when that person has their own children, each child will have - because it's only on one of the two pairs of chromosomes - and during meiosis only one of those two will be transmitted to each child. So each child will have - whether it's male or female doesn’t matter in this case - will have a 50/50 chance of inheriting the mutation.And in a disease like hereditary breast cancer, obviously, because it may be transmitted in lots of males - that don't have as high a risk, as Melissa has already said - you get lots of families that may carry this mutated gene but don't show many cases of breast cancer; which adds a further challenge to trying to identify these genes.So these mutations are then passed on - these may have occurred, originally, 1000 years ago and have been distributed in people throughout the world; so we sometimes see the same mutations that are very common in certain populations. There are mutations that we see, very generally, geographically dispersed. In particular in BRCA1 and BRCA2 there are mutations that are in fairly high frequency in Ashkenazi Jewish individuals, so that they are at higher risk of breast cancer, in general, because of these fairly frequent genetic variants that give them an increased risk of disease.In fact, in the study that was published in March 2012, we found the same mutation in a number of the different families that we looked at. 

SHANE HUNTINGTON
David, given that many of these genes have a very broad role throughout the body, do they know why they affect breast tissue specifically?

DAVID GOLDGAR
Well, I think the short answer to that is no. It's a very intriguing question that people have been working on. There are various hypotheses about why breast tissue may be more susceptible to mutations in the DNA repair genes.There's another class of DNA repair genes that mutations in those genes tend to cause colorectal and endometrial cancer. Part of it may be the kind of genetic damage that's done by the specific lifestyle or hormonal factors; the specific kind of tissue in terms of how rapidly that tissue regenerates, how many cell divisions it goes through; which then each of those give rise to the chance for doing DNA damage. But in general, I think we don't really know the answer to that question. 

SHANE HUNTINGTON
Melissa, now that you've identified the role of XRCC2 in breast cancer what are the next steps?

MELISSA SOUTHEY
This has actually been identified very quickly at the beginning of a very large project. The project that David and I are involved in has very broad international links. There are many other projects in other parts of the world that are doing exactly what we're doing. So I would anticipate that there would be many other discoveries like this now that the technology is available to researchers in this area.I think, probably, they will all be discoveries of genes that have very rare mutations and account for another, but a very small proportion of familial breast cancer. But together I think we'll start to make it possible for women entering clinical genetic services to be more optimistic that an explanation for their cancer predisposition will be identified rather than, at the moment, the most likely outcome of clinical genetics testing is that no explanation will be identified.

DAVID GOLDGAR
I think the other aspect for this gene - at the moment we know that it's associated with breast cancer. But we don't have a tremendous idea about what the risk is - if a woman was found to have one of these genetic mutations in this gene - what we would advise her as to what her lifetime risk of breast cancer would be so that she could then make decisions about potential surgical prevention or other preventative options.That will require - because these mutations are rare compared to, say, BRCA1 and BRCA2 we need to gather very large sets of families from around the world - as many as we can possibly get - in order to be able to estimate these risks so that we can counsel these individuals appropriately.

SHANE HUNTINGTON
Professor Melissa Southey from the Department of Pathology at the University of Melbourne, and Professor David Goldgar from the Department of Oncological Sciences at the Huntsman Cancer Institute, University of Utah School of Medicine, thank you for being our guests on Up Close today and talking about this exciting new discovery in the fight against breast cancer.

MELISSA SOUTHEY
Thanks, Shane; my pleasure. 

DAVID GOLDGAR
Thank you, Shane; mine as well. 

SHANE HUNTINGTON
Relevant links, the full transcript and more info on this episode can be found at our website at upclose.unimelb.edu.au. Up Close is a production of the University of Melbourne, Australia. This episode was recorded on 29 March 2012. Our producers for this episode were Kelvin Param and Eric van Bemmel. Audio engineering by Gavin Nebauer. Background research by Dyani Lewis. Up Close is created by Eric van Bemmel and Kelvin Param.I'm Shane Huntington. Until next time, goodbye.

VOICEOVER
You've been listening to Up Close. We're also on Twitter and Facebook. For more info visit upclose.unimelb.edu.au. Copyright 2012, the University of Melbourne.


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