Ovarian cancer genome

Monday 9 January 2012 5:44PM (view full episode)

An international research project, with the participation of two Australian scientists, has mapped genetic mutations in the most common form of ovarian cancer. This gives hope for the development of new, targeted treatments.

This program is a repeat. It was first broadcast on 18 July, 2011.

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Norman Swan: Fascinating and ground breaking research at the Peter MacCallum Cancer Centre in Melbourne has discovered that ovarian cancer comes in far more forms than people have imagined, defined by differences in the tumours' genes. These findings are beginning to explain why some women do better than others, perhaps what treatments might be more effectively targeted and as you'll hear questioning fundamental assumptions about the extent to which ovarian cancer is even ovarian cancer.

Professor David Bowtell is Head of the Cancer Genetics and Genomics Program at the Peter Mac and a senior researcher in what's called the Cancer Genome Atlas Study, this TCGA.

David Bowtell: What it set out to do is essentially create a blueprint or a road map of the disease to try and understand all the changes in the genes that had occurred as the cell went from a normal cell to become a cancer cell. And we needed that information to understand what made the cancer grow and what determined the response to the therapy.

Norman Swan: How many different types of ovarian cancer are there?

David Bowtell: There are four main common histotypes, or histological types.

Norman Swan: By that you mean when you looked down the microscope you see different shapes and patterns?

David Bowtell: That's right and there's a whole grab bag of things that are called other that are much rarer. One of the things that's surprising about ovarian cancer and through our work and work in North America and the UK in the last few years is we've come to realise that ovarian cancer is actually a real misnomer, most ovarian cancers are not from the ovaries.

Norman Swan: They are from the fallopian tube that attaches to it.

David Bowtell: That's one site, endometriosis is another site, mucinous cancers which were thought to be the second most common type of ovarian cancer turn out to be mostly metastases cancer that's spread from either the appendix, or the bowel, or sometimes the stomach.

Norman Swan: And endometriosis is a source of ovarian cancer?

David Bowtell: Yes, so clear cell and endometrio cancers are associated with endometriosis so we contributed to a study last year that was in the New England Journal of Medicine showing it was the sort of molecular link between endometriosis and those cancers.

Norman Swan: Now there are a lot of women listening to us who've got endometriosis which is a painful condition where you get spread of the uterus, the tissue that's inside the uterus in different parts of the body which during the menstrual cycle can bleed and cause pain and discomfort and is a cause of infertility. You've now put fear in their hearts - what's the link between endometriosis and ovarian cancer?

David Bowtell: Well as I said the endometriod and clear cell cancers come from endometriosis, but fortunately many, many more women have endometriosis than those that develop those types of ovarian cancer so whilst it's a risk factor for them most women with endometriosis obviously won't go on to develop ovarian cancer.

Norman Swan: Now the one you've been looking at is called serous ovarian cancer and it's the commonest isn't it?

David Bowtell: That's right, it accounts for about 65% to 70% of the cases.

Norman Swan: And is it a cancer in the ovary or is it one of these funny ones which is either the tubes or the peritoneum or somewhere like that?

David Bowtell: This is the one where we now think that it's probably, at least a large fraction of them probably come from the distal fallopian tubes so that's the part of the fallopian tube that's closest to the ovary. Sort of like a catcher's mitt surrounds the ovary.

Norman Swan: So that's to catch the egg to take it to the uterus and it gets fertilised along the way if sperm are around.

David Bowtell: That's right.

Norman Swan: So what have you been doing with serous ovarian cancer because you've been looking at the genes and this if you like pathway to cancer?

David Bowtell: Right, so we've been doing a lot of work ourselves on serous cancers as part of the Australian Ovarian Cancer Study and a couple of years ago we showed that they weren't just one type but in fact they broke into four different types, we could see that when we looked at the genes and that women who had the different types tended to have different outcomes. So if they had one type they tended to do much better, whereas if they had another type they tended to do worse. Something like what would have been found nearly a decade ago in breast cancer.

Norman Swan: Tell me about this most recent study.

David Bowtell: The study that was just published in Nature was part of the Cancer Genome Atlas Project. This was a collaborative study involving labs through North America and in Europe and obviously our group in Australia. And so we started with 500 what are known as high grade serous cancers so these are a sort of a nasty form of serous cancers and they were put through a process of looking at the activity of the genes, the number of copies of genes and mutations in the genes right across the whole of the cancer genome for nearly the 500 samples.

Norman Swan: And you made various discoveries, one of which was about what's been called a breast cancer gene, the BRCA1 and BRCA2 which is now well known to be associated with a high risk of ovarian cancer. What did you find with BRCA1 and BRCA2 which is commoner in Ashkenazi Jewish women?

David Bowtell: That's right, well we found that those genes were mutated in ovarian cancer, we knew that, and they could either be mutated or broken as an inherited mutation that had been passed on down the generations. Although it could actually be damaged during the life of the individual - that's called a somatic mutation. They are part of a molecular machine that repairs DNA when it's damaged and there are other parts of the machine. You can think of it a bit like a watch which has cogs, springs and so on, well they're like some of the cogs.

So there are other components of the machine and so by looking at the mutations in all the genes in these cancers we could add up different ways that that machine could be broken and in about half of the cancers the machine was broken in one way or another.

Norman Swan: Did they segregate into sub groups where you could say this woman has genes X, Y and Z and that woman has A, B, C and D and therefore they categorise easily?

David Bowtell: Sort of, so the way it worked is that they could either have a germline mutation in the BRCA1 or a germline mutation in the BRCA2.

Norman Swan: That means they got it from their parents?

David Bowtell: That's right so they could either have inherited defects in those genes but they wouldn't have both. They would have either one or the other. If it was damaged during life that tended to occur when they hadn't inherited it, so one way or another the gene was mutated in that way in about 30% of the patients and then in the remaining 20% there were mutations in other parts of the complex that repairs the DNA.

Norman Swan: Do you feel now you've got a good fix on the pathway to cancer formation?

David Bowtell: Yes, in a way. Last year I proposed a model for the way that high grade serous cancers evolve and the study the TCGA study supports that. So what we think is that one of the first events in them is that they have this defect in their ability to repair DNA in a certain way. And that that leads to very wide spread changes in the numbers of copy of certain genes in the cancer and as a result of that, that pushes the cancer down one of these four main sub-type pathways. What was surprising in the TCGA study is that we looked at nearly 20,000 genes to find mutations in them and compared to most other solid cancers that are being examined in that way at the moment, we were surprised that we found rather few mutations in other genes and that fitted with the idea that this is a cancer that is controlled mainly by increasing or decreasing the number of copies of genes rather than damaging the genes per se.

Norman Swan: That sounds potentially like good news because other cancers where you might have a 20 gene line of changes to lead to cancer, the frustrating thing that happens is you find a drug that hits one or two genes in that pathway and then the cancer with the devilry that it has in itself finds ways round because there are all these other genes to choose from. So if there's a smaller repertoire of genes in ovarian cancer it might make the tantalising prospect of treatment easier if you could find the right way in.

David Bowtell: I wish that were true but I think it might not be because these are called amplifications and deletions involved in the end thousands of genes so I actually think that in these cancers they have an even larger repertoire of change that they can choose from to evolve.

Norman Swan: So whilst there might be few mutations they are sitting if you like at the headwaters of a river which has all sorts of other genes attached to it.

David Bowtell: Exactly.

Norman Swan: So where does it sit now because what people want to know is what causes ovarian cancer, how can you prevent it, how you can detect it early and how can you treat it more effectively?

David Bowtell: Well certainly we know quite a lot about the genes that increase a woman's risk of developing ovarian cancer by a lot. So those are BRAC1 and BRAC2 and a couple of other genes less commonly and those mutations are much more common than we originally thought. So we think that any woman who has at least this type of ovarian cancer should be offered genetic testing. That's probably the best strategy we've got at the moment for prevention because we know that in someone who's carrying one of these mutations they have a risk of developing ovarian cancer of around about a 30% to 70% to 80% lifetime risk. But we know if we intervene, remove the ovaries and now the fallopian tubes especially after the woman has had her children and particularly around the time of menopause that we can cut the risk of developing ovarian cancer by about 95%. So that's a very effective intervention, not one that you take lightly but given the choice between maybe an early menopause or developing ovarian cancer it's a very viable option.

Norman Swan: And is this a genetic analysis of your blood or of the ovary?

David Bowtell: Of your blood, so that's to look for inherited mutations in those genes.

Norman Swan: So they're not confined to your ovary, they are more general throughout your body?

David Bowtell: Yeah, that's right. Early detection is tough actually for ovarian cancer because although it's sort of been the Holy Grail in a way it's actually a disease that's not suited to the kind of screening that we do say for bowel cancer, or cervical cancer, or for breast cancer. The reason for that is that when these cancers arise in the fallopian tube those cells are continuous with the rest of the abdomen, the fluid that surrounds the organs and the rest of the abdomen. So the cancer can just slough off the surface of the cells and travel to the surface of the fallopian tubes then travel all throughout the abdomen very easily. Whereas a bowel cancer for example has to develop quite a long way before it can penetrate through the wall of the bowel and spread to the rest of the body.

So that makes it really very difficult and a study just published from the United States suggests that screening for ovarian cancer doesn't actually improve outcome.

Norman Swan: And in fact we just heard that on the Health Report prior to this interview. So in other words what you're saying is that there might be a genetic strategy for screening women at high risk?

David Bowtell: Yes definitely, I think that it's becoming really very clear that we should be offering screening to all women who develop ovarian cancer, partly to help guide the therapy but also to inform them about the risk to their daughters or sisters.

Norman Swan: What about guiding therapy - are you finding genes that we know there are targeted drugs that affect those genes?

David Bowtell: Yes. About three years ago we found that a gene called cyclin E1 which controls how cells divide is amplified like we were just discussing in women who fail primary treatment. Most women with ovarian cancer, at least serous cancers, have a very good response to chemotherapy and surgery. But about a quarter to a third of them the cancer recurs very quickly. In those women there's amplification of this gene - now what we're excited about is that we find that the protein that that gene works with there's a drug towards it and when we treat cells with this amplification with that drug it kills them.

Norman Swan: What drug is that?

David Bowtell: CDK2 inhibitor, CDK2 is like a partner that works with cyclin E to control the cell cycle so we think that that could be a good candidate for treatment of women with that amplification. Interestingly women that have amplification in cyclin E tend not to have these BRCA mutations, the BRCA1 or BRCA2 mutations. That's important because it's the group without the mutations who tend not to respond well to these new generation drugs called the PARP inhibitors, so we need new therapies for them, so that's something we're working on very hard at the moment.

Norman Swan: Tell me a little bit more about this Australian Ovarian Cancer Study?

David Bowtell: This is a study involving about 2,500 women that we recruited a few years ago now. These were women who were presenting for surgery for suspected ovarian cancer and they were consented and enrolled in the study and we collected their blood samples and their tumour tissue on about 60% of the women and we've been following them for the last 10 years, some of them, to see how they've done. And that's provided probably the largest resource in the world now for research into ovarian cancer. It's been important in supporting research in five countries around the world as well as in Australia in our own lab. And so we've been looking at genetic risk factors, we've made major contributions in finding new genes involved in the risk of ovarian cancer, all the molecular studies on the tumours and understanding why some women respond to treatment and others don't. And we've also been looking at lifestyle factors being led by Penny Webb at the QIMR in Brisbane.

Norman Swan: And what have they found with lifestyle factors?

David Bowtell: I guess mostly the things that we knew about in terms of oral contraceptive use and smoking and alcohol intake.

Norman Swan: And it should be said that oral contraceptive use is protective.

David Bowtell: That's right, that's a good thing about the fact that it cuts the risk substantially. So what we're interested in now is having found some of these new genes, how does lifestyle and the genes that we are born with intersect to increase or decrease your risk of ovarian cancer.

Norman Swan: Professor David Bowtell is Head of the Cancer Genetics and Genomics Program at the Peter MacCallum Cancer Centre in Melbourne.


The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011;474:609-615


Professor David Bowtell
Head of the Cancer Genetics and Genomics Program,
Peter MacCallum Cancer Centre,


Dr Norman Swan
Brigitte Seega

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  • Gabrielle Mylonas :

    14 Jan 2012 1:13:50pm

    This is such important information to get to the public. There is so little information on the implications of the widespread condition of endometriosis. This research alerts women and gives them a chance to speak with their doctors about preventative measures.
    Thank you to Professor David Bowtell and his team for engaging in this imporatant area of research that will help millions of women worldwide.