Researchers Sequence Cancer Genome A genetics team sequenced DNA from both cancerous and normal tissue from a patient with the white blood cell cancer. The researchers then compared the two sequences to identify 10 mutated genes that appear to be associated with the formation of the cancer.
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Researchers Sequence Cancer Genome

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Researchers Sequence Cancer Genome

Researchers Sequence Cancer Genome

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You're listening to Talk of the Nation: Science Friday. I'm Ira Flatow. Up next, cancer genetics. About 10 years ago, when the project to sequence the human genome was getting under way, cancer researchers in St. Louis got the idea that they could learn a lot about cancer by looking at the genes of a cancer patient.

Now most cancers are caused by something that goes wrong in the genes, so they started planning and waiting. Because at that time it would have cost somewhere in the neighborhood of a hundred million dollars to do that genome sequence. But as the years went by, the technology (unintelligible) cheaper, and the cancer researchers backed by a philanthropists got their wish.

They were able to sequence the genome, well, actually two genomes, really of a woman who died of leukemia. They sequenced the DNA from both her tumor and her skin, so that they could compare the healthy and the cancerous genes, and see genetically what went wrong in the cancer cells.

So, what did they find out now, that's what we are going to talk about with Dr. Timothy Ley, he is an M.D. and a professor in the department of medicine in the Oncology Division at Washington University in St. Louis. Thanks for being with us today.

Dr. TIMOTHY LEY (Oncology Division, Washington University, St. Louis): My pleasure, Ira, nice to be here.

FLATOW: You're welcome. My number is 1-800-989-8255, if you want to talk about the cancer oncology and genealogy of it, and if you're - if you want to twitter, we have a new feature we're doing now. We are twittering. You can join a conversation by tweeting your ideas at scifri@scifritter. Just write the @ sign, followed by scifritter. That's S-C-I-F-R-I-T-T-E-R. So tell us about this, about the leukemia first, so we can understand what you found, Doctor.

Dr. LEY: Well, this is a big project that involved many, many people. First, Ira, I have to say that this brought together two distinct groups of researchers at our university, the cancer doctors, the physician scientists who study leukemia and take care of our patients, led by John (unintelligible), and the Genome Center.

We did all the sequencing and analysis in a close collaboration with Rick Wilson and Elaine Martis there. And then of course, there's nothing without our patients who have the disease, and who took the risk to get their genomes sequenced, and I have to thank them for participating in these studies. So, the disease itself is acute myeloid leukemia, and this is a bad disease. I think a lot of people have - know someone who's had the disease.

FLATOW: Mm-hmm.

Dr. LEY: It's cancer of the blood. It occurs in cells that make blood, which normally reside in the bone marrow. And these cells acquire genetic mutations during the course of the person's life, that lead to abnormal proliferation of the cells or signals that cause them to die at the wrong time, die too late or to fail to differentiate. And what happens is these abnormal cells basically take over the normal marrow space.

They crowd out all the normal blood-making cell. So that you develop severe anemia and need blood transfusions. So that you're more susceptible to infections, because you don't have normal white cells. And also you have a tendency to bleed, because you don't make the normal platelets in the marrow, which are important for clotting.

FLATOW: Mm-hmm.

Dr. LEY: So that combination is a lethal trio and it's a very bad disease. And even though we do a pretty good job of treating it, in most of our patients (unintelligible) this disease, still.

FLATOW: And so you wanted to sequence the genome of a person who had that disease?

Dr. LEY: The problem is that we don't know what causes the disease for the vast majority of our patients. We don't know the genetic underpinnings yet. And we've been trying and many investigators around the world for years and years to understand the mutations that cause this disease, and with the advent of the modern genomics, we've thrown the book at patients with this disease. Tried every new modern platform imaginable that looks at all of the genes expression, and whether they're present or absent.

Everything's been tried and we sequenced lots and lots of candidate genes that we thought we understood, and we thought that might be involved with leukemia development. But none of these approaches after years and years of preparation and work with patients , who had participated with us, none of these approaches were really telling us what the genetic disease is comprised of.

What are the real mutations that are causing the disease? And a couple of years ago, when this new technology became available for a very, very high (unintelligible) rapid sequencing at low cost, called Next-Generation Sequencing. We decided really the only chance we had to find these mutations was to just bite the bullet, and sequence the whole genome. And we had prepared for this for years and years, by getting skin samples and tumor samples from patients with leukemia, who we saw here at (unintelligible) Cancer Center, and we banked them all the way.

Now we looked at hundreds of them to pick one patient who would be perfect for the first analysis, who would have just two copies of all of her genes, and with a very common kind of a disease that we faced very often, and in whom we know almost nothing about the mutations that caused the disease. So she was picked as our first patient.

FLATOW: And you found the difference between the cancer genes - the genome in the cancerous tumor and in her normal skin cells.

Dr. LEY: We did. We knew that we had to sequence her normal cells and her tumor, because there's an enormous amount of generic variation that exists between individuals.

FLATOW: Mm-hmm.

Dr. LEY: For the first few genomes that have been done, we know that there are millions of differences between each of us, and those are called SNPs or single-nucleotide polymorphisms in the genome. They're normal variations in the genome that probably, you know, help to make us the different people that we are, but we don't know how they contribute to diseases yet, and we don't know how they contribute to diseases like this one.

So we knew we would find millions of differences between her genome and other genomes that have been sequenced, but how would you ever know which ones are responsible? So we had to sequence her normal genome, and we had to sequence her tumor, independently, and then compare the two to find the differences. What we found really - it astonished us that we only found 10 differences between her tumor genome and her skin. And eight of these were completely new. They are mutations that had been acquired in the tumor. They were not present in her skin. They were in genes that we had never before suspected in this disease.

Two of the mutations that we found, we knew about before we went in. Those are genes that are commonly mutated in patients with this disease. They don't cause the disease, but we think they contribute to its progression. We know they are involved with the disease, but they don't cause it per se. So, these eight new mutations were not on our radar. Now in retrospect, they all make a lot of sense to us, because they're involved with things that's easy to imagine how they might be participating in the genesis of this cancer. We don't know exactly what they do or how they fit together yet, but just to find them for the first time and to know all of the mutations that might be contributing to one person's cancer, is really a milestone for us...

FLATOW: Mm-hmm.

Dr. LEY: In terms of thinking about how to really figure out the genetic roots of this disease.

FLATOW: 1-800-989-8255 is our number, talking with Dr. Timothy Ley. So does that mean that you can use this as a screening technique or not, in normal people? It doesn't sound like you can just screen people for these mutations, because if you take their skin cells for example, you're not going to find them in normal tissue.

Dr. LEY: That's right. These are mutations that are acquired in the tumor. Our current understanding of cancer suggests that a cancer starts maybe with one mild perturbation, an acquired mutation that gives a cell a little bit of an advantage.

FLATOW: Mm-hmm.

Dr. LEY: And that advantage persists over time until another random event occurs that gives the cell a little bit more of an advantage, and over time these mutations accumulate in the cells that have more and more of an advantage, and these cells basically just start to take over. Now, our guess about this patient's tumor is that these 10 mutations basically were in almost all of her tumor cells.

FLATOW: Mm-hmm.

Dr. LEY: Nine of them in every single one, and one, probably the last mutation that she acquired, was present in most of her cells, but not all. So, our guess would be that each one of these mutations contributed a little something to the tumor.

FLATOW: Right.

Dr. LEY: And that as they accumulated over the period of time that her tumor was growing, they all were important, and they all added a little bit of something that was relevant for her disease.

FLATOW: Mm-hmm. And the fact that you found eight new ones was a very significant there.

Dr. LEY: We would never have found these with any other method. That's one of the biggest lessons for us, is I think that we have to use these unbiased approaches to find these mutations. Ira, we just don't know enough about cancer yet, to guess correctly about the genes that might be involved.

You know in retrospect, you know, you hit yourself in the forehead and said, yeah, of course, these genes make a lot of sense for a cancer, and I can see how they (unintelligible) be involved, but prospectively, we didn't have these on our radar. We hadn't thought about these genes as things specifically involved, and no one had sequenced them in patients with this disease, because we just hadn't thought about them.

FLATOW: Hmm. And I have a question from Second Life, from Bauer(ph), who says, I am wondering why this was surprising, he expected fewer than eight mutations or more? Did you expect more or less?

Dr. LEY: Nobody knew.


Dr. LEY: Nobody knew. I think the greatest fear in the cancer community was that we have this concept of cancer as being a genetically-unstable disease. And that's because in lower-resolution screens of some cancers, there are many variations in there. In the copy numbers of genes, there are lots of chromosomes that seem to accumulate or are lost in certain kinds of cancers, so I think our greatest fear was that there would be thousand, or perhaps tens of thousands of mutations. They weren't relevant for the cause of the disease, but were just passengers.

FLATOW: Right.

Dr. LEY: And not really particularly involved in causating(ph) - in causation. So, you know, I think our greatest fear for many cancer biologists was that these tumors would have tens of thousands of mutations. And the old theories of course was that cancer was caused by a couple of mutations in different pathways. The two-head hypothesis by Nutzen about 30 years ago, where two different mutations would contribute to the pathogenesis of the cancer.

FLATOW: Yeah..

Dr. LEY: So, we never thought it would be that few. There were lots of studies that suggested that it would be in the dozens perhaps or, you know, in five, or 10, or 15. But our fear was that it would be a thousand or 10,000, or a hundred thousand.

FLATOW: Hmm. Well, knowing these few numbers. What do you do with this information now? Will this help you figure out what causes cancer to begin with?

Dr. LEY: Well, it will eventually. This is the first step sequencing a whole cancer genome. And the lesson is a good one. We can do it. With this new technology, the cost has been reduced to the point where it's no longer just fantasy to think about sequencing hundreds or thousands of cancer genomes over the next several years, which is really what needs to be done. What we don't know right now, Ira, what are the rules of cancer? What are the kinds of genes that need to be mutated to make it cancer? What combinations can occur to get you there?

FLATOW: Mm-hmm.

Dr. LEY: And what kinds of pathways are affected in cancers of different types? So this is just, you know, the first step in a marathon, I think. And I think that what we've learned is this technology will probably get us there. But it might be the only way to do it. The other lower resolution platforms...


Dr. LEY: For studying the genomes of cancer patients really have not told us what the answer is.

FLATOW: Well, where do you pick up a genetic possibility? I hear that some of the genes might have been passed on from, you know, in the family. We know that cancer has some sort of genetic component, right?

Dr. LEY: It does. And...

FLATOW: Is that lost here or because you would not see them in the skin? You would not see them - they'll be the same, would they not, in the skin as in a tumor.

Dr. LEY: That's a great question. And it's one of the biggest problems that we face, is that is the genetic variation that exists among individuals, is it relevant for cancer susceptibility? So how do you answer that question? Well, the way you have to do it is identify families that have cancer, and you have to sequence their genomes. And compare them with the genomes of lots and lots of other people, who don't have cancer. And in that way, by comparing, basically whole genomes against each other, in what we call now genome-wide association studies, which are snapshots of genomes, but not the whole genome, we can begin to understand how individual variations in people's inheritance affect their susceptibility of cancer.

FLATOW: Mm-hmm.

Dr. LEY: The beauty of sequencing her normal cells and her tumor cells is of course we have all that information. We know what the patients inherit, and we know it's acquired. And some day, when thousands and thousands of these units have been sequenced, I think we'll have a very clear understanding of which inherited mutations are susceptible mutations...

FLATOW: Mm-hmm.

Dr. LEY: Which could be screened for in individuals, and which are the ones that were acquired, and whether there's any relationship between the two.

FLATOW: Talking with Dr. Timothy Ley, on Talk of the Nation: Science Friday from NPR News. Sorry, is that Dr. Ley, isn't it. It's - I always get everybody's name wrong so you should feel right at home, doctor.

(Soundbite of laughter)

Dr. LEY: So, would it be possible to intervene some place along the line, saying, hey, we know about your genome, and we know you're susceptible, before the cancer strikes.

Dr. LEY: Yeah, that's the hope. It's already being done for many people with the male cancer syndromes.

FLATOW: Mm-hmm...

Dr. LEY: And people with some kinds of breast cancer that - where it runs in families, screening is initiated much earlier.The same is true for patients with some kinds of inherited mutations that can affect colon-cancer development for example. And screening techniques can be applied. For diseases like acute leukemia, the one we're studying here in this paper, the benefits also can be sooner rather than later.

For years, we've actually looked at the genomes of patients with acute leukemia, by looking at their chromosomes. And we've known for a long time the work of many, many people around the world, that some people have a good prognosis, because their chromosomes are a certain way. And some are going to do very poorly.

FLATOW: Mm-hmm..

Dr. LEY: And we actually use that information to customize the therapy of the individual, right after they're diagnosed. People who are going to do very badly, we may make a decision to do a bone-marrow transplant as part of their initial therapy. Because if we don't, we know that they'll die in the disease very quickly. As we get these genetic rules of cancer from sequencing genomes, I know that we will find the mutations that portend a poor prognosis. And that will impact what we do immediately. We won't need designer drugs.

We will be able to use the information to immediately impact on the care of patients, which is what this work is all about. Because we'll know who is going to do well, and who's going to do poorly. It will be able to customize the treatment of patients up front. That's one of the goals and one of the reasons why this disease was chosen to study...

FLATOW: Mm-hmm.

Dr. LEY: Because we knew we wouldn't have to have new drugs in order to (unintelligible) 6:06 really personalize medicine with the kinds of information we get.

FLATOW: Right. Would you choose other cancers now or other diseases?

Dr. LEY: Well, I think that they all have to be done. There's an international consortium, looking at other kinds of cancer to sequence. And 50 tumor types have been preliminarily selected for study. I think the hope is that we can do hundreds of each of these 50 common tumor types over the next decade or so, to really get at this issue that you mentioned. One of the rules of cancer, are the susceptibility, mutations that people inherit, and how do they interact with acquired mutations in the tumors.

FLATOW: Would studying identical twins work at all here?

Dr. LEY: Identical twins, one of whom gets cancer, one does not.

FLATOW: Yeah. Yeah.

Dr. LEY: It's something that people have thought about and done, and certain kinds of hereditary-cancer syndromes. And that can be very interesting and informative in certain pairs. Sometimes people don't get cancer at exactly the same kind as their identical twins. And that tells you that many cancers have different kinds of progression pathways. Or...

FLATOW: Or one could be a smoker.

Dr. LEY: Sure.

FLATOW: One could be in a factory or someplace where there (unintelligible)...

Dr. LEY: There are environmental factors that could affect the mutations that contribute to the cancer. As it develops, and they are just aren't random things that can happen. And comparing those kinds of genomes between twins who get cancer at different times, or different kinds of cancer could be extremely informative.

FLATOW: Dr. Ley, we've run out of time.

Dr. LEY: OK.

FLATOW: Thank you very much. You're very informative and good luck to you.

Dr. LEY: My pleasure. Thanks so much, Ira.

FLATOW: You're welcome. Dr. Timothy Ley is an M.D. and professor in the Department of Medicine in the Oncology Division at Washington University in Saint Louis.

We're going to take a break, and come back and talk more about some really interesting news stuff in diabetes. Treating diabetes without using insulin, some other research published this week. Stay with us, we'll be right back. I'm Ira Flatow, this is Talk of the Nation: Science Friday from NPR News.

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