Decoding the Genetics of Cancer

         

Dec. 30, 2009 – Research into the genetics of cancer has rapidly expanded in the last few years with the aid of new equipment and new techniques like those pioneered by the the Genome Center at Washington University School of Medicine in St. Louis. In this edition of Breakthroughs in Cancer Research, Genome Center director, Richard Wilson, PhD, explains not only the basics of genetic research but also what scientists hope to learn from studying the genetic origins of cancer and how they hope to apply those discoveries to the treatment of patients in the future.


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TRANSCRIPT OF AUDIO FILE

On this edition of Breakthroughs in Cancer Research, we’ll talk about how advances in genome sequencing are helping scientists better understand cancer.

Host: Thanks for downloading this podcast from the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St Louis. I’m Gwen Ericson. I’m talking with Richard Wilson, PhD, director of the Genome Center at Washington University. One facet of the Genome Center’s research focuses on cancer, and that’s what we’ll be discussing today. Dr. Wilson, thank you for joining us.

Wilson: My pleasure, Gwen. Thank you.

Host: Before we talk about the impact of genome science on cancer research, give me a little background on the Genome Center.

Wilson: Well, the Genome Center at Washington University has been around since the early 1990s, back at the beginning of the Human Genome Project. Some folks may be saying, “What’s a genome?” Well, it’s the collection of DNA that you have in pretty much all of your cells, and it carries the information that you inherited from your parents. That collection of DNA is what makes each of us humans very similar and yet different as well. And we’d like to study that to get some idea as to why some folks get sick with certain diseases and other folks are very healthy all their life, why some of us respond well to some medications and others have a bit of difficulty.

Host: I’ve heard it said that cancer is a disease of genes or that all cancer is genetic. If that’s accurate, what would that mean?

Wilson: Cancer is certainly a disease of many factors. It’s genetic in some aspects. It’s also environmental. There also may be infectious agents involved in some cancers. But basically, it all boils down to genes. If genes are changed during the course of a person’s life by some environmental factor like cigarette smoke, cancer can result. It’s those changes that we really want to study and try to understand.

Host: Can you tell me the kinds of changes in the genes that result in cancer?

Wilson: I’ll give you one very famous example. There is a type of cancer called CML, or chronic myeloid leukemia. In fact, the basketball player Kareem Abdul Jabbar has just told folks that he has CML. One of the causes of CML is that two chromosomes break apart and then come together in a wrong way. They essentially create a new gene, and the product of that gene causes that cancer. Once scientists were able to get a lot of detail about that new gene, exactly where it was and what it was like, it was possible to design a new drug that basically knocks out that new protein caused by that gene, and that destroys those tumors and makes them go away. This is exactly what we’d like to do for a lot of different cancers. We’d like to find those changes to genes that might underlie the disease and see if we can’t learn more about the disease, come up with better diagnostic approaches and come up with better treatments.

Host: Is it as simple as a single gene? Is one change enough to cause cancer?

Wilson: I wish that was the case. And actually in some cancers, it may be sort of true, but typically what we believe is that several changes have to occur for a normal cell to become a tumor cell. One of the things that we clearly understand is that we’ve got pretty good defense systems built in. Our cells are pretty good about going through and finding mutations and repairing many of them. So if our genomes can repair themselves, then it shouldn’t be a problem. Or if there are redundant genes that help cover up problems that happened to some, then our cells would stay normal as well. Quite often, it’s what we call multiple hits on the genome that actually lead to the disease. So it’s a little bit more complex than just a single gene.

Host: So it makes sense that the ability to decipher the sequence of genes and identify mutations will make a significant difference in understanding cancer and treating it. Tell me about some of the ways you’re using sequencing technology to study cancer in the Genome Center.

Wilson: Well, one of the methods that we’ve really pioneered here is the approach of looking at the entire genome. It used to be maybe four or five years ago that researchers would say, “I’m interested in a particular type of cancer (let’s say lung cancer), and from all of the research that’s been going on for the last decade or two in many labs, I know that there are four or five or six genes that might really be important in lung cancer. Let’s go off and sequence those genes from a whole bunch of patients and see if we can find additional mutations.” And you start to find some, but you don’t ever get the whole picture. We’re kind of left with this incomplete picture, and we really don’t know what’s going on in that particular cancer type. So what we’ve actually tried to do, instead of going fishing with a rod and a reel and a single lure in the water, is come at it with a very large net and try to throw that net around the entire genome – not just a few genes that we think might be involved but all of the genes in the human genome. Now this hasn’t been possible until just the last couple years, when some new technology has come on board and become available to us that really makes this feasible both in terms of the amount of work required for a center such as ours as well as the cost.

Host: Let’s talk a little bit about that new technology. How fast can you sequence a genome?

Wilson: When we started sequencing the human genome back in the early 90s, it was very slow and very expensive. That first genome sequence took us about 10 years and cost about a billion dollars. Now with this new technology, we’re actually able to sequence genomes in a much shorter time frame. The first cancer genome that we sequenced a couple years ago took us a matter of months and cost about $1.5 million. And now we’re at the point where we can sequence cancer genomes in a few weeks, and the cost is down around $50,000.

Host: Tell me what you mean by cancer genome?

Wilson: Well that’s a great question. If you are a cancer patient, you likely have a tumor. So what we’d like to do is to biopsy that tumor and take some of those tumor cells and isolate the version of your genome that is present in those tumor cells. We also like to take a little bit of normal tissue, and we’d sequence both of those genomes and then compare and look for the differences that have become present in the tumor DNA – the cancer genome, if you will – that aren’t present it in your normal genome. Those typically are the suspects that we look at as the cause of your disease, and they might help us to understand how best to treat you.

Host: So I understand one of the latest projects you’re working on is comparing this genome of an AML tumor to the genome of normal tissue in a single patient. Tell me about that research.

Wilson: Well that was actually the first cancer genome to be sequenced. It was a patient who had acute myeloid leukemia, which is a very deadly disease. And what we did was to take a little bit of her tumor sample as well as a little piece of skin and sequence both the DNA from her skin, which represented the normal genome, as well as DNA from her tumor. We found 10 genes that were mutated in the tumor. It was very interesting because all of these were in genes that are known to have some relationship to the formation of cancer. So that gives us some initial clues about how this disease may have been caused. Now we have since gone on to sequence genomes from additional AML patients, and we’ve found quite a few similarities to the first patient. So we think through this type of analysis, by actually sequencing these cancer genomes from a great many AML patients, we’re really going to learn what the basis of the disease is. I think it’s really exciting because very early on we’re going to be able to use this information to better utilize the drugs that we already have to treat leukemia. And that’s really going to have an impact soon.

Host: Explain that a little bit further: How does that information help you better utilize available drugs?

Wilson: So we’ve actually found in some of our sequencing some gene mutations that would allow us to take patients and say, aha, here’s a mutation in a gene, and we know that correlates with a poor outcome. So these are patients that we’re going to want to treat much more aggressively, where maybe we’ll want to do a bone marrow transplant, for example. Bone marrow transplants can be difficult for the patient, difficult for the family, and if we knew that we didn’t have to go to that extreme, if we could simply treat with the chemotherapy drugs that we have, that would make a big difference just in terms of the quality of life for those patients.

Host: Give me a sense of the size of the human genome.

Wilson: The genome is three billion letters of code. It takes a tremendous amount of time and tremendous skill and a huge amount of computing infrastructure. We actually had to build a building across the street from the Genome Center to house all the computational hardware. Right now we have a lot of different sequencing projects going on here at the Genome Center, but if we said OK, we’re going to take this one genome and get it through our pipeline as quickly as we can, we could basically sequence a person’s genome in about a week and then probably take another couple of weeks and do the analysis and come up with every single interesting base in that genome in that time. It is just amazing.

Host: So that’s the present. In the future, how are things going to change?

Wilson: Well, I have this idea of a sequencing machine that is so easy anybody can use it. I’d envision it looking like a desktop computer with a little CD drive or door that pops open. And I basically have some sort of a chip that I pipetted a DNA sample on, and when I push it back into my computer, in 15 to 20 minutes, it does all the chemistry and all the analysis and pops out an answer that says mutations in this gene, this gene and this gene and here’s what it means. That’s not going to happen in the next couple of years, obviously, but that’s really the goal is to have some sort of gene machine that gives us real medically relevant answers. This is a 15 to 20 years down the road sort of thing, but I think it’s going to happen.

Host: Dr. Wilson, thank you for joining us.

Wilson: It’s been my pleasure, thank you.

Host: The Genome Center is widely known for its prominent role in sequencing the human genome, and it now has ongoing sequencing projects in many species, including bacteria, fungi, plants and primates. Recently, the Genome Center received funding for a project to generate cancer genomes for 20 different types of cancer. If you’re interested in learning more about the Genome Center, visit its Web site at genome.wustl.edu.