Searching Family Trees for the Seeds of CancerJan 15, 2014
Our genetic code is made up of 3.3 billion base pairs of DNA, and one single base pair change can be enough to put someone at risk for developing disease. Dr. Nicki Camp, a professor of genetic epidemiology at the University of Utah, uses one of the world’s most extensive resources of it’s kind, the Utah Population Database, to hunt down the tiny changes that trigger inherited cancers, including multiple myeloma. She explains what she has found so far and how her work might one day help patients worldwide.
Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on The Scope.
Interviewer: Just one tiny change within our vast genetic code can put someone at risk for developing disease. Using a unique resource, the Utah Population Database, University of Utah professor Nicki Camp has made headway into finding the variations that trigger inherited cancers, including multiple myeloma. Dr. Camp, what's multiple myeloma and why is it important to study?
Nicki: Multiple myeloma is a cancer of the plasma cells and your bone marrow. Until recently it was one of the cancers that had the shortest survivals so we've been trying to figure out ways in which we can both diagnose and maybe understand the disease a little better so we could develop new treatments and therapies for myeloma.
Interviewer: What is your approach to identifying the genetic variations behind this disease?
Nicki: Our specific way of doing this, and we do this for many cancers, is to try and study families where they have an increased rate of, in this case, myeloma because the idea is that if we can see it clustering in a family and we study that family, that that's more likely to be due to genetics. So we've increased our chance to be able to find those underlying genetic factors.
Interviewer: As I understand it, you use the Utah Population Database. Can you describe that resource?
Nicki: Yeah. It's actually an amazing resource, one of the reasons why I'm here in Utah. The two key factors that I'm using for my multiple myeloma resource are, one, the genealogy. In other words, kind of how people and their parents and their grandparents are all linked together in genealogical records. There's about two-and-a-half million people who we know at least three generations of their genealogy in the UPDB. We have that back to the pioneers.
Then what we have on top of that is a mandated Utah Cancer Registry. The cancer registry has been in place since the late '60s and every cancer that's diagnosed or treated primary cancer in the state of Utah goes into that registry. If you can imagine looking in front of you at a genealogy, like an enormous family tree, and then throwing cancer diagnoses on there, suddenly you can just see these constellations of cancers.
Based on that, without asking anybody to recall their family history, we can identify these families which look extremely powerful to be able to study and then through a mechanism that's in place at the Utah Cancer Registry, because of course I don't know who these people are, I can say here's a family I would really like to study. Then they invite those people. They say, "Nicky Camp at the university would like you to be part of one of her studies." If they say, "Yeah, that sounds great," then we get their contact details and we invite them into the study.
That mechanism is, I think, a very unique one. In fact, precisely because myeloma had such a short survival rate there's been a real struggle in the field as a whole of being able to study families because people have passed away, whereas what we've been able to do is identify them and then go straight to the people who fortunately are still living. Actually, that's the other great thing about Utah. So many people are very willing to be part of genetic studies too, so we get a very high participation rate. We have probably some of the largest and well filled out pedigrees that there in myeloma in the world.
Interviewer: That's amazing. Have you identified a number of families?
Nicki: We have. We have identified and enough people have participated in 15 different extended pedigrees. Eleven of those pedigrees are part of my Utah genome project.
Interviewer: Basically, you're taking a closer look at the DNA sequences within just these pedigrees?
Nicki: Yes. First, a lot of projects that are out there in cancer are to do with taking an independent set of cases and an independent set of controls, no family structure, and they will say, for example, sequence these two and say, okay, what are those variants that the cases seem to have more often than the controls do? That has good power.
That works very well if what you're looking for is quite common. It doesn't work so well if what you're looking for is quite rare. You can have a thousand cases and a thousand controls. If you see it three times in your cases and zero times in your controls, what does that mean? Is that a real difference? Is that just an anomaly of three versus zero?
The advantage of doing it in pedigrees is you're expecting to see that very same mutation or base change to be carried by these people who will have a common ancestor. So the strategy that we have taken is first of all, we kind of do this ladder of genotypes across the whole genome and we do that to try and understand which chunks of chromosomes look like they're being shared more often than they should.
Interviewer: I see.
Nicki: So that gives us some focus because what you've got to remember, as I said in the beginning, 3.3 billion faces, where should I look? Of course, it's all statistics and sometimes statistics tell you the wrong thing so we still have the sequencing everywhere else, but it gives us a way in which we can kind of make sensible roots through these enormous datasets.
Interviewer: Do you have some leads or have you narrowed down regions of interest?
Nicki: What we're really excited to find is we've got 10 really exciting regions of which five are either regions which have been shown in this case controlled type analysis, so the nice thing is they're overlapping with what's known from totally different study designs. A couple of the regions are known somatic sites of translocation.
In other words, what we're studying is what is in your inherited DNA that might predispose you to disease? Well, once these people get disease and you have a cancer cell then the cancer cell starts making changes of its own. Some of those are unique to the cancer, so what we know is that if you look at the tumor cells in myeloma there are certain chromosomes where pieces of one chromosome translocate and move elsewhere. On those boundaries where those translocations happen we seem to be finding some germ line, some inherited changes that appear to be happening in those same regions.
So, again, that's very intriguing that maybe there's some maybe genetic predisposition as to why those translocations might happen. Anyway, they kind of make all of these pieces of cancer biology and what other parts of the fields are doing with cases and controls, they kind of help us put our work in perspective, what's more likely to be real versus, like I said, something that's just coming out of the background noise and isn't a real signal.
Interviewer: If that connection is made and makes sense, what can be done with that information?
Nicki: I guess my hope would be many levels. To start with, just basically, we understand the disease mechanism better. Then that gives us insight into the disease and that might give us reasons to figure out different treatments strategies.
If we know something is going to predispose someone to a disease we can screen them quicker. We can start treatments earlier; we can elongate their life that way. We might suddenly understand how the genes are acting, reacting in inappropriate ways and maybe that's going to give us better ideas of drug targets or how a drug that's already used in, say, another cancer could be used specifically here.
Interviewer: I imagine much of your work is done at the computer. How does it feel to have this connection with real lives?
Nicki: It's thrilling and it's also frightening. I have coordinators that actually go out and draw the blood, talk to the patients, and I am most of the time sitting in front of a computer and these are numbers. To think that we might be able to make a difference in these people's lives is really thrilling.
Frightening because in some ways you just feel like there's so much at stake, especially for the people involved. These things take such a long time. In some ways I wish there was something in the short-term that we could give back to these people which participate, which usually we can't. Usually these are studies that take five, 10, 15 years. It takes a while to go from initial findings to realizing how significant that is for it to get back into the clinic.
Interviewer: I think something to emphasize is that your work will impact more than Utahns.
Nicki: Yeah. Actually, it's a really important point. Again, I suppose the excellent examples of this are the breast cancer genes, BRCA1 and 2, and things like P16, and myeloma, and APC gene in colorectal cancer. The genes that have been found here in Utah have all had complete relevance in other populations.
In fact, many of the genes and the variants identified here in Utah are among the top ones that have been part of the genetic counseling that have moved on. So, yeah, it certainly isn't just that what we find here is relevant here. They've been relevant across the United States and also worldwide.
Interviewer: Tell us how you got here and why you decided to stay.
Nicki: I arrived in 1998. I had just finished my postdoc in the central north of England at a place called Sheffield. My idea was to come for 18 months to come and see what this Utah Population Database was about. Here I am 15 years later married to a Utahn and two kids. I've never looked back. Now it would be really difficult to ever leave because there's just so much more we can do here. If you want to do pedigree studies it really is just the best place.
Announcer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.