Following the Family Tree to Understand CancerDec 20, 2013
Dr. Lisa Cannon-Albright helped discover the hereditary breast cancer genes BRCA1 and BRCA2 as well as a gene that predisposes people to Melanoma. Listen to her explain how Utah’s rich genealogical resources have enabled the discovery of cancer genes by allowing researchers to find genetic similarities in large families with histories of cancer. In recognition of her inventive and creative research, Cannon-Albright recently was made a fellow in the National Academy of Inventors. In her current work, she is on the trail of a gene that might predispose men to prostate cancer.
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Interviewer: Today we're speaking with Dr. Lisa Cannon-Albright. She's a professor of internal medicine at the University of Utah and the chief of the division of genetic epidemiology. She specializes in cancer research and in that capacity has been involved in major discoveries involving breast cancer genes and skin cancer. So tell us, what got you into cancer research?
Dr. Cannon-Albright: I actually came to Utah because I was looking for a change of pace, maybe grad school, maybe a new job. I had heard about this genealogy that was being used for genetics of cancer research. So I really came to Utah looking for that group. I met that group almost immediately and I just completely fell under the spell of this concept of using a genealogy linked to medical records to try to explain the genetics of cancer. That was in the late '70s. So I joined Dr. Mark Skolnick's group and I never looked back.
Interviewer: Describe just a little bit more in detail, if you would, the genealogy and how you use that for cancer research.
Dr. Cannon-Albright: Absolutely. Because of the rich Mormon heritage here in Utah the population has really high quality genealogic data. The university brought Mark Skolnick here with the cancer center probably back in the early to mid-'70s with the idea of doing something special with the fact that the state had genealogy data and that the state also had a tumor registry that had been statewide since 1966.
I love this story because it involves so many people who had vision way back when and made the commitment to collecting, computerizing different types of data. Nowadays we all take advantage of it and consider that it's always been there, but without the foresight of these individuals, Mark Skolnick, who was a geneticist from Stanford, Charlie Smart, who was an oncologist, Roger Williams, a cardiologist, these men all had this vision of what you could do if you had a population and you knew all the genetic relationships and then you also knew what diseases people had you could then begin to study the genetics.
Does this particular disease cluster in relatives more than you would expect? Can I find a high-risk family for this particular disease I'm interested in? That's where it all started.
Interviewer: If a disease cluster is more in relatives, what's to be learned from that?
Dr. Cannon-Albright: I always like to tell people that what we do really has a strong intuitive component. So if you say to yourself, "Well, I wonder how I could see whether breast cancer was genetic," then maybe you could take all the breast cancer cases and look at how they're related to each other. Just by two at a time, look at all the pairs of breast cancer cases and say, okay, wow, I see mothers, and sisters, and cousins, and all kinds of stuff. Then you'd say, "But is that different from what I expect in the population?"
Then you take a bunch of women just like them, randomly selected from the population, so born in the same decade, born in the same state, etcetera, and you look at how related you would expect them to be. Your intuition tells you, well, if those breast cancer cases have more relationships with each other than you'd expect when you compare these control-matched women, then that tells you that that is a disease that clusters in families.
From there, you want to say, well, does it cluster in families because families share the same behavior or is it genetic? Then you can begin to answer that question by looking at are all the relationships that I'm observing in close relatives who actually share maybe a lifestyle, an occupation, etcetera, or am I seeing an excess of relationships even in distant relationships, fifth cousins where people don't really know each other and certainly don't take on each other's diet, etcetera. If you can see that excess in the distant relatives, now you have evidence that there's a genetic contribution, not just environmental.
Interviewer: You were involved in the discovery of the BRCA1 and BRCA2 genes.
Dr. Cannon-Albright: There was a group in California that first recognized that there must be a gene somewhere on chromosome 17, but their pedigree resource wasn't near as powerful as the Utah pedigree resource. So we were immediately able to go to our families and localize where that gene must be. Again, this was just a huge collaboration of statisticians, and geneticists, and molecular biologists, and oncologists. It was a huge collaboration and depended very much, as I say, on these unique and powerful Utah resources and Utah people.
Interviewer: Once you got all this information, this statistical information, then what? You put it into a computer and came out with all sorts of algorithms?
Dr. Cannon-Albright: Basically, you can analyze a particular pedigree and genetic markers. What you come up with is statistical evidence that sort of tells you about the likelihood of you observing what you just observed and what that tells you. You can get very good statistical evidence, for instance, that a small piece of chromosome 17 has actually segregated through the family to every single individual with breast cancer. So the statistical evidence tells you, wow, it is incredibly likely that the gene you're looking for in this family is right there on chromosome 17.
Then you partner with molecular biologists that can actually go in and find variance and mutation screen. Someone was asking me this the other day. They said, "Was there this moment when you were like 'Oh, my gosh, you guys! We found it!' Jumping up and down."
It wasn't like that at all. Every day you have a little bit more analysis. Maybe a new family tells you something new, but it just seems to me, even today, that discovery is this really slow process that builds and builds until suddenly, it's not that you realize, "Oh my gosh, we found something," that stage kind of gets lost and you just say, wow, what we have here is true. It's valid. This is a real thing.
One of the things I do with my group nowadays is I try to stop and celebrate the little steps because I realize now, having lived through that, that sometimes you really miss the big bang at the end because it's just such a slow, steady crawl to the point of discovery that you don't realize it and you really do need to celebrate these successes.
Interviewer: Of course. Through this long, gradual process you went through with this whole collaboration of people, the BRCA1 and BRCA2 genes were identified as well as one related to melanoma, I believe.
Dr. Cannon-Albright: Right. Right.
Interviewer: That brings us to what I'd like to move on to. So you were part of these discoveries. The gene mutations were identified. What then?
Dr. Cannon-Albright: This discovery of these genes has allowed a real life test, which can be combined with clinical knowledge to tell you how you should behave. For instance, the melanoma gene-how should you behave in the sun? Are there things you can teach your children about being out in the sun that will maybe reduce their risk? Someday I think we'll know if there are different ways to treat people who have this mutation versus that mutation. That will result in less illness and maybe even less death.
Interviewer: Of course, recently you, I believe, identified a gene that predisposes people to prostate cancer?
Dr. Cannon-Albright: This is kind of what I was describing before about science. It's really hard to get to the point where you say, wow, we've got something and it's real. We found a gene that explained about three of our hundreds of high-risk prostate cancer pedigrees. We saw variants segregating in these families that segregated with the prostate cancer, so on a day when I'm just feeling really good about myself I'll say we discovered a prostate cancer gene.
Then there are days when I say I'm not convinced yet. It's not used in testing. It hasn't gotten to the point of being useful. I'm not convinced yet that we really did find a useful prostate cancer gene, but I have since the early '90s been studying hundreds of high-risk cancer pedigrees. My colleagues will tell you that I could say this almost every day of my career but I really feel like we are close on the trail of several prostate cancer predisposition genes.
Interviewer: I'm curious what your thoughts are on the role of creativity in your research and in scientific research in general?
Dr. Cannon-Albright: It's a really interesting question because as a student of Mark Skolnick and as a colleague of some of these other people I mentioned whose foresight led to what we're doing today, I always notice that, wow, you always have really good ideas and you have really good intuition. I realize that what it was coming from was taking a step back and getting the big picture.
That's such and important part of the creative process because, number one, you have to think about what do I have today and how can I use it better than people were using it last year or last decade? Because our tools are changing so quickly. So I spend a lot of time thinking about the Utah Population Database, the different registries we have. I think I'm actually quite proud because I feel like that's something I learned as a graduate student: how to get creative and what might some people in the future might be happy that you created that you thought of.
Interviewer: It sounds like you've got some work to do for a few years ahead then.
Dr. Cannon-Albright: Yes, I have plenty to do. I want to leave my group sort of like what I was given from my mentor. I want to leave my group with excellent resources so they can have the same fun that I did thinking of new ideas, discovering new genes, and reducing illness and death.
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