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Interviewer: Having an accurate family health history is just as important as exercise and eating right, maybe even more important. But where do you start? We'll talk about that next on The Scope.

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Interviewer: Dr. Joshua Shiffman is an expert in hereditary cancer at University of Utah Health Care. Let's talk about family history for a second. For what you do, it is absolutely crucial that you know a family history, but what about for the rest of us?

Dr. Shiffman: Obtaining an accurate family history is one of the most crucial things that you can do as a patient to help your doctor understand what your disease risk is.

Interviewer: So I made the claim that maybe this is as important as exercise and nutrition, would that be an accurate claim?

Dr. Shiffman: I think it is a very accurate claim. For instance, if we know that a patient is at genetic risk for a specific type of cancer, or cancer syndrome runs in that family, we're able to institute screening to do early tumor surveillance. Studies that we've done here at the University of Utah and with other collaborators across the country have shown that if we know you're at risk for cancer, and we screen you accurately for that, that your three-year survival is 100% if we detect the cancer early. That's opposed to 20% if you don't undergo screening.

Interviewer: So that's for cancer, but what about other medical conditions?

Dr. Shiffman: The same is true for all sorts of diseases. For instance, if you know that you have a genetic predisposition for diabetes in your family, well then you better watch what you eat, and be careful to limit some of your sugar intake. The same is true for cardiovascular disease and just about any type of disease that's out there.

Interviewer: So how many people actually have an accurate history that's complete and useful to a physician?

Dr. Shiffman: I would say very few. Very, very small, in the single digits. Many of us have some idea, and we know that Aunt Millie may have had some type of disease, but we can't remember what it was, and there was a cousin with cancer, but no one really spoke about it. So when you start to dig a little deep, we begin to realize, in the clinic, really, that we don't have that full and complete picture.

Interviewer: And you're talking about some common types of diseases, but there are a lot of things that run through families that people aren't even aware of, like mental illness for example.

Dr. Shiffman: That's very true. We know that sometimes suicide runs in families, depression certainly runs in families. Almost every disease is genetic, but just because you have the genes doesn't mean you'll get that disease. However, if you have a family history, I would argue that's even more important than the genetic risk.

Interviewer: So it sounds like an accurate family history is considering a broad range of potential diseases, not just the big ones, like so-and-so had diabetes, or so-and-so had cancer. How would you actually start to collect a family history? So when your doctor asks you that question next time, you can go, look at this, bam.

Dr. Shiffman: Right. And that is exactly what we need. We've done several different studies and we've shown that despite the growth of different tools that are available, they really don't seem to be doing the trick. It seems that people are relying too much on their own recollection.

So what we recommend, the first step of taking an accurate family history, is sit down, and call up your family members. Ask them, what was it that you had? What year was it that you had that? How was it treated? It's really important to know the distinction of what was actually diagnosed versus what you think was diagnosed.

Interviewer: So it sounds like it's a family activity, it's not just a one-person activity trying to remember, and details are important.

Dr. Shiffman: Details are crucial. You need to know what age did that person develop their disease? It's much different to have an 80 year-old with diabetes than it is to have a 12 year-old with diabetes.

Interviewer: There are a lot of things that I think would be difficult to keep track of. Is there a tool or something that can help you do this? I don't think my legal pad is going to cut it.

Dr. Shiffman: Exactly, and you're not alone, Scott, a lot of people feel the same way, as do I. So that's why we've been working through our program in personalized health and also with the Department of Pediatrics here at the University of Utah to create such a tool. We've been working on something called ItRunsInMyFamily.com, and what this tool will allow others to do is to collect an accurate family history with the help of other family members.

Scott: And how far back do I need to go?

Dr. Shiffman: Usually a three generation family history is sufficient, but you also need to know, when you report to your doctor, is it something that occurred on just one side of the family? Was it both sides of the family? Because that makes a difference too in trying to define your risk.

Interviewer: And beyond immediate family, how far out am I going?

Dr. Shiffman: So you really want, you know, your siblings, your own children, if you're older, you definitely want your parents, your aunts, your uncles, your grandparents, and your cousins.

Interviewer: Right, and get everybody's recollection and try to get it as accurate as possible. So once you get all this information together, what do I do with it now?

Dr. Shiffman: Well, you should really keep it in a safe place. So you need to write it down, or have some way of storing it so that when your physician asks for it, you have it there. If you come in prepared, and you have that family history in hand, then you can really spend the clinic visit focusing on what you need to do because of that family history.

Interviewer: And so, having a family history has been important for a long time, but it's becoming more and more so, can you explain why that is?

Dr. Shiffman: We know now that family history is really one of the most accurate predictors of disease risk for an individual. We also know now that genetics plays a role. So we're able to combine DNA information, genetics, genomics, things that we're experts here at the University of Utah and combine that with family history and of course no one needs reminding that genealogy and family history is a real key component of living in Utah.

So putting those together at this time in this genomics revolution really helps us to understand what are disease risks and most importantly how do we actually prevent disease, how do we do something with that information that we obtain.

University of Utah and our program in personalized health and our department of pediatrics with its focus on prevention is really the perfect place to focus on family history. People have known for decades that family history is important. But I think now we're at a time and a place with the resources available and the expertise available here at the University of Utah to really build a tool that is useful, not just for the people in Utah but for everyone around the world.

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Interviewer: Elephants rarely get cancer. A new study may explain why.

Announcer: Examining the latest research and telling you about the latest breakthroughs, The Science and Research Show is on The Scope.

Interviewer: I'm talking with Dr. Schiffman, a pediatric oncologist at the Huntsman Cancer Institute, University of Utah School of Medicine and Primary Children's Hospital. Dr. Schiffman, this is a great story. Before we get into it can you explain what you found?

Dr. Schiffman: Well, what we were able to show was that elephants, despite their large size, being 100 times the size of people and living for 50-60 plus years, almost rarely develop cancer. This is surprising because with so many cells dividing for so long a period of time, you would think that almost every elephant would develop cancer at a very young age. What we were able to show was that elephants may be protected from developing cancer due to extra copies of genes called p53 that protect us from cancer.

Interviewer: So might this have implications for developing new therapies?

Dr. Schiffman: We know that if we're missing working copies of these genes that there is an increased risk of cancer. In fact, we know half of all human cancers don't have p53 that works properly. The elephants on the other hand have 20 times as many p53s as people. And we think this is the reason that they don't develop cancer. Now what we're trying to do in the laboratory is figure out how do we mimic this effect of these extra copies of p53.

Interviewer: I love this idea that you're basically following nature's lead. Nature's already come up with a solution. We just have to figure out what it's done.

Dr. Schiffman: What we're trying to do in the laboratory here at the University of Utah is take a page out of nature's playbook. Just like you said, nature's already figured out. What we want to do is learn from that and see how do we apply this to children and adults who already have cancer or maybe at a genetically high risk to develop cancer.

Interviewer: One thing I was wondering is, you say that elephants really get cancer. But do we really know that? I mean, could it be that no one's been able to find it?

Dr. Schiffman: We looked at 644 recorded elephant deaths, mostly from elephants in captivity, to try to measure what is their cause of death. What we found was the cancer attributed deaths of those 644 elephants that we looked at, less than 5%. So 4.8% of these elephant deaths could possibly be due to cancer. In humans, the estimated mortality from Cancer is 11% to 25%.

Interviewer: And actually elephants aren't the only large animal that rarely gets cancer. You did an analysis of many types of animals

Dr. Schiffman: We looked at a database that the San Diego Zoo maintains. You would expect that those animals that live longer, that have more cell mass, that they would also have an increased risk for cancer. Because the more cells you have, the longer those cells are dividing, just by chance alone, the opportunity to accumulate mutations and eventually transform into cancer would be present. But what we found was that, actually, there wasn't a relationship. If anything, the larger animals like the elephants, like lions, like moose and so forth, they seem to be slightly protected from cancer.
So we think that nature has evolved to protect different species from cancer, so that they could grow large, so that they can live a long time. We believe as we expand our studies and we look further that every different animal that is protected from cancer will have evolved a slightly different way of avoiding cancer or becoming cancer resistant. This concept of evolutionary medicine of learning, what we can from nature around us is very exciting and we think holds great promise for treating our human patients.

Interviewer: So how did this even get started? I mean, it's not like laboratory scientists work with elephants every day.

Dr. Schiffman: Several years ago I was at a conference that was discussing the evolution of cancer. And one of the speakers, Carlo Maley, from the Arizona State University, was describing this phenomenon called Peto's Paradox, which is the observation that large animals like elephants develop much less cancer than you'd expect by chance alone. Carlo went on to describe that he had looked at the genome of African elephants in his laboratory and there they found that these elephants seem to have extra copies of this p53 gene.
I went up to Carlo after the talk and was discussing that in our lab at the University of Utah, we take care of patients and study patients who have something known as Li-Fraumeni syndrome, who are actually missing working copies of p53. And we said wouldn't it be wonderful to try to get elephant blood to try to compare that elephant blood from elephants that don't get cancer with patients that seem to get an awful lot of cancer, sometimes a 90-100% lifetime risk of cancer?
It was a few weeks later that I happened to be at the zoo with my children watching the elephants. Well, they went on to say that once a week at the Hogle Zoo, they draw blood from these African elephants to make sure that they're healthy and their hormones are in balance. Well, a light bulb went right off. It took several months of paperwork and scientific an ethical review from the Hogle Zoo. But since that time, I'm pleased to say that our clinical study coordinators go directly down to the whole Hogle Zoo where they receive the blood and we rush it back to the laboratory and that's where we've done our experiments.

Interviewer: What did the elephant blood show you?

Dr. Schiffman: When we look at the response of elephants cells to radiation or chemotherapy, DNA damaging agents that normally cause cancer due to mutations. We find that the elephant cells are exquisitely sensitive. It's almost like all of these elephant cells are on high alert, we think because of these extra copies of p53. When these elephant cells are exposed to these DNA damaging agents, they almost immediately undergo apoptosis, which is cell death or cell suicide. It's as if the elephants have said, "It's so important that we don't develop cancer. We need to not try to fix the cells but let's just kill them and start over from scratch."

Interviewer: How did that compare with the response from cells from people?

Dr. Schiffman: We were able to look and compare to our patients with this Li-Fraumeni syndrome and show that their cells actually don't die that frequently in response to DNA damaging agents. They continue to divide and go on with these mutations, which is what we think leads to their increased risk of cancer. But the elephant cells, much more than the Li-Fraumeni patient cells or the human controls, they, again, all went on to have this cell death or apoptosis.

Interviewer: So even healthy human cells don't go through as much self destruction or apoptosis says the elephant cells do?

Dr. Schiffman: That's right. In fact, a third to a half of all humans will develop cancer throughout their lifetime. So there is some p53 triggered apoptosis, definitely, in human cells. But it's not as good as the elephant apoptosis. The elephant apoptosis is more than twice the amount of the humans and we think that seems to be enough to protect these elephants from developing cancer.

Interviewer: Is that something you expected, I mean, that these cells would just basically get rid of themselves rather than, I don't know, try to fix the problem?

Dr. Schiffman: This was a complete surprise to us. We expected the elephant cells to just repair really quickly. But we were shocked to see that the elephant cells were repairing the DNA damage at about the same rate as the human cells. It was only when we looked at the measurement of cell death that we noticed the big difference.

Interviewer: So you know all of this is based on the fact that elephants have these extra copies of p53 - 40 of them compared to 2 in people. How they even get that many copies?

Dr. Schiffman: Yeah, that's an excellent question. When we look carefully at the sequences of these extra copies, what we discovered along with our research collaborators was that these extra copies appear to be what's called retro genes. This means that these genes have been reinserted throughout evolutionary time back into the elephant genome. So throughout the past 55 million years as the elephant developed into a large animal with a long life span, we think the reason it was able to do so was because these extra retro genes were reinserted into the elephant genome.
The other thing that we were able to show in the paper is if you take an elephant retro gene and you put it into a human cell, so we used human cell lines, we were able to actually see that there was some indication that these retro genes, these elephant genes can actually be active in a human cell and trigger some of the same responses in the same genes to be involved as we see with normal p53. This is very exciting because it opens up the door as a potential therapeutic using these elephant genes in humans.

Interviewer: And so what comes next for you?

Dr. Schiffman: What we want to be able to do is try to figure out can we actually develop a drug or approach to help these children that we care for, that other people are caring for children in hospitals all across the country and adults as well? Is there a novel way that we can discover to use this information to try to treat these cancers?

Announcer: Interesting, informative and all in the name of better health. This is The Scope Health Sciences Radio.

Interviewer: Imagine knowing whether or not your child is at risk for cancer. There would be the possibility to prevent the disease before it even starts. Pediatric oncologist Dr. Joshua Schiffman is part of the first initiative of its kind that promises to do just that.

Announcer: Examining the latest research and telling you about the latest breakthroughs, the Science and Research Show is on The Scope.

Interviewer: Dr. Schiffman, tell me about your study.

Dr. Schiffman: Right now, we've instituted a very large study through Primary Children's Hospital and the department of pediatrics to investigate every new child diagnosed with pediatric cancer in the state of Utah and the surrounding states.

Interviewer: Oh, really?

Dr. Schiffman: This program, called the Primary Children's Hospital pediatric cancer program, is one of its kind across the globe. We are doing whole-exome sequencing on every child and their parents and, when applicable and available, their siblings. This enormous unprecedented genomic sequencing effort is all to determine which children are at risk for cancer and why so that we can start to develop unique and effective prevention strategies and hopefully go on to expand this to a global population to one day hopefully prevent childhood cancer.

Interviewer: Have you started doing that?

Dr. Schiffman: We have started doing that, and we're starting to find some very interesting patterns of inheritance. Also tied into that project is not just genetic risk but trying to understand what are the long term consequences for childhood cancer in terms of late effects, what is the cost of treatment to these children, what are the immediate toxicity of these cancer therapies that we're giving, and what are the pharmacodynamics and pharmacogenetics of these therapies.
What we hope to do, going forward in the future, is take our genetic information and tie it all together to try to determine is there a genetic risk that we can identify for long term side effects, a genetic risk for toxicity, a genetic risk for drug levels in the bloodstream. There's no better place to do that type of work through the department of pediatrics with all of its collaborations and team building.

Interviewer: Yeah. I think an important point of that is this information may not just be beneficial for the patient but for the knowledge of how cancer works and the genetics of cancer.

Dr. Schiffman: Absolutely. We are in our initial phases of this pediatric cancer program, and our goal is to build this into something larger in order to take this to the globe around the world. It's not just our children in Utah that we care about. It's every child. I often say that one child diagnosed with cancer is one child too many. Through all of these different genetic efforts, epidemiology efforts, using tools like the Utah population database, we hope to reduce that number to no child diagnosed...

Interviewer: Can you give a specific example of how that information could help somebody.

Dr. Schiffman: One day if we are successful in identifying who's at genetic risk for cancer, you can imagine that it may be even possible to check a child at birth to see if they've inherited the genetic risk for cancer. If that's the case then there may be, one day, a drug we could give or a vaccine to intervene before that child develops his or her cancer, or in the very least screen closely so that cancer is identified the moment it begins. There is lots of new technology out there circulating, tumor DNA, imaging, and so on, where we can try to identify cancers at their earliest stage.

Interviewer: That's really exciting.

Dr. Schiffman: It's a very exciting time to be a pediatric oncologist. I should say that in pediatrics, which is how I'm trained, we always talk about prevention. We would rather prevent disease than have to deal with disease after it already develops. All of these genetic and genomic efforts here at the University of Utah in my mind are all to advance that mission of prevention which is so important and is our guiding light in the field of pediatrics.

Announcer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.

Announcer: Examining the latest research and telling you about the latest breakthroughs, on the The Science and Research Show is on The Scope.

Interviewer: My guest pediatric oncologist, Dr. Joshua Schiffman, is on a mission to let physicians and patients know that in the case of childhood cancers there is a good chance that some are inherited. Knowing this information can make a big difference in patient care and even in preventing cancer in family members.
Dr. Schiffman, what prompted you to look at the inheritance of cancer?

Dr. Schiffman: When a new child is diagnosed in the middle of the night, the parents typically ask three questions. The first question that they want to know always is, will my child live or will my child die? Now fortunately in pediatric cancer we cure 80% or more. So we can reassure the patients, yes, yes, your child has a great chance of survival based on all the great stuff that we're doing as the Department of Pediatrics and Primary Children's Hospital and around the country.
Now the next question that often comes up is why did my child get cancer, and that's something that we're studying in our laboratory here at the University of Utah, trying to answer that question. For now what we tell the families is, well we don't quite know. It's probably a combination of environment and genetics, but we're working on it.
But the third question that always, always comes up is are my other children also at risk for cancer. This is an especially important question in Utah, where families have five, six, seven, sometimes as many as ten children.

Interviewer: Right.

Dr. Schiffman: And in the past the only answer that we had for this question, which is asked at every new diagnosis, was we don't think so. We think probably not, this was just random chance. But we don't know for sure.

Interviewer: You did a study looking at the families of children with cancer. What did you find?

Dr. Schiffman: This was a fascinating study. We were able to use the Utah Population Database to look back to 1966 to determine how many cases of childhood cancers there were in Utah, and of those cases where we were able to have a family history, which was approximately 4,482; how many of those children also had other family members with cancer.
We were able to show that yes indeed, if you are a child diagnosed with cancer, that you have a two to four-fold risk of having another first degree relative, often a sibling, with childhood cancer. Now there's a very important caveat here, which was that increased risk was only found in those families that already had an increased history of cancer.

Interviewer: And what could knowing that information mean for family members?

Dr. Schiffman: Based on this study, we can now say that in order to answer the question, are your other children at risk, what is your family history of cancer. And if they say, we have no family history of cancer, and then we can confidently say, based on our study, that we don't think your other children are at increased risk for cancer. It's the same as the population.
However, if they tell us, well actually yes there is a strong family history in our family of cancer, and then we could say, well, we know now that your other children are at a two to four-fold increased risk of cancer.

Interviewer: And what is the difference between an inherited cancer and an acquired cancer?

Dr. Schiffman: We often talk about the two-head hypothesis in cancer.

Interviewer: Right.

Dr. Schiffman: In the normal, health population like you or I, it often takes a lot of time and it's really a chance phenomenon that you would randomly get two mutations in the same gene that go on to develop that actual cancer.
In children in families with inherited cancer syndrome, they are already set up with their first hit. They are already far down the runway of cancer development. They just need their second hit, and once they get that second hit that's when they develop the cancer.

Interviewer: If you knew that one of the children you were seeing had an inherited cancer, how would that change how you treat the patient?

Dr. Schiffman: That's an excellent question. One of the things we know is that in terms of inherited cancer that in many of the children with these syndromes their cells do not repair DNA the way that normal cells do. That may translate into an increased risk of secondary cancers. So when choosing the therapy for a patient who has an inherited cancer syndrome, we take into consideration the risk that they could develop additional cancers if we don't choose the right therapy.

Interviewer: And so an inherited cancer would probably mean that you'll get it earlier in life?

Dr. Schiffman: That is correct.

Interviewer: And have you had cases where knowing whether a cancer is inherited within a family has made a difference for them?

Dr. Schiffman: Absolutely. We are now able to initiate at the University of Utah whole body MRI screening. We are able to screen patients at inherited risk for cancer who don't have any symptoms from head to toe in a single procedure in less than an hour and we have countless examples where we have found cancer before the patient even knew they were sick; before they had a single symptom.
Now imagine that; this completely shifts the paradigm of cancer. If we can identify who is at risk, then we can screen cancer, find it at an earlier stage and make a difference. We have found brain tumors. We have found lung tumors. We have found kidney tumors. We have found carotid body tumors. We have found pheochromocytoma in the adrenal glands. The list goes on and on. By knowing that a patient is at increased risk, we can improve survival and decrease morbidity.

Interviewer: Do oncologists normally take family histories of cancer patients?

Dr. Schiffman: Unfortunately the world of clinical oncology is a very busy place. There are many time constraints, there are many patients; there are insurance companies to talk to. There are pharmaceutical companies to talk to, there are clinical trials. There is so much going on that unfortunately family history often gets lost in the shuffle.
So we are working with other colleagues across the country to try to figure out a way to implement an easier and more fascicle way to collect family history and get that information to the clinician and also help the clinical oncologist to interpret that data to better understand if their patient should be referred for further genetic testing and evaluation by genetic counselors, and clinical oncologists with an interest in cancer genetics.

Interviewer: And what would your recommendation be for the cancer patients?

Dr. Schiffman: For cancer patients I would recommend that they sit down with their other family members and that they take a very careful family history; that they try to figure out what diseases run in their family, have there been other cancers that have occurred to figure out if they were, for instance, bone cancer. Was it truly a bone sarcoma, or was it another tumor, like a breast cancer, that had spread to the bone.
All of this information helps us in the world of cancer genetics along with the genetic counselors, who are by the way indispensable to this effort, to try to determine what the genetic risks are for disease in this patient. Once they've collected their family history, I would recommend that they talk with either their primary care oncologist, or to even their family medicine doctor, or general internist, or general pediatrician. Share that family history to see if there is a risk for inherited cancer syndrome in the family.

Announcer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.