 Okay. Good morning everybody. I'm Fuki Hisama from the Division of Medical Genetics at UW and I'm very pleased to be here. My job today is to talk to you about the genetics of kidney cancer. So this is a brief overview of my talk. Today I'm going to give you a little bit of background about my field, which is medical genetics. When I moved to Seattle eight years ago, I met my neighbors across the street and they asked me what I do and I said I'm a geneticist and I said I'm a doctor and then they said what kind of a doctor and I said I'm a geneticist and they said oh you're not a real doctor then. So I think what they were thinking is that all geneticists do research but I actually do have a license to practice medicine in two states and I see patients every week so I think I am a real doctor. So I'm also going to go over when should a kidney cancer patient be referred to see a genetics provider. I'm going to tell you about some of the known hereditary causes of kidney cancer today and then just at the end for a few minutes I'll touch briefly on direct to consumer genetic testing because this is a very popular question. So the field of genetics basically is the study of heredity and seeks to explain the basis of individual variation that you see in the room as you look around and also variation among different animal species. So medical genetics is a clinical specialty of medicine that deals with genetically influenced variation that is pertinent to human health and disease and so there are over 20,000 genetic disorders and in the slide here you can see going from left to right two children who have progeria or Hutchinson-Gilford syndrome where small children become prematurely aged and frequently die of heart attacks or strokes at the age of 10 or 12. In the middle is a little girl who has chromosome aneuploidy condition that many of you have probably heard of down syndrome caused by having an extra copy of chromosome number 21 and on the right is a little boy who has albinism which is a disorder hereditary disorder of pigmentation where people make less melanin. So as far as genetics healthcare providers I am a medical geneticist and the director of the clinic at UW and the SCCA and a medical geneticist is a physician who has gone on to do specialty training in the field of medical genetics which includes the diagnosis, treatment and management of inherited conditions. We work closely with genetic counselors and so a genetic counselor is a person who has a master's level degree and specializes in the medical genetic and also the psychosocial effects of having a genetic condition in the family. When you come to my clinic, medical genetics clinic visit, there's often a lot of preparation both from our side and from the patient side so I just want to let you know that should you come to our clinic. We need to review the medical history, the family history, often do a physical examination but frequently we ask for medical records for family members because if the person who's affected is not yourself but your family member we do want to look closely at those records to make sure that we are on the same page. So medical genetics is traditionally been thought of as a field of pediatrics and perhaps prenatal or reproductive medicine but it's increasingly recognized in the past 10 or 15 years to be important in adult patients and adult medicine. So I put here a couple of examples, famous examples that you may be familiar with. So first is Angelina Jolie who was very public and written about in the New York Times as far as her decision to disclose that she was at risk for her auditory breast and ovarian cancer and went through genetic testing and was found to carry a BRCAG mutation. Hank Gathers, the basketball player, died suddenly and unexpectedly from a genetic condition that affects about one in five hundred people called hypertrophic cardiomyopathy. And this is frequently the cause of sudden death in athletes on the field of sports. And on the right you may not know him by name but J. Monahan was actually, what was her name? Yes, Katie Courix husband, thank you. And J. Monahan died unfortunately at a young age from colon cancer which is caused by inherited condition called Lynch syndrome. So this is basically the statistics for our clinic at the University of Washington. Our clinic actually started in 1959 and was founded by Dr. Arno Matulski who's the founding division head of medical genetics here in Seattle. So you can see that we have exceeded 2500 patient visits per year and about half of the patients that we see now or over 1000 patients a year are seen for a cancer genetic indication. I love this photo from 1962 so you can see Dr. Matulski is sitting here and this is the clinic conference and they actually just brought the patient into the room and they all met with him simultaneously. So this is the current staff of our clinic and again the largest group of patients that we serve is patients with cancer genetic indications. We also see patients with cardiovascular genetic conditions, neuro genetic conditions and basically any other inherited condition that can present in adults. We are unique in that we are the only medical system in the state of Washington that has the physicians who specialize in the care of adults with genetic conditions and five of our physicians have been named in Seattle Magazine or Seattle Metropolitan Magazine as top doctors in their field including me. So if you happen to have a copy of the February 2016 Seattle Magazine lying around then you can read a little bit more about me and my career. So to get to the topic for today we know that cancer is common and unfortunately affects between one in two and one in three people in their lifetime and it's estimated that about five to ten percent of all cancers are strongly hereditary. What I mean by that is that you are born with a mutation in a gene typically a tumor suppressor gene that protects you from developing cancer. We have two copies of every gene so if you have a mutation in one of the two copies you've lost half of the natural protection from that gene and that means that over a lifetime you're more likely to develop the cancers that are associated with loss of function of that gene. Hereditary cancer conditions increase the risk for well-known common cancers such as breast cancer and colon cancer and hereditary cancer conditions can also include very rare cancers such as adrenal cortical carcinoma or retinoblastoma which is a childhood eye cancer. So what I do a lot of the time is take a family history and talk to people about medical conditions in their family so why do we do this why do we spend the time which can frequently be extensive and also obtaining medical records for family members why do we take a family history and look specifically for a genetic predisposition so this is an example from colorectal cancer and what you can see here is that the red line at the bottom is the baseline or population risk to develop colon cancer starting from age 20 to age 70 so you can see that the risk rises slowly with age and overall about six percent of people will develop colon cancer in their lifetime contrast that with these two well-known hereditary colon cancer conditions so this stands for hereditary non-polyposis colon cancer or Lynch syndrome and so the lifetime risk of colon cancer by about age 70 is about 50 percent okay and the risk to develop familial adenomatous polyposis actually I would say it's closer to a hundred percent okay so the idea is what we would like to do with these individuals is to identify them before they develop colon cancer okay through genetic evaluation and testing and then to prevent them from developing colon cancer with surgery or with screening particularly with Lynch syndrome there's often a long phase where patients have tubular adenomas or pre-cancerous polyps and if they can be removed before they become cancerous then that person may never develop the cancer associated with this condition so is there a hereditary cancer condition in your family again remember that most cancers are sporadic meaning not strongly genetic and are caused by some of the risk factors that Dr. Taikodi brought up so clues to the presence of a hereditary cancer condition in the family include things like a cancer diagnosed prior to the age of 50 okay and again this is a rule of thumb it's not an absolute rule having the same or genetically related cancers in multiple generations so if there are two generations in the family who've both had kidney cancer or three generations we at least ask the question or start to become concerned that there could be a hereditary basis for those cancers there are some cancers that are genetically related such as colon cancer and uterine cancer and again if we see these patterns in the family then we think about particular genetic predispositions another rule is having primary cancers impaired organs so a woman who has bilateral breast cancer or a woman or man who has bilateral renal cancer is more likely to have a underlying again genetic predisposition to have developed that cancer and then finally individuals who have certain types of rare cancers such as any man who develops breast cancer we consider whether he had a genetic predisposition to develop that and that again is some caused by some of the same genes as that cause early onset breast cancer in women but additionally some other genetic causes that don't that do not affect women so I have the same slide as Dr. Tycote so I feel good about that that we have the same information so there are almost 63,000 new cases of kidney cancer diagnosed in 2016 so five percent of those would be estimated to have a genetic cause so about 2,500 cases of kidney cancer per year would have a strongly genetic basis and this is a list of some of the hereditary or genetic kidney cancer syndromes I'll give you just a minute to absorb these okay but rather than just sort of giving you all of these rare diseases and rare names of things that are very difficult to to recall I thought actually it might be helpful to just share with you a couple of the patients that I've seen so the first case is a 37 year old woman who had shortness of breath night sweats and noticed a mass in her neck and so she underwent a lymph node biopsy which showed a carcinoma with that was consistent with a primary papillary renal cancer so her past medical history was significant actually for having fibroids when she was very young so fibroids of course are extremely common in the population but they typically happen at older ages so the fact that she had fibroids in her severe fibroids in her 20s to the extent that she actually had surgery for it is unusual her family history is notable for having two children four brothers and her mother in her 70s also had fibroids with an early hysterectomy but has had no cancer diagnosis and her father died in his 50s of heart disease so what I thought of for her is actually a genetic condition called hereditary liomyomatosis and renal cell cancer or reed reed syndrome and it has three major features so the first one is having actually fibroids on the skin okay which you can sometimes see on physical examination the second feature is uterine fibroids in women and these are like the regular fibroids that women develop but they happen at younger ages and they tend to be multiple and severe and the third feature is renal cancer so the combination of early fibroids in herself and her mother and the type of renal cancer that she had made me consider this condition for this woman so this basically just goes over some of a little bit more detail of the cutaneous liomyomas or fibroids the uterine fibroids and the renal tumors and notice that not everyone with this condition develops kidney cancer so only about 10 to 15 percent of people who have reed syndrome develop kidney cancer and it typically happens at a younger age so again following that rule that inherited cancers tend to affect people at younger ages than sporadic cancers so there are screening recommendations for this condition and we know that reed syndrome is caused by mutations in the fumarate hydratase gene so genetic test results I will let you know are not always positive or negative any genetic tests can come back as positive negative or uncertain and so when we sent testing for this patient she actually did have that third category of genetic result so it was not a definitive result but she had a substitution of one protein building block called arginine for the normal protein building block called glycine at position number 97 so the difficulty that I have as a geneticist with this particular result is that I very strongly suspect clinically that this is the disease that she has however because we're not absolutely certain about the significance of the genetic test result I would not want to use this in a predictive way to test unaffected family members and to make irreversible that is for example surgical decisions we did counsel her family that we do consider them to be at higher risk and that they should undergo screening for kidney cancer and evaluation for the skin findings the second case is a young man who was sent to my clinic for overgrowth so the reason that that's considered to be potentially a genetic condition is that people who are very big and large there and there are a number of described genetic overgrowth syndromes some of them are associated with increased risk of cancers and so that's what this young man was sent for so he was six foot eight he weighed 247 pounds and when I measured his head circumference it was 65 centimeters and again 60 centimeters is almost at the top of the curve in terms of being very large so I had them stand next to one of the genetic counselors in our clinic robin benefit there on the left so you get a little perspective and then on the right you can see my shoe size which is seven compared to his shoe size which is 16 and a half okay so when it turns out when he had been six years old he was actually evaluated for overgrowth he was already big at that time and the parents were told when he was six years old that he might have a different overgrowth condition called pso do syndrome but at the time there was no genetic testing available to confirm or exclude that one of the features of pso do syndrome is advanced bone age so he did have a bone age x-ray which was normal in the meantime from then until the time I had seen him seen him he had actually developed some paupules or growth on his gums which were removed because they were bothering him and they were consistent with hammer tomas which is a benign kind of tumor but that actually gave me potentially a clue to what the diagnosis was that he actually has when we're talking about things like height and weight it is important to consider the family background and his parents his father and his sister are both quite tall actually oops okay so I'm sorry this is so blurry but I took a picture of his tongue because he also had some of these paupules on his tongue here so little extra bumps and so I considered that he had a genetic condition called cowden syndrome also known as pp10 hammer coma syndrome because they have various types of hammer tomas as well as overgrowth including characteristically a very large head size and so his results were positive for a single base deletion that results in a what we call a premature termination codon so basically typically you start at the beginning of a gene you read through to the end stop reading and then you produce a full length protein in this case what this causes is a shift in the reading frame and so basically the protein gets chopped off earlier than expected so this is clearly a disease causing mutation and consistent with the diagnosis of cowden syndrome in him so once we identify a mutation in a family like in this young man we can test their relatives to find out who is at risk and then offer them appropriate screening and who is not at risk and then they wouldn't need to go on and have more screening so the first woman that I mentioned we would recommend continued screening for all of her close family members because we don't we can't tell through genetic testing who is and who's not at risk in this case we could offer testing to his sister and other family members and see who does not need to have screening for cowden syndrome so these are the major and minor criteria for cowden syndrome for the aficionados in the audience and then these are the cancer risks that are specifically associated with cowden syndrome so notice that there is a significant lifetime risk of kidney cancer but importantly it's not the only cancer risk associated with cowden syndrome and in fact we do consider this to be a breast cancer risk condition as well the thyroid cancer risk is high enough that routine screening for thyroid cancer by physical examination and thyroid ultrasound is recommended and there are some other associated risks there as well so some of you have probably seen president obama's address in which he talked about precision medicine and how do we turn the science of genetics into actual medical therapies so one of the things that we can do is basically we can change someone's care quite soon after we make a genetic diagnosis so these are specific recommendations for the management of individuals who have been confirmed to have cowden syndrome so for example for women it changes when and how often they start to have mammography women should consider having endometrial biopsies or ultrasound for the risk of endometrial or uterine cancer as I mentioned annual thyroid ultrasound is recommended colonoscopy screening is recommended to begin 15 years earlier and then routine screening for the kidney cancer risk as well beginning at age 40 the last case that I'll present to you today is a 35 year old man who came to our clinic because he already knew that he had a genetic condition in his family and so we had seen and evaluated other family other members of his family and he was at risk so in terms of what the medical problems in the family were several family members had presented with something called spontaneous pneumothorax which basically means they part of the lung collapsed and then they have acute shortness of breath and went to the emergency room for that when they went to the emergency room they could treat it but didn't really know what caused it other family other members of his family had had kidney cancer and so he came and we had seen other family members we had the information about what the mutation was in the family and so he came because he was interested in knowing whether he was affected or not so because I already had all of this background information I was very clued in to what he could have and I knew the diagnosis so in meeting him he actually had and it's quite subtle here I don't know if I can turn the lights down at all but he has can I turn down the lights in the front or can you see this he has like little tiny bumps on his forehead I don't know if you can see that or not but because I was looking for them so intensely oh perfect thank you see these little things so these are actually the skin manifestation of the genetic condition that he has okay and so those are called fibro folliculomas and they are a cardinal feature of another genetic condition associated with kidney cancer called burthog duvet syndrome and again individuals who have this have a greatly increased chance to have spontaneous pneumothorax compared with the average person there are other skin findings and importantly of course they have an increased risk for renal tumors which tend to be chromophobic tumors burthog duvet is caused by mutations in a single gene called folliculom and since we knew the mutation in his family we didn't need to go searching through the entire gene we could just go right to the position of the known mutation in his family and give him a clear yes you inherited it or no you did not inherit it kind of an answer because of the nature of burthog duvet syndrome affecting different organ systems they may present to a urologist with a renal tumor or an oncologist because of the kidney cancer again they may be seen first by an emergency room doctor or a pulmonary specialist because of the pneumothorax and a number of patients with burthog duvet actually present to dermatologists because of these skin findings which are benign but which are an important clue to the presence of the underlying genetic condition I will say that had he not had the little skin bumps I still would have offered him genetic testing because a number of patients actually don't have the fibro folliculomans so to summarize in terms of red flags for kidney cancer I think the most important one is someone who's diagnosed with kidney cancer at a younger age has a greater chance to have it because of an inherited genetic reason bilateral kidney cancers again is a clue that increases the chance that there's an underlying genetic reason for the cancers a positive family history for kidney cancers or especially other cancers before the age of 50 pneumothorax that's unexplained and again certain skin finding suggestive of some genetic conditions so in the last few minutes I just want to talk about home DNA testing so about 12 years ago Thai magazine named the home DNA test the invention of the year and they said that from a simple at home test you could find out your risks for many many diseases so fast forward to 2013 and the FDA actually sent a cease and desist order to 23 and me which is the most well known and popular home DNA testing service by this time over a million people have actually ordered and had DNA testing at home where you just spit into a little tube send it in for a while 23 and me was giving reports where they gave they estimated what your risk of certain conditions was and the FDA objected to that so now they no longer provide those reports but they do give you the raw data basically your DNA sequence of the AC's T's and G's and they say you can go look this up yourself as a geneticist I don't recommend this okay both because I think it does take a lot of experience and training to really be able to understand and interpret genetic test results in a medical context and also because I personally and my colleagues in our clinic have seen unfortunate examples where people have misunderstood or misinterpreted genetic test results and that has led to some unfortunate consequences okay so that is the end of my talk no no that's dubs he's the official mascot of UW I've met dubs though happy to go ahead um so okay we should talk come and see me in the clinic excellent question so so that's a good question that applies to I think a lot of people in the audience whereas your particular question we should probably delve into more one-on-one right and my follow-up to that was when you have family members tested are they covered well not only that but can it prevent them from getting insurance coverage because like at the cancer patients I have trouble getting insurance coverage right on melena right yes yes okay excellent questions thank you for that so first of all genetic services usually are covered by insurance um including Medicare and including Medicaid so there's two types of genetic services the first one is the visit and the second one is the testing right so again usually the visit with a doctor the genetic counselor is a covered benefit um insurances differ as to how the extent that they cover genetic testing all insurances will cover some cancer genetic testing typically for the most well recognized and common conditions like breast cancer genetic testing and colon cancer genetic testing for the rarer we get the less likely it is that the insurance company has a pre-existing rule or coverage decision so oftentimes what we need to do especially for rare genetic conditions uh is pre-authorization so where we work with the insurance company and we explain to them why we want to order this testing and what the medical necessity of it is so that's part of the service that we provide um before and after the visit all of the patients that I showed you had clinical genetic testing covered by insurance in terms of family members again that's a very important question so um again if we identify a mutation in the family we can offer site specific um testing to family members which cost one tenth of what the original testing cost is so typically our genetic testing cost between two thousand and five thousand dollars but for a family member who's at risk with a no mutation the cost is more like two hundred and fifty to five hundred dollars um in terms of discrimination there was a federal law that was enacted during uh George W. Bush's administration called the genetic information non-discrimination act which makes it illegal to discriminate against people based on genetic test results or family history um so if you have a diagnosis um it what I want to say is that it's different to in terms of how insurance rates are affected by a diagnosis of cancer versus a genetic being having a positive genetic test result but having no cancer diagnosis so in that latter case they cannot drop you from health insurance or raise your rates based on a genetic test result to see what I'm saying and most insurances would consider it to be um medically necessary in a covered benefit if you're if you have a close relative first or second or third degree relative who has a positive genetic test result because in the long run it's less expensive to prevent cancer than to treat it you're welcome early on in your discussion you you mentioned the uh the gene that actually targets cancer you said if uh and we have two of those genes uh the one who's gone and um we're at a hard risk have they figured out a way where they can actually introduce that gene into a person's system to to actually go after the cancer and and what have the effect of after you've uh been found to have cancer um so uh again just to just to repeat that part of the talk for people who may not remember it so I was explaining that um so there we have genes that do many different things in our bodies right so some of our genes have a natural role as what we call tumor suppressor genes so they exist to protect us from cancer and all of us have those genes so um in general we have two copies of every gene one inherited from mom and one inherited from dad and so for these tumor suppressor genes a person who has a hereditary predisposition to cancer has one normal gene and the second copy of the gene has a mutation in it so that's why they've lost half of that natural protection um from that uh tumor suppressor gene uh what you're talking about is something along the lines of gene therapy where you would restore the function of a gene um I'm sorry but we're not quite there yet okay so that's something to work on for the future definitely and there's certainly there's a lot of um news now about gene editing technology and how you can you know basically with molecular scissors cut out a gene that's not working and replace it with a version of the gene that is working um that's not being done in people yet at this time it's still in development