 So, our next talk is entitled is my kidney cancer genetic and our members of my family at risk. I can tell you that one of the things that's changed over the last decade is more and more people with kidney cancer are asking that question. And there are a group of experts in our country, one of which is Oro Gordon, who's the director of our genetic risk program who can really start to put some content on the relationship between your kidney cancer yourself, your family's risk, and what you should be thinking about. So welcome, Oro. Thank you for coming and talking to us. Hi. Good afternoon, everybody. I will try very hard to keep you awake after lunch. Okay. So, the first thing that most people think about when you start to talk about genetic testing, risk susceptibility, your family, the consequences is a whole range from I want to know everything to I don't go to a fortune teller why would I possibly want to get into this genetic information. And I think that you'll see in the next few minutes that really there's a lot of practical, very important information and we approach every individual and every family as a unique circumstance and what's right for one may be right for it, may not be right for another. I'm going to give you a five-minute primer on genetics 101 and don't worry, there will not be a quiz at the end. So there has been an extraordinary evolution in terms of the information that we have gained from the human genome projects and sequencing of our human genome. And what we have culled from that is that we have a lot fewer genes than we thought we did, but there's still a whole lot of them, about 25,000. And of those, there are several hundred which are causative for susceptibility to malignancy. So within the last five years or so, there has really been great advances in two arenas, one in identifying single genes that cause kidney cancer and other disorders or other tumors as well as the trying to understand well, what's the vulnerability for somebody who has what appears to be a sporadic cancer? Is there some kind of susceptibility that can be identified? And also the genomics or the genome of the tumor itself and how do we use that to target therapy to exquisitely kill off the cancer that is unique to that tumor? We all carry deleterious mutations, every single one of us. The question is whether we can identify it, if it manifests in a way that brings to attention that we need to look for something or we do carrier screening because of family planning, we have four to five, at least, what we call deleterious or harmful genes that we carry within our body. This just sort of walks you through kind of the various spectrums of genetic disease and how things are identified. And what we call genomics is really looking at less one single gene. Did you get it? Did you pass it on? But more the gestalt of your DNA. How is this interaction between your genome personally and your environment? How does that work? How does that make you vulnerable to disease, particularly chronic disease of adulthood, response to therapy and other kinds of things? What I'm gonna talk to you about today really is much more in the arena of the single gene disorder to really try to give you some practical guidelines about whether your kidney cancer could be part of a hereditary susceptibility. And how do you go about approaching that? So this is an old adage, all cancer is genetic, only 10% is inherited. And that has held pretty true. So within the kidney cancer arena, it's estimated between about five and 10% are due to single gene susceptibility. So that there was a intrinsic change in your DNA or in a person's DNA that put them at risk for developing their kidney cancer. And in all, in many common cancers, we see this same genetic susceptibility. Familiar, so when we use this language, it means, well, there's more than one in a family, and can we identify something or not? When there's only one or two cancers and not in the spectrum of things that I'll talk to you about kind of these harbingers of syndromes, it's much harder to identify a single vulnerability. And it's much harder to identify who's really at risk. So this is sort of the classic development of cancer. And so when we think about tumors, it is when the genetic makeup of the cell becomes aberrant, and it loses its ability to do what it was supposed to do. Whether that be stop dividing, whether that be respect its neighbors, whether that be die off. And so that's what cancer is. So all cancer is a result of an acquired set of mutations or errors in the DNA. It gets very confusing because we now hear a lot about tumor testing, genomic testing of the tumor, trying to figure out is there a targeted therapy that is appropriate for that specific cancer? And so people feel like well, I had genetic testing. They sent off my, my tumor was sent off and I had some genetic testing. There are two different kinds of genetic testing. One is what we call germline, which is what is in every cell of your body that you were born with. And the other is what we call somatic, or in the tumor itself. The germline mutations cause the familial hereditary susceptibility. From in the egg or the sperm and in every cell of the body. It is not doing anything problematic until its function is lost. And then that cell becomes more vulnerable to acquired injury, which ultimately may become cancer. Those are the ones that you can pass down. The somatic mutations only occur in the tissue. A question that's going to be emerging as we do more and more tumor testing is will we identify genetic changes in the tumor that are in fact reflective of what's inside that person's germline as well? And will we perhaps find people who are at risk for familial syndromes by actually testing their tumors first? So this is all very new and very novel, but there are kind of two approaches. The classic approach is based on the family history. So for those of you who aren't used to drawing family trees, first of all, I want to encourage you because Thanksgiving is National Family History Day and it really is a great opportunity to just take a little time and get information on family members and pass that down and kind of make it a legacy to be able to be clear. It's amazing how much good information people have about their family members and how much misinformation they have, particularly when you get about a generation back. So what we call these cancer syndromes are autosomal dominant with incomplete penetrance and what that means is that you carry a susceptibility. It's in every cell of your body. You have a working copy and a non-working copy. When you reproduce, when you make egg or sperm, you either pass on the good copy or you pass on the copy that has the mutation. You have to lose the working, the other copy is normal and you have to lose or that one has to become injured in order for that cell to become vulnerable, which is why not every person who has a hereditary susceptibility develops cancer and in fact the lifetime risks really range from 30 to 40% perhaps a risk for kidney cancer to 60 to 70%, but not 100%. In fact, there are only a couple of cancer syndromes where there really is the expectation that unless you do something that person will develop cancer. So here's just a list of sort of some common cancers, all of which have at least this 10% underlying genetic cause for which we can identify a mutation and figure out who's at risk and who's not at risk. Here are some that can cluster in families but that are felt to be much more environmental. But even this is evolving as I was talking about sort of the genomics, it's the, well, what's my genetic may loo? And maybe that's why I'm more susceptible to smoking or more resistant to smoking related cancer. I apologize that this is a little hard to read. But basically the cancer syndromes and syndrome means a bunch of things that seem to be unconnected going together from one the same etiology. So they historically had a whole bunch of names, most of which from European physicians who have kind of unusual names. And so Von Hithlalindau, Lee Fraumani, Bert Hogg-Dubay. These are all just guys who decided that for their epitaph, they wanted to have a syndrome named after them. The more recent syndromes, we start to describe what it is we're actually talking about. Like hereditary papillary renal cell. You know what that is because that's what those words are. And the hereditary leomitosis and renal cell, you may not know what leomitosis is, but you can figure it out. But the important thing is that there are benign things that people probably would never even think about. Conditions that could be going on within the family. Not connected to the person who has kidney cancer. That could in fact be all part of the same underlying genetic vulnerability. So what I say is if you have one of these in your family. In fact, if you even recognize these words, it probably means you need to come in and see me. They are individually quite rare, most of them. A few, like Lyoma, which are fibroids on the uterus, are incredibly common. Lots of ladies will have fibroids on their uterus. Just having a fibroid does not mean that you're at risk for kidney cancer or part of a kidney cancer syndrome. But some of these otherwise benign but very distinctive, like a fibrofoliculoma, is a little popular, like a milia. Like when babies get the little white bumps on the face, the trunk, the back. Nobody would ever put it together with somebody else in the family having kidney cancer. But those are the kinds of clues that say, hey, there might be something going on here. I know this morning in the pathology lecture that was touched on to about certain kinds of the histology that certain kinds of cancer speak to a higher genetic vulnerability. And that also very much so. So if there's a chromophobe tumor within your, you've had it yourself, an oncocytoma, the papillary renal cells. These have a much higher component of an underlying genetic susceptibility. So just in case you don't know, when we talk about a first degree relative, people get this all confused. So your first degree relatives are your parents, your siblings, and your kids. And from there on it goes on. And I won't get mad if you call your second cousin your third degree relative and you get that all jumbled up. It's okay. So what we, the genetic counselors who work with me take a lot of time to really try to get a very careful family history. The other thing that people actually stop paying attention to is that all of the cancers have to be actually on the same side of the family for it to really pull together as a genetic susceptibility. If you have a mom and a dad who've had kidney cancer, that may impact your risk, but it's not likely to be due to a single gene. Because unless they were distant cousins or related somehow. So you're really trying to track everything from one side of the family and everything from the other side of the family. Familial kidney cancer, so this has been, this is sort of a semantic description when there's more than one kidney cancer within the family. Generally felt to be the same histologic subtype. So it's papillary or it's a oncocytoma or it's RCC or it's a clear cell. And that there's no underlying known syndrome. There doesn't appear to be anything else going on. The rate or the amount of this is really shifting because we have done so much in terms of being able to increase the number of genes that we can identify. I forgot to mention, let me just go back. So this list on the left of all these letters. These are the letters encoding the names of the genes that cause these syndromes. And historically somebody who was thought to be part of a syndrome would come in, see me, I would do a clinical exam, I would scour their skin, I would look for things, I would ask them things that seem totally unrelated like, do you have you ever had problems with your thyroid? Have you ever had fatty tumors that have been taken off and all kinds of other stuff? And then I would make a decision, I'd say, this seems to be syndrome leaf romeany, this seems to be von Hippolindo. And I'm going to proceed with one single gene test, which costs several thousand dollars and the yield was pretty low. We now in the last year have been able to do something called next generation sequencing, look at huge amounts of genetic information at much reduced costs, very expeditiously. So now all of these genes are available to be tested all together on one panel for half the price of testing, one of them singularly. So this has really been this massive revolution in terms of being able to get data and that's why that familial component may really be changing because people were not getting tested before or the genes weren't available. That said, if you've gone through genetic testing, if there are multiple kidney cancers in your family, there's nothing clinically that seems to be explaining it and all genetic testing is otherwise negative, then you are left with this sort of familial risk. And when there are two or more cancers, we do recommend screening to the next generation. So in first degree relatives, siblings or children, very unclear in terms of what's the modality, should it be ultrasound or should it be CT? How often it should be? There was one series that was very long term out of the National Cancer Institute picking up two of about 150 people who had been screened because of the family history. But I think that that's really very limited in terms of trying to understand what's the best way to identify that empiric risk if all else fails. When there is sporadic cancer, only one kidney cancer is not recommended to screen the family members routinely. So these are sort of the red flags, the walk-offs in terms of what to, if could this be part of your family and your personal history with your cancer. Early age of onset, in the older I get, earlier becomes later, but under the age of 50, some say 45, but I say 50 in my clinical practice. Bilaterality, which means you've either had two separate kidney cancers, or you have tumors that are on both kidneys. Multifocalody, so with the exception of oncocytomas, you would expect with multiple primary tumors to be higher likelihood of having our hereditary syndrome. And then if there's family history, particularly of these clasts that are called neuroendocrine tumors. And these are really tumors that probably most people have never heard of. But if you've had someone in your family or you, with a pheochromocytoma, or a paraganglioma, or something called a gist tumor, it is, again, very high probability that there is in fact an underlying genetic susceptibility as the cause of that cancer. So I thank you all for your attention. I'm very impressed that nobody has passed out from their turkey, their turkey sedation, and I open it for questions. Thank you. So, and we'll have a couple of moments for questions, but Cora, help them understand what they would do if they come to your office. You do a genetic screening, you identify a risk. What do you, how do you act on that risk in a general sense? You know, that's, thank you so much because what happens, so somebody comes in and we take a lot of time in terms of getting records and family history and really trying to clarify things and we undergo genetic testing. If we find that you or someone in your family carries a mutation, it is not a diagnosis and that's a really important message. This is just recognizing that there is elevated risk. So then I start screening and prevention, whatever the constellation of cancers or other kinds of clinical findings. So for example, in Burt Hogg-Dubey, we would do chest x-rays to see if that person might have the cysts that could put them at risk for having their lung collapse and make preventive recommendations before they fly or go to high altitude. So those kinds of practical things. If it's cancer susceptibility, there may be cancer susceptibility of the colon or the uterus or the ovaries connected to what was just appeared to be the kidney cancer. And so that we do high risk screening in some situations, recommend preventive surgery, for example, hysterectomies after childbearing. Those are the kinds of empiric things. We don't have medical primary preventive options currently for kidney cancer, but this is all sort of part of the emerging, what the hope is in terms of going forward and in research is really saying, how can we identify somebody at risk before they have cancer and do something to intervene and intercede so they don't get cancer? So please, stand up. While you're walking there, let me just ask one or one more question. So there are familial syndromes, but people who have family members over the age of 50 who have kidney cancer still have an increased risk. Right. How do you help those people as compared to those that have the germ line abnormalities? How do you approach that? It's a much more gray area. And so a single family member, later age of onset, there is a small increase in risk. Sometimes we feel more confident if we feel that there's some strong environmental component, very heavy tobacco history in that individual, not by others. But I tend to try to advocate for some surveillance to at least do baseline ultrasounds because there isn't radiation to do screening. But there's no guideline. And it's really kind of an open arena in terms of how often can I get it covered by insurance, what should I be doing? But I do, especially if there's more than one cancer in the family. If there are 12 siblings and there's only one person with kidney cancer, provide a lot of reassurance. I'm wondering what you suggest if you have very little family history or almost no family history, if you suggest doing something? Because I wonder about my children. I have very little family history because I'm adopted and so on. Right, absolutely. So people who are adopted the threshold, obviously you can't use a family history. So then we really hone in on just the individual. So if when you had your cancer, the age that you had your cancer, I would advocate that a very thorough exam that we basically, the benchmark comes all the way down because we don't have, the power of the family history is either to describe something that looks like a syndrome or to give a lot of reassurance saying there's so many people with nothing that we feel better about that. But without, if you have, you're estranged from your family, you're adopted, everybody passed away early from other causes. Then you should come in kind of based on the age or if there's something characteristic about your cancer. Thank you. Thank you, Laura.