 Thanks, Tracy. Good morning, everyone. So, I'm Mary Dunn. I'm a nurse practitioner at UNC. I tell people that I have the best job in the world because I get to work in urology and medical oncology. And in my spare time, I'm the co-director of our hereditary renal mass clinic. I joke that that's why I look so well rested all the time. So, forgive me if I'm a little bit tired this morning. So, I apologize in advance to any geneticists in the room. I don't pretend to be a geneticist by any stretch of the imagination, but I kind of find all this fascinating. I'll talk to you kind of about a clinic that we run at UNC specifically for patients and families who have kind of genetic mutations that lead to their kidney cancer. So, I'm going to talk about some kind of very basics about genetics and then talk about the specific disorders that are linked to some of these particular genetic abnormalities. So, we could have an entire day-long, weekend-long conference about genetics. So, this is going to be a very small brief overview just so people kind of get a sense of some of the terminologies. So, these are all pretty important things when talking about genetics and what we inherit from our folks. So, what is a cell? It's the smallest structural and functional unit of an organism. DNA, I think you've probably already seen, all seen really beautiful pictures of DNA and chromosomes and strands and all that stuff have beautiful pictures of those things. So, DNA is hereditary material that's located in the nucleus of a cell. A gene is a unit of inheritance and genetics is the study of those individual genes and how they impact us. So, again, a gene is a physical unit of inheritance. It's passed on from parents to their offspring and it contains a lot of very specific information that's needed to specify all kinds of different traits that we inherit from our folks. So, genes are arranged on structures that are called chromosomes. Chromosomes contain a single long DNA molecule of which only a portion corresponds to a single gene. So, genetics and how things develop and all of that is a very complicated process. So, what are some different things that can happen? So, we have all different types of sets of genes. So, different sets of genes are turned on in different types of cells. So, for example, nerve cells or muscle cells turn on different types of genes and then cells decode the information in those particular genes to build proteins. And then every protein carries out a unique function. So, this particular slide shows different examples of different proteins and how they function within the body and then all those proteins work together to carry out the functions of the cell and they interact in a very complex way. So, whenever any step in this process is disrupted, it can lead to particular genetic alterations and mutations. So, how do mutations occur? So, there's a germline mutation. You'll hear that terminology germline versus somatic. So, germline means inherited so it occurs in the germ cells which transmit genetic material to future generations. So, thanks mom and dad and somatic which are acquired. So, it occurs in every other cell in the body except for the germ cells. So, in other words, these are mutations that are not inherited. So, more about inheritance. Each cell in the body has 23 pairs of chromosomes. One pair comes from mom and the other pair comes from dad and the chromosomes contain the genes that you inherit. I really like pictures. So, I think this is a nice picture of a cell, the nucleus within the cell, the chromosome within the nucleus and the DNA within the chromosome. It's just kind of a nice picture of how all of these really complicated kind of invisible processes work together. So, how do genetic disorders kind of happen? Where do they come from? So, there are many processes. There's autosomal dominance. There's autosomal recessive. There's x-linked and y-linked. I'm not going to kind of go into all of that. But kind of the two things that we think about mainly in the cancer world are the first is autosomal dominance. So, what does that mean? That means that each child has a 50% chance of inheriting that particular mutation. So, you only need one mutated gene to be affected by an autosomal dominant disorder. So, if you see the picture here, you'll see that the father carried a mutation and passed it along to two of his children whereas the mother did not have that particular mutation. In autosomal recessive, there are two mutations. One from each parent are needed in order to develop the disease. So, you see both mom and dad have that particular mutation and that passed along to their children. So, if you see the one that is in, I think it's a boy there in purple, inherited that particular mutation that will likely affect him, but then the two middle children are carriers and then one of the children is unaffected. So, how does cancer occur? Well, it arises from loss of normal growth. There's a picture there of normal cell division and then the bottom there kind of what happens and it's kind of a multi-step process that happens when cancer comes from, when cancer develops and it becomes this uncontrolled growth that your body just can't figure out what to do with, unfortunately. So, what about genetics and inherited mutations and inherited disorders as it pertains to renal cell cancer? So, there are some genetic alterations that have been identified that are specific to kidney cancer. They only really account for a very small percentage of kidney cancer. So, in other words, most kidney cancers are sporadic and not the result of an inherited mutation passed along from mom or dad. That being said, there are likely a lot of undiscovered genes that we just haven't kind of figured out whether or not they are associated with the development of kidney cancer. So, as genetics research becomes more prevalent, we've got really smart people working in the lab behind the scenes, we are more likely to uncover different genetic alterations that could potentially be linked to kidney cancer. But, for right now, we know about a handful and I'm going to kind of go over what each of those looks like. So, these are the four major syndromes that are associated with kidney cancer as far as acquired genetic mutations from mom or dad. And I'm going to go over kind of what each of these looks like, what the types of kidney cancer are that are associated with them. And then we'll talk a little bit about whether or not genetic testing is recommended for you or your family members, or at least a consult with a genetics counselor or specialist. This is just a table that goes over the four syndromes. The particular gene that is mutated as a result, the different, the histology is what the cells, the kidney cancer cells look like under the microscope. So, we'll talk about each of these individually. So, von Hippel-Lindau, which for short is called VHL, is a germline mutation in the VHL tumor suppressor gene. The prominence of this is one in 36,000 live births. It is autosomal dominant, and generally speaking, the type of kidney cancer associated with a VHL disorder are clear cell renal cell carcinomas. Frequently, we will see kidney tumors on both kidneys, and sometimes they will have a cystic appearance to them. The table there, the blue table goes over other manifestations of this particular genetic mutation. So, along with the increased risk for kidney cancer for folks who have these genetic mutations, there are multiple other manifestations and consequences of the mutation listed there. So, you can see kidney cancer down on the list. For folks that have VHL, the age range is kind of broad there, but mostly occurs between 25, age 25 and 50, and folks with VHL have upwards of a 50% chance of developing a renal cell cancer in their lifetime. Some studies even show that it might be a little bit higher than that. So, quite common in folks who have this particular germline mutation. So, one of my take-homes for folks who have these genetic alterations is that it really does take a village to care for these patients. So, it is not just the kidney cancer aspect of all of this, but you see the different manifestations there that have to do with the eyes and the brain, the spine, the pancreas. There's all kinds of different manifestations outside of kidney cancer, so it really does take a team of folks to help make sure that folks with these genetic mutations are properly managed and are getting the best comprehensive care. So, Burthog-Dubei or BHD is exceedingly rare. The last kind of paper I looked at said that there was roughly 500 families worldwide. That said, with these extraordinarily rare genetic mutations, it's almost impossible to know the exact number of families and individuals who are affected. In my clinical practice, I have about five patients who have this genetic mutation. So, while it's rare, I feel like I have kind of a big number of folks. Again, it's an autosomal dominant mutation on the FLCN gene, and these are the particular manifestations that can happen as a result of that. So, of the three kind of manifestations, so people can get fiber folliculomas, which are skin lesions on the face, and cysts in the lungs. Also, kidney cancer, but kidney cancer is actually not as common in folks who have this genetic mutation as are the other particular manifestations. And these are the team of folks necessary to help take care of folks with BHD. This is always super fun to say. Hereditary gliomyomatosis and renal cell carcinoma. I can definitely not say that three times fast. So, shortening it to HLRCC is always much, much easier. So, again, autosomal dominant of the FH gene. This also is exceedingly rare. So, under 2,000 patients worldwide. I think in my clinic right now, I probably have between five and 10 patients who carry this particular mutation. So, there are three very distinct manifestations for folks who carry this mutation. So, fibroids in the uterus. So, men, you get to check one thing off your list so you don't have to worry about. Skin gliomyomas, which can happen kind of all over the skin, but particularly on the arms, face, and back, we see. And then renal cell carcinoma, but particularly papillary type 2. This can be a particularly aggressive tumor in folks who had this mutation. So, one of the reasons why it's important for folks to be seen in kind of clinical centers of excellence when they have these extraordinarily rare mutations is that sometimes for folks who have tumors on the kidney that are really small, we will elect to watch them to monitor them. And folks who have this particular mutation that's not always appropriate because they can act pretty aggressively. So, almost always we recommend surgical intervention for patients even if the tumor on the kidney is very small. And these are a list of folks who help me on a weekly basis take care of folks. So, the last kind of of the big four that we see here in our practice is hereditary papillary renal cell carcinoma. So, again, I feel like I sound like a broken record. These things are extraordinarily rare, but it just kind of goes to show that, you know, my take home message is that the majority of kidney cancers are sporadic and they don't come from an inherited mutation. So, folks who have this, I don't even, I think I might have one patient in my clinic right now who carries this particular genetic mutation, but usually tumors on both kidneys, multiple tumors on both kidneys. And that's really all associated with this, just the kidney cancer and nothing else. And these are folks who help me with these patients. So, this is just a little commercial break, if you will. Go get some popcorn and take a nap, if you must. So, here at UNC, I'm very proud to say that we have a VHL Comprehensive Clinical Care Center. So, underneath that umbrella, we see folks the VHL, but also the other disorders that I mentioned, and also a disorder called tuberous sclerosis complex, we see those folks under this kind of umbrella. We've been a clinical care center since 2012. This was started by Dr. Kim Rathmell, one of my mentors who is now at Vanderbilt. Underneath this umbrella, we have over 30 specialists who help take care of patients with these genetic mutations. Dr. Tan and Dr. Rose are two of them. And so, you know, it takes a village. So, my role is that I'm the co-director of the center along with Dr. Billy Kim, who's a medical oncologist. And I kind of serve as the center of these people's care, and then kind of refer them out as necessary. And I see them on an annual basis and do their kidney screening. So, we get a lot of folks from around the state, but also along the northeast and southeast as well, just because there are so few centers, there's less than 30 nationwide. So, we get a lot of referrals from all over the country. So, for those of you who are interested, as part of the VHL Center on the VHL website, which I have in a slide coming up, there's a database where the VHL Alliance is collecting information about patients to see if we can get more information about individuals and families so that we can better understand manifestations of these particular disorders so we can have a bank of information so that we can help maybe discover bigger and better treatments to help folks and help match patients into clinical trials, which there are not a lot of clinical trials because if you think about how rare these things are, there's just not a lot of patients that we can plug into different clinical trials so that we can learn more useful information about how to help folks. So, a question that we get a lot or anyone who has cancer regardless of the cancer is, is my family at risk for developing my cancer and what do I need to tell my kids, what do I need to tell my siblings, etc. So, my take home is always ask your provider. You know, if it's not a conversation that's been had between you and your urologist or you and your medical oncologist or a nurse practitioner, a radiation oncologist or anyone who's kind of touched you along the way in your cancer care, ask. Not everyone with kidney cancer will need to speak with a genetics counselor. That said, it can provide a lot of peace of mind. The genetics counselors are phenomenal. I mean, they take this extraordinary family history. They go through kind of risk benefit of having genetic testing done so having all that blood work done and the potential consequences of that and if they would recommend that for you and or any of your family members. So, my go to people are always refer to the genetics counselor if there's, if there's any question about that. So, they can provide very specific recommendations for testing. This is part of the reason why it's always super important to provide a really good family history to any of your providers because sometimes that'll trigger something in our brains that we may not have thought about. You know, if, if you say, oh, you know, my, my father also had a kidney tumor and my, you know, maternal grandfather had something wrong in the brain and spine that may trigger to say, oh, like maybe you're at risk for VHL. So, the reason why we ask you so many questions when you come to see us is because it's really important to know what the family history is because it might trigger us to refer you to the genetics specialist to talk about these things in more detail. So, we're not just pestering you, I promise. It's all for good use. So, if you ever do end up having genetic testing and you have a mutation, then what the genetics counselor do is they, they provide you with recommendations for subsequent screening and get you plugged in with the appropriate providers for that kind of follow-up. So, these are just a list of different resources. So, all of the different genetic mutations, the big four that are associated with kidney cancer, each have really nice websites. I like them because they, they can link you to support groups. So, you can talk to other folks who are kind of going through similar experiences as you. They've got resources for providers as well. These things are so rare. It's always good for, for healthcare providers to stay on top of these things as well. So, in summary, the vast majority of kidney cancers are not caused by inherited genetic mutations. However, patients with these genetic mutations should definitely be evaluated by specialists who are familiar with the potential manifestations and familiar with the screening recommendations. Your individual kidney cancer provider will be able to tell you whether he or she recommends a referral to a genetics counselor. And I also believe in most institutions that's something that you can also initiate on your own as well. You don't always need a referral. Part of the problem is there's, there's no general consensus kind of outside of people who have no mutations. There's no general consensus on who to refer to genetics and who not. So, a lot of times we'll refer people who have kidney cancers diagnosed at a very young age in their 30s and 40s. We'll refer them to genetics, but there's really no general consensus outside of folks with these no mutations or people who have family history. So, as I mentioned earlier, as research in the study of cancer genetics grows, we may learn more about kidney cancer genetics. In fact, I, I hope that we do. I think a lot of what we know was just the tip of the iceberg. And as research develops and we get funding and we've got really smart people working in the lab to figure this stuff out, then we'll know more and be able to help patients and families more than we do already. Big thank you to everyone who touches these patients. Just one quick caveat of a story is that I had a patient come through the VHL Center recently. She was probably her mid 30s and she carries the VHL mutation and her father had VHL and I said, you know, how are you doing? You know, is there anything additional I can do to support you? And she said, yeah, do you think it'd be a bad idea for me to send my dad a thank you card for this on Father's Day? And I was like, I don't know your dad well enough to answer that question, but if you think he'd find it funny, I think it'd be okay to include the thanks for the VHL in his Father's Day card. So, you know, it's, it's good to have a sense of humor. So, at the end of the day, these things can be extra, it's isolating enough sometimes to have cancer, but it can be extraordinarily extraordinarily isolating to have a very rare disorder that comes with a lot of uncertainty. So, providing kind of that emotional support and online support for these patients is, is also a huge part of what we do. You can grab me, I'm probably over my time. So, if you guys want to grab me in the hall and we're done to, again, I'm not a geneticist, but I can help with, with basic stuff. Thank you so much for having me. It's, it's a pleasure to be here with you guys.