Inside the GENOME

Myriad Live - Let's Talk Renal Genes

February 14, 2022 Myriad Oncology Season 2 Episode 3
Inside the GENOME
Myriad Live - Let's Talk Renal Genes
Show Notes Transcript

Myriad  Live episodes are recordings of an open-forum webinar hosted by Dr. Thomas Slavin. The opinions and views expressed in this recording do not necessarily represent those of Myriad Genetics or its affiliates. To participate in a future recording, visit for a list of dates, times, and subjects.

Links referenced and shared in this episode:

Bratslavsky et al. Genetic risk assessment for hereditary renal cell carcinoma: Clinical consensus statement. Cancer. 2021 Nov 1;127(21):3957-3966. doi: 10.1002/cncr.33679. Epub 2021 Aug 3.

Carlo MI, Mukherjee S, Mandelker D, et al. Prevalence of Germline Mutations in Cancer Susceptibility Genes in Patients With Advanced Renal Cell Carcinoma. JAMA Oncol. 2018;4(9):1228-1235. doi:10.1001/jamaoncol.2018.1986

Cryoablation versus Partial Nephrectomy for Clinical Stage T1 Renal Masses: A Systematic Review and Meta-Analysis,



0:00:13.3 Speaker 1: Welcome. This episode of Inside the Genome is a recent recording of Myriad Oncology Live. A webinar hosted by me, Dr. Thomas Slavin, Chief Medical Officer for Myriad Genetics. The opinions and views expressed in this recording do not necessarily represent those of Myriad Genetics or its affiliates. To participate in a future recording, please visit Myriad Live for a list of dates, times, and subjects. I look forward to exploring the world of genetics with you all.




0:00:40.9 Speaker 1: Hello everyone. Welcome to Myriad Live. Sorry, the music played on for a little bit, I was trying to find a good break point and it just kept going. And I see, is this your wake up music? From Terry White, [chuckle] thank you. Thank you for coming on today. This is one of the first of the years, we've had one other Myriad Live this year. Very excited to be back. Everybody's getting back up to speed. Today we're talking about renal genes. A little housekeeping, as always though, to start, one, we do record these now, and the reason we record them is because they are at select times in the day, people really wanna have a way to listen to them, if they're in clinic or can't make the webinar. And so, we record them, we're putting them up on the inside the Genome podcast, which I'll... Let me pull that up.


0:01:41.9 S1: So, this is our new web page actually, so if you just type in Myriad Live, we used to call it Myriad Oncology Live, now switching to Myriad Live, just... I'm increasing the breadth of things that we'll talk about beyond oncology over the year, probably bring in some prenatal discussion topics, just so everyone can learn pharmacogenomics, just things that are out there being heavily used in clinical practice. If there's other topics... If there's other things that people wanna discuss, we certainly do not need to keep them on things that Myriad has particular interest in. So, if there's things that you wanna learn about, feel free, just shoot me an email and we can figure out if we can work it in or find an expert guest for everyone to learn.


0:02:30.0 S1: We're talking renal genes today in March, March 1st. Lauren helped coordinate a very good talk that I'm excited to hear with Dr. Richard Boland. So, he's one of the historical figures of Lynch Syndrome, research in clinical practice, so it's gonna be a really exciting one. Please, come on. If you've never heard him speak, he's excellent. Again, coming on March 1st. We did build out the rest of March and into April, however, we're just kind of tweaking some dates and times and discussing with some guests, and we'll be posting those shortly. So, hang tight. And then inside the Genome podcast, like I said, we are recording these, we do put them up. So anything that says Myriad Live is just one of the past Myriad Lives. And these are the recording from... These sessions are about 45 minutes or so.


0:03:29.2 S1: And then anything that doesn't say Myriad Live, just to make it not... [chuckle] It's confusing, I agree, but if it doesn't say Myriad Live, these are just me and a special guest, just sitting down doing a one-on-one and talking about whatever the topic here is. We had... I see Terry on, I don't know if Todd's on, but we have Rob Finch in today's... It kind of got an overlap of urology, so if you wanna... If you're a urology focus, there's a good one with Todd Cohen that I did not too long ago. I'm not sure if Todd's on, but... And then today, I wanna introduce who we have joining us, so the chat will be handled by Lauren. Thank you, Lauren. So, if you... She is a medical science liaison in oncology, and feel free to send her any questions. If you haven't been on Myriad Live before, unmute yourself, ask whatever you want. This is totally open forum. The focus today is renal genes, but jeez, if you wanna ask about breast cancer for some reason or whatever else is on your mind, let us know and we'll see if we can at least get that answered for you.


0:04:41.9 S1: But definitely unmute, ask questions. We love the... The interaction always makes these flow really nicely and it's fun learning for everyone. But if you don't wanna unmute yourself and ask a question, definitely just send a chat to Lauren and she will triage those and make sure they get answered. You can also just put a chat just in general, but if you put it to Lauren, we'll definitely make sure we see it and it gets answered. And then today we're joined by a few special guests, so we have Rob Finch. Rob is a Medical Science liaison and a genetic counselor, and he works for Myriad. I'll let you introduce yourself in a second, Rob, and then we also... I can't see everyone easily on, but we should also be joined by Randy Rolson and Amelia Hodges. So they are our oncology clinical genomics scientists. And what we'll be talking about today is, we will be adding renal genes to our my risk panel very shortly.


0:05:50.8 S1: So we wanted to do a little overview of renal in general. I know it's always just a hot topic. There was actually... I was on the City of Hope webinar yesterday, and there was a really good case, I presented renal, and yeah, it was just nice to see that and there were a lot of people really interested. I just think it's a topic that's evolving really rapidly in our space, and a lot of people just wanna learn more about it. Truthfully, I learned a lot about it this week, because I don't know when I first put this thought together that we should do renal with Shelly, and then we talked to Rob, I was thinking, "Oh, we can talk about renal." And I was thinking of VHL and all the different syndromes I've seen over the years, but then as I started really digging into things, I realized, yeah, I haven't really been keeping up with what's been going on in the field of hereditary renal for the last couple of years, and particularly around some of the chromosome 3 translocations, things like that.


0:06:48.1 S1: I mean, I learned a lot this week, so excited to share those things, make sure they get woven in. So, I have been talking a lot. Let me take a pause there and I will turn it over to Rob. I mean, Rob, if you wanna introduce yourself, tell people kinda what you do, what your background is and everything, and then, I know you have some content to share, which is probably a great place to start. But again, feel free, anyone can interrupt us at any time. We encourage interruption, so feel free to interrupt us and ask whatever you want. So, Rob? 


0:07:18.3 Speaker 2: Great, thank you. So my name is Rob Finch, I'm the medical science liaison in the urology business Unit. I've been with Myriad for almost 19 years, so I've sort of seen a lot of the changes that have happened to hereditary cancer testing, and so, I'm excited about this one as well. So I'm gonna present a little bit of content. Let me find my share screen here and make sure that I'm sharing the renal germline slides rather than the atomic codes, 'cause I have both of those presentations up. So does everybody see the renal cancer slides? 


0:07:52.0 S?: Yes.


0:07:53.7 Speaker 2: Okay, okay. So I'm only gonna present 10 or 15 minutes of just some basic background. As TJ alluded to, we're all sort of learning a little bit more about renal cancer. It's not a disease state that we have spent a lot of time with at Myriad, and so I'm hoping that just this little bit of background will inspire some conversation that we can all learn from.


0:08:15.2 S2: So just some background statistics, approximately 74,000 cases of renal cancer are diagnosed annually, and about 15,000 individuals die from the disease annually. This rate has dropped about 1% per year. The average age of diagnosis is the age of 64, and it's very uncommon for us to see it under the age of 45, but as with a lot of the other hereditary cancers, if we see it under 45, that's a big red flag that it could have a hereditary component. It's twice as common in men. It's also more common in African-Americans. Some of the risk factors are some of the same risk factors we see in all the other cancers, smoking, obesity, hypertension, family history, which we're particularly interested in. The data shows between SEER data and some of the other articles that have been published, anywhere between about 3% and 8% renal cell carcinoma is considered hereditary.


0:09:12.9 S2: You know, obviously, as we start testing for the renal cancer genes, we may find that this number increases. That seems to be sort of what has happened with all of the other organs that we do genetic testing for is that, we think it's probably less or we think that it's less than it actually is at the beginning, so. And then end stage...


0:09:33.4 S1: Sometimes. Sometimes we go the other way.


0:09:33.4 S2: Sometimes. Sometimes. Sometimes we go the other way, yes. [laughter] And then end stage renal disease...


0:09:37.0 S1: Anyway, we have to hone down on it a little bit.


0:09:39.7 S2: Exactly, exactly. [chuckle] Some of the signs and symptoms are hematuria, flank pain, that's easy to say, weight loss, flank mass, fatigue. And then the vast majority of renal cancers are actually detected incidentally when people are getting imaging for abdominal complaints or for other reasons. Unlike prostate cancer, in the urology space, there are no risk categories. In a prostate cancer, the NCCN guidelines have risk categories for prostate cancer, but this is a little bit different for a urologist in that there's no risk categories with the renal cancer. So cancer...


0:10:20.6 S1: I do have one question I see there.


0:10:22.6 S2: Okay.


0:10:23.2 S1: Oh, I see Daphne answered about... Robin Palmer asked, what's the general population risk? And thank you, Daphne, about 1.7%. 'Cause that does frame it a little bit in the sense of where it lives in the spectrum of cancers that we're at risk for. So that's not far off of pancreatic cancer, for instance.


0:10:49.6 S2: Great, yeah, it's hard to see the questions when you're presenting it, so thank you for interrupting there.


0:10:54.5 S1: Oh yeah.




0:10:55.1 S2: Renal cancer stage is very similar to some of the other cancers, in that their stage 1 through 4, you can see the T and an M stages there, as well as the characteristics. A lot of the characteristics, at least at the beginning of the diagnosis are based upon the size of the tumor. So tumor under 7 centimeters you have stage 1, over 7 centimeters, a stage 2, and then when we start to get the spreading to the local and then distant metastasis.


0:11:24.1 S2: So primary treatment for renal masses really depends upon the tumor size, the tumor location, the number of tumors, is it a single tumor or is it multifocal or bilateral, and then the extent of the tumor invasion as far as how far it has spread outside of the actual kidney. So, as far as treatment options, this is a lot different than some of the other organs that we do testing for, but very similar to prostate cancer, in that a lot of times at the time that it's diagnosed, immediate surgery is not in the cards. It's not what needs to be done. And so, a lot of these individuals will go on observation, something we also call active surveillance, and that's for any mass that's under 4 centimeters, has a single focus, no extension, if the age is appropriate for someone with renal cancer, etcetera. Once it's...


0:12:17.5 S1: And the interesting thing there too, just a little commentary...


0:12:21.9 S2: Sure.


0:12:22.0 S1: Is that a lot of times it's done without a biopsy, which is...


0:12:26.5 S2: Correct, yeah.


0:12:26.7 S1: Really interesting. And I can't say I had... I think because I've always lived my life in the hereditary genetics realm in clinic, and renal as we're talking about here is just really emerging as something we need to address here. So in my personal career, I could honestly say I just feel like I haven't worked with a lot of renal oncologists or nephrologists. So, it's just really interesting to learn more about how these are being followed. And it is one of the rare cancers in the sense of workup, because most of the time you wanna see a tissue diagnosis immediately. And a lot just get followed on imaging over time until the tumor starts getting big.


0:13:15.4 S2: Yeah. And many of you know that we have Prolaris, which is a prognostic tool for prostate cancer that we run on biopsies. And it's something that we've considered in renal cancer, but because there's not a lot of biopsies being done, it's just... That figures into the conversation about whether we can really do a prognostic marker for a renal cancer.


0:13:35.6 S1: And I said nephrologists. It might be good to allude there. Really, urologists at this point will be taking care of these patients, getting back to your comment there.


0:13:45.6 S2: Correct. Yeah. And then once the masses start to grow, then a partial nephrectomy is an option. And then the other option is the radical nephrectomy, once they get larger and necessitate the need for the removal of the entire kidney. Very survivable if it's detected in the localized stage. Even if it's just started to spread regionally, it's very survivable. But you can see the dip-off there once it starts to spread outside of the kidney into distant places in the body that the survival drops way down to about 12%. But about 75% overall five-year survival rates.


0:14:33.4 Speaker 3: Hey, Rob, there's a... Sorry to interrupt you. There's a question...


0:14:35.4 S2: No, please.


0:14:35.7 Speaker 3: I'm wondering that you can answer from Robin in the chat. She was asking if renal cysts are concerned for RCC? 


0:14:45.2 S2: Well, as TJ was saying, there's not a... This is all seen on imaging. There's no way of knowing for sure whether it's an actual cancer versus just some other type of mass. And so, I'm still learning, just like the rest of us are, but I would imagine that that would still be a concern.


0:15:06.3 S1: Yeah, I mean, it does seem... Again, others, feel free to chime in. We have all kinds of specialties on. I can speak from my own personal experience of doing imaging for people at risk for hereditary cancer syndromes, Li-Fraumeni, whatever, going to through whole body MRIs. And I've had many a conversation with a radiologist trying to figure out what something is, it's like 1.2 centimeters sitting on a kidney. And most of the time, they actually have pretty good ideas, just based on the imaging, because different... Whether it's angiomyolipomas, etcetera. Usually they can do some distinguishing from different likelihoods, but it is interesting. And again, yeah, when you don't have a biopsy, a lot of times you're just kinda taking some... There's always some element of guessing in it. And that's why usually are bringing these people back in for recurrent imaging every six or 12 months.


0:16:06.6 S3: TJ, I'm wondering if you can answer the question that was after Robin's from Alison about why renal biopsies aren't pursued, is it because it's difficult to access or is there any sort of other limitations? 


0:16:21.6 S1: Yeah. That's a great question. I don't know if Todd's on the line. Probably should have had him on.


0:16:27.7 S2: He said this morning he might try to pop on, but he had a conflict with some of the time, so I'm not sure.


0:16:32.0 S1: Yeah.


0:16:34.1 Speaker 4: No. I think Rob or I can answer that. Rob, you wanna...


0:16:39.2 S2: I mean, I think that it is difficult to biopsy. I think that that's part of it. Terry, go ahead if you have any other insights into it.


0:16:48.0 Speaker 4: Well, the key thing is, what do you do with a biopsy? Because they have imaging, and imaging is pretty easy. The question is, if I biopsy, would that change anything? And right now, no, because it's based on size and how I treat from there. So that's what Todd has said to us is, it's a little... It's more difficult to biopsy. It needs to be, I think, radiographic. I think there needs to be some other things like an interventional radiologist does. But it's really about, what do I do with it other than the imaging? 


0:17:21.1 S1: And, Terry, I don't know if you wanna introduce yourself for those on.


0:17:27.6 S4: Oh, the old bald guy. [chuckle] And I do appreciate your walk-up music. That was nice, TJ. I'm Terry White, General Manager for Urology. And I follow Rob's orders when it comes to this, 'cause he's our smartest guy in renal [chuckle] urology business unit. And we are interested because, obviously, urologists treat most of these men and women, and so, this is an opportunity for us to learn more, and how we will leverage this going forward.


0:18:01.2 S1: Thank you. Yeah. It's been something people have wanted as part of MyRisk, or at least a Myriad offering for a long time. So that was part of the [0:18:10.1] ____ So later, and once we go through this a little bit, I'll give an overview of the new gene panel for all.


0:18:21.3 S2: Great. Okay. So for the guidelines. The NCCN guidelines for the initial workup of kidney cancer, it says, "If there's multiple renal masses or if someone is diagnosed at or under the age of 46, or if there's a family history, consider further genetic evaluation." Once you get into the guidelines for the further genetic risk evaluation, you can see some of them are very similar to what we see in other cancers. If there's a close blood relative with a known mutation. An individual with renal cell carcinoma, again, diagnosed at or under the age of 46. If it's bilateral or multi-focal tumors, where if there's one or more first or second degree relatives with renal cell cancer. And then we start to see some of the histologic characteristics of the different genes that are associated with hereditary renal cancer. And that would be something that we would see on the path report to know whether or not individual has some of these histologic features.


0:19:23.7 S1: And one thing they came up on the city hub call yesterday, which was interesting is that, right now, there's really not... There's really an absence of guidelines on what is familial renal cancer. So, when you're talking about an unaffected person that has a few people in the family with renal cancer.


0:19:48.0 S1: I don't think there's much to cite. I can think of... For a firm guideline, I can think of one older paper, but it was a point of discussion that it's a real need for the field. There was some discussion about if you have two first degree... Two close relatives, not first degree, but two close relatives with renal cancer that at least some of the providers on the call were talking about. Those would be families, obviously, we'd be a little bit more concerned of. And then there's a gap though, also, a lot of times in trying to get those people tested.


0:20:29.1 S2: So here are the renal genes as well as what they're associated with, the syndrome that they're associated with. I'm not gonna go through all of these in detail, because again, TJ will go through them when we're talking about what genes are going on the MyRisk panel. Here's also a pretty good summary chart or table of the different syndromes and genes, as well as the histology of the different types of a renal cell carcinoma, and some of the other major clinical features. And you can see with VHL and tuberous sclerosis, there were too many to add into this table, and so there are separate tables in the NCCN guidelines to go through all of the extrarenal clinical features of these genes.


0:21:12.3 S1: Yeah, thanks, Rob. And maybe I missed it. We could go back to that slide real quick.


0:21:15.2 S2: Alright.


0:21:15.4 S1: We could probably sit on this for a second. So... And I don't know off the top of my head, but the vast majority of renal cancer is renal cell, usually clear cell, to my knowledge. I don't know the percentage. I don't know if you do? 


0:21:30.8 S2: I don't know the... Yeah, I don't know that.


0:21:32.6 S1: Yeah. But the reason I bring that up is because when you look at non-renal cell cancer, like, some of these other rare forms like the chromophobe when you get an angiomyolipomas and things, the rate for having a germline mutation does seem like it goes up. I'll try to find what I was looking at, but... Just because they are just rare, especially things like chromophobe, because those are really just odd, they're a small percentage overall of renal cancer as a whole.


0:22:10.3 S2: You said you wanted to sit here for a few minutes, so do you have any other comments? [laughter]


0:22:12.8 S1: Oh, no, no. Well, I mean, if anyone has any other questions on the syndromes, but, yeah, I mean, just... BAP1 is just incredibly rare. I don't know if people have been seeing that in clinic, but, yeah, I used to work with one of the people that helped really map that gene and had an original gene patent on it. That was at... When I was in Hawaii. At the time, there were only a few families, even known worldwide, that had BAP1 mutations, and it's really... Mesothelioma and melanoma are really key components of that, and the uveal melanoma was a big one, to the point where I used to think of it more as like... [chuckle] I tried to convince that team to call it MUM syndrome, which was mesothelioma, uveal melanoma in my mind, but it didn't catch on.




0:23:10.3 S1: But it seemed like that was a key component of having BAP1 mutations, and then, yeah, a lot did get renal cell cancers as well. And then, yeah, I mean, a lot of these people have probably seen in their practice. Tuberous sclerosis is definitely out there. You'll see how they can have really varying presentations, which is interesting. Many of these, though, remain pretty rare in my mind. I think people are starting to see more the hereditary paraganglioma, pheochromocytoma syndromes floating around. Again, usually, the presentation's pretty obvious in families, but not always, so... I don't think there's any questions... We can take a pause there and see if there's any questions too, Lauren.


0:23:57.8 S3: Yeah, there's a couple that I figured we could wait until we had a pause. So, the first one was, "Going back to imaging, can cysts be differentiated from solid masses on a scan?"


0:24:10.8 S1: Yeah, usually. Yeah, that's been my experience. Just because of the way they look. They're not dense and they're usually fluid-filled.


0:24:20.1 S3: Yeah, I was looking that up as we were going through, so that seems to...


0:24:24.3 S1: But then, yeah, the concern was, is there always something behind it or what. Yeah, is there something you can't see, sometimes. A lot of times, they still get followed to some degree.


0:24:35.1 S3: Okay. And there was another question that came through. "When would you do a cryoablation versus partial nephrectomy?"


0:24:42.7 S1: That's a great question. I don't have the answer to that. I don't know if anyone on the line does.


0:24:49.6 S3: I can look into that while we continue as well.


0:24:52.2 S2: That would definitely be a Todd Cohen question.




0:24:54.7 S1: Yeah.


0:25:00.1 S3: Other than that, I don't see anything else that came through. And Lynette had put in a comment about cysts versus solid masses with imaging, so thank you Lynette for putting that in there.


0:25:13.1 S2: Great. So as TJ said, a lot of these are pretty rare. And so, I found this one study out of the MSKCC, out of their impact study that looked at 254 patients with advanced renal cell carcinoma, and they identified mutations at about 16.1% of them. So, 14 or 5.5% had mutations and some of the syndromic associated genes that we've been talking abouts, so that lands right there in the 4 to 8% that we talked about in the first couple of slides. But what I found interesting was that the most frequent mutations were in genes that are not necessarily associated with renal cell carcinoma, like CHEK2, for instance.


0:25:54.6 S2: And that's something that I think that we're seeing in prostate cancer as well. CHEK2 is not necessarily associated with prostate cancer, but we're seeing a lot of prostate cancers that have CHEK2 mutations. And so, here's the distribution of the mutations that they found in this particular study. And as you can see, there are a lot of culprits in there that we wouldn't necessarily think about with renal cell carcinoma, but I think that this helps us understand that as we start testing these individuals, we are going to find renal cell carcinoma patients with a B2 mutation, for instance. And so I think that we still have a lot to learn about genetics in renal cell carcinoma. And I think that that was where I was gonna stop and just sort of open it up for conversation and let you talk about the genes that are going on the panel. Let me stop my share.


0:26:48.4 S1: Yeah, thanks, Rob. And I think it was Carlo...


0:26:51.6 S4: And TJ, I think the other thing is like if you look at FH and CHEK2, those are the less common, right? I think I just saw that.


0:26:58.9 S2: Yeah.


0:27:00.1 S4: I think our big question is, it's the so what. I know Lauren's gonna ask Tod about the differences in treatment, but what am I going to do different if I have those most popular mutations? What's the answer to that? And so if we don't have it, I think it's something we need.


0:27:18.7 S1: Yeah, there's a real lack of guidelines across the field, like HLRCC is actually... I would argue is extremely rare, and that's from the FH mutations. However, there's one FH variant that does pop up a lot. It's like a dupe AAA off the top of my head, in the 500s, and that one, it has a high population frequency, and there's been a lot of question on what to do with those folks because most of those families don't look like classic HLRCC, hereditary leiomyomatosis and renal cell cancer syndrome families, and so that's a real confusion.


0:28:05.3 S1: And then, yeah, like you bring up, CHEK2 is a hard one too, because it's not... What I would say is, it's a clear... It's not a clear cut renal cell associated gene at the moment, I would say it's like emerging, and just like you see CHEK2 pop up in a lot of studies, I mean, pretty much any cancer study that we look at, we see a lot of CHEK2 carriers, there's a high background population risk, it likely does increase the risk for many other cancers like thyroid, and you see renal, like we just showed, pops up, and it's just hard to know... Yeah, we have... Probably many people on this call are very used to seeing CHEK2 mutation carriers, and, yeah, right now, there's no recommendation that I'm aware of, correct me if I'm wrong, to recommend renal cancer imaging or following these people.


0:29:00.2 S1: And then even when it comes to more of the well-known syndromes, there remains a lot of confusion on best ways to follow people, you know, ultrasounds and urine screen. I think of even some of the urothelial cancers that are associated with Lynch syndrome. I just saw there was a good article by Matt Collette. I think he was the last author that just came out, that was... They were looking at analysis on patients with Lynch syndrome and following them, and really it didn't catch anyone with any type of renal cancer, it led to a lot kind of false positive type work-ups for different things, so it's... We just have so much to learn about, not only the predisposition and the association, but more importantly, like you bring up, what to do with a lot of folks that do come back positive.


0:29:58.1 S2: There are a couple of papers to look at sort of the rate at which tumors grow based upon the genetics behind it. That was the next slide that I didn't present, but some of them are... The papers are not in the guidelines yet, but some of the people are clearly saying, if you have a mutation in this gene, this is not somebody we wanna watch, this is not something we wanna just observe, we wanna be more definitive with the treatment for these individuals, so a little bit more like prostate cancer, where we know that some genes predispose to a more aggressive type of tumor.


0:30:32.2 S1: Yeah, and that Carlo paper that you are showing at the end there, that's the paper that talks about non-clear cell renal cell cancer. So in that paper of the non-clear cell renal cell cancer is more than 20% had a germline mutation, so that's... That's a good... Good amount.


0:30:55.4 S1: Good. So I'm gonna pause there. Any questions? I wanna make sure people's questions are getting answered. And thanks for posting the paper, Lauren.


0:31:03.9 S3: Yup, I don't see any other questions in the chat, and Lynette posted a paper about cryoablation versus partial nephrectomy. I haven't heard back from Tod yet, but I did put the conclusions of that paper and where one may be considered over the other for certain patients. But it seems like there's a couple of things to consider when deciding between the two options.


0:31:28.8 S1: Yeah, thanks. I will show... Yeah, so for those interested... Let me stop sharing real quick. Let me reshare here. So, for those interested, I'll show an update of our gene panel that'll be launching pretty shortly here, and the additions that we'll be having. So renal is a large part of the addition, so this kind of walks through... This slide just walks through the current MyRisk, which is 35 genes, and then moving to the new panel, which will be 48 genes, and then the genes that will be part of that.


0:32:11.4 S1: And so, we really do try to follow fairly stringent recommendations for when we're putting genes on, and we had a lot of debate. A lot of it is around management guidelines, as Terry just brought up, and we know that not all of the things on here have management guidelines, but the ones that were keeping, we think that if they don't have pretty good management guidelines right now, they will have fairly soon, and I would say EGFR for instance, is one that is in that category. And then we're looking for things that have a high absolute risk for cancer and two to three full risk for cancer themselves, so much of the current MyRisk content will be unchanged, and then the additions are shown here. The blue are the renal, so that's what's denoted down here in this key by the different colors. And then some overlap like that one MITF in toad have some overlap between renal and Melanoma. And then many have endocrine. I mean, clearly, the succinate, dehydrogenase genes have endocrine overlaps and... Sorry, let me switch this, sorry, to presenter mode. Yup let me go to the bottom and make it easier for people to see. Yeah.


0:33:49.2 S1: Sorry, almost there. This is... I just flip. I don't know why it keeps doing that, strange. Let me try to go a little slower. Oh, I see what's happening. Here, let me switch... Yes, can people see that now? 


0:34:06.9 S3: Mm-hmm.


0:34:09.4 S1: Alright, so... Yeah, so we have removals here, so gallon 12, RSP20, RNF43, and then NBN. We really remove these because we didn't have mutations really popping up in a lot of these genes at all. Two of them, we never actually had any mutations, and then one really just, even in cases where we thought there might be a mutation, we just never thought there was a strong association for colorectal cancer, I think that was RPS20. And then NBN, we've spoken about that previously. We had a good Myriad Live with Fergus Couch. I don't know if there's any comments there, but happy to walk through NBN again, but a lot of the more recent studies, including some of our own internal Myriad research has shown that there's no strong association with breast cancer, at least to the two to three-fold cancer risk, so we decided to take it off. So, questions about what we have on our panel right now? Happy to talk through anything.


0:35:37.1 S3: Barry asked if there is a timeline for these changes yet.


0:35:44.4 S1: Yeah, they're coming very soon. Don't have a firm timeline but we'll be coming to a theater near you very shortly, Barry, so thank you. [chuckle] And then we have our... Let me stop sharing that. We have our other special guests on. I don't know if you wanna unmute yourself and we can talk through... Now that we're talking about adding genes to the panel, we have Randy and then Amelia on. Randy or Amelia, any challenges or nuances that you've come across as you've gone through and tried to figure out how to add genes? 


0:36:26.0 S5: Yeah, we've been working on these for quite a few months now and going through different challenges and how we're gonna approach classification. We consider a lot of different things, so also looking ahead to how can we downgrade potential VUSs that we might see. And so one of the ways we do that is to look for homozygous spines or veins that are in trans with a non-pathogenic. And so we assess each of the genes for whether we can safely reclassify a variant based on that information. And so it's been interesting with... For an example of just an interesting classification decision with the SDH genes, so biallelic loss of function for those SDH genes causes a very severe mitochondrial disease. And typically, that mitochondrial disease, we see onset of it in infancy or early childhood, however, there are some rare reports in the literature of unaffected family members that are homozygous for the same variant as their affected family members, and so that kinda gave us pause and we had to discuss it. And ultimately, we decided we'd probably will not be downgrading on SDH homozygous spines because of that. So, while probably most of the time, it should reliably result in a mitochondrial disorder, we know that there are rare cases where it's not fully penetrant.


0:38:02.8 S1: Yeah, that's really interesting, 'cause yeah, those are crucial genes to the Krebs cycle.


0:38:08.8 S5: Yeah.


0:38:12.4 S1: And yeah, the... Will those normally be followed by a call-out or anything? I don't know if we've talked through that.


0:38:19.0 S5: Well, so if we find variants that are identified in mitochondrial disease patients, we'll definitely be considering that for classification. Yeah. And so that would be a potential upgrade. Yeah. But if we were seeing a homozygous in an unaffected individual and there's no lit for patients with the disease, we would just choose to leave it at VUS for the time being because of that uncertainty with penetrance.


0:38:51.1 S1: Yeah, yeah. Any other, really... OH, go ahead? 


0:38:53.6 S3: Oh, sorry. I was gonna say there's a question kind of on that same vein a little bit but about how we will be reporting pathogenic variants in genes that cause autosomal recessive syndromes, but not hereditary cancer syndromes, like the two mutations in VHL that cause autosomal recessive erythrocytosis.


0:39:14.6 S1: Mm-hmm.


0:39:15.0 S3: I'm wondering if we...


0:39:16.6 S4: A great question.


0:39:17.7 S3: Yeah, perfect.


0:39:19.5 S4: That's a great question, that's something we talk about a lot. We talked about it with that R200W that you're referring to that causes the Chuvash polycythemia. We've talked about the variant that, TJ, you alluded to, the 477 dup in FH that causes a fumarate deficiency but it doesn't cause HLRCC. So, it's definitely something we're actively working on and actively discussing, as far as what those reports are going to look at. We're collaborating with our Myriad Women's Health colleagues on autosomal recessive criteria in order to best figure out how to send out those reports. So TBD... We'll have more solid answers for you on that hopefully soon.


0:40:03.4 S1: Yeah because a lot of this work, as well, we have to comb the management guidelines and everything that's out there. I don't know if anyone wants to comment on all the work that's been done there because we are also trying to make reports that are not only "yes/no" on a mutation in the gene assessment, but also how to care for that patient to some extent and where providers can go. Many of us have the luxury of having some genetics training but there's certainly a large swath of the population doing hereditary cancer testing, they that have really no underlying knowledge of where to go and where to find resources when some of these rare genes come back positive.


0:40:47.9 S3: While we had just like a break in our conversation, I wanted to bring this question up. And I was gonna answer it in the chat, but I think it would be good for you to address TJ. Do we offer RNA analysis? 


0:41:00.4 S1: Yes, yeah. And we just tried to streamline our process a little bit more for that. Although I'm learning it is not getting into the portal at the moment, so on our regular TRF, we now have... Yeah, I won't really get into it, but our regular test request form, I could show a picture of it, but we have now a checkbox for RNA analysis. It's really more of an ease of use because the way we've been doing our RNA analysis is we do something called the allele-specific RNA analysis, which is really the best way to classify variants. And the way it works is, if a splice site variant is identified, that we think would a good candidate for a allele-specific analysis, we have been going back to the provider and then trying to get a second RNA tube on that patient, because it needs to be... Blood at that point needs to be an RNA stabilizing tube, bringing it back in, and doing the RNA analysis, which is done in our RNA lab. And it's really a detailed analysis where we actually... And Paula is not probably on...


0:42:08.8 S1: But we'll actually pipette out into about 100 wells to try to get down to just one molecule of that allele. And then that gets made up into RNA and we can actually then figure out, of the final product, how much of one allele was expressed versus other, which has really helped us definitively classify a lot of our leaky splice site variant variants. So what we recently did was we now have a checkbox where if it's checked, then patients... Then we can go directly to the patient for a mobile phlebotomy too, for instance. It just makes it a lot easier to get that RNA tube in-house.


0:42:49.1 S5: I think it's important to note that we have been doing RNA analysis. This is not a new enhancement to our process or methodologies, it's been available for quite some time.


0:43:00.4 S1: Mm-hmm. Yeah, we've been doing it since 2015 and literally thousands of test reports have been changed by our RNA analysis at this point, so got you covered there. And the reason we haven't made the changes in the portal for those people that are ordering on the portals, we're actually revising our entire portal. So we have the current portal, and then there's a whole new portal coming, so the thought was just put that energy into the newer portal, which is now in the process of rolling out.


0:43:29.1 S1: Some of you may have heard, we've just soft launched a tumor product offering and that will be on the new portal and everything. So that's in oncology, and that's a 500-plus gene, comprehensive genomic assay for figuring out targeted tumor therapies and includes MSI and IHC and PDL-1, and it's... It really is impressive to say the least. So it's probably one of the more exciting things that we'll be doing in 2022. So it's really just out there right now for our OB-GYN customers that have been looking for... Or sorry, I should say Gyna customers, that are looking for something that goes beyond our/my choice assay as itself. And that's our homologous recombination deficiency assay, so then this brings my choice with germline, with large-scale tumor testing. So that's all just actually, this week is launched. So very exciting. So... And then, we'll have the new portal, so hopefully the new portal updates with RNA will get their soon too. But even if you don't check that box it's fine, the patients are still eligible, we just have to come back and contact the person ordering.


0:44:50.0 S3: That was all I had in the chat, but... Sorry to interrupt, Randy and Amelia, I felt like that was timely questions with what you were discussing.


0:45:00.1 S1: Yeah, there's some trickiness to some of these genes as we brought up. And it's just been interesting to see how the field's evolved. TCS1 and 2, similar other genes that have patents at the time, you could really only order them from one lab and they're fairly big genes that will probably get some really interesting results there. I think there are many really mild tuberous-sclerosis patients that... I remember one in particular that I couldn't get over that the person really did have a... They had a splice site variant and TSC, I forget if it was one or two, but just had no findings, and a very mild family history, and the only finding they had was a ungual fibroma in the nail bed, which was really interesting, but it did kinda confirm that that's what was going on. But you would never know. And the person had a full-time job, busy family, everything else, so it's an interesting condition. Yeah, so any other questions on the renal additions that we're doing? 


0:46:12.8 S1: We're pretty excited. As you see, we'll have some melanoma, we'll be building out the gastric cancer with CTNNA1 as well. And even though many people haven't really been asking for that, but there's new hereditary diffuse gastric cancer linkage consortium guidelines that do bring in CTNNA1. Something I personally did a lot of research on over the last six or seven years. I think we have a lot to learn about that gene in particular as it comes to diffused gastric cancer risk. There's gonna be another paper, I think I'm on it, that will be coming out, I think it just got submitted or accepted, and we'll go through... I forget how many families, but we have a lot of CTNNA1 families as part of it, so more to follow there. But it did make its way into the hereditary diffused gastric cancer.


0:47:07.1 S1: Linkage consortium guidelines is something that should be considered strongly when you're doing CDH1 testing, so it's ripe for time to get brought in. And EGFR, that's been a real interesting gene. As we're doing more tumor testing, we're seeing a lot of people come back with EGFR mutations, particularly when they're getting evaluated for lung cancer. It has some ramifications in lung cancer treatment. However, it's a really common gene that is found in lung cancer tumors, and we just know that if people have variants usually before they're treated with a tyrosine kinase inhibitor, that some of these people actually have germline mutation. So it's been an interesting gene, and it's something that people wanna test, usually when they have strong family histories of lung cancer. And then yeah, we'll be adding MEN1 and RET, these are ones that well known to probably many people on this group. However, there's some nuances there as well. I don't know if there's been discussion around the V804M in RET, but that's another tricky, sometimes low penetrate one. At least I think I'm saying that right. It's in my memory. [chuckle] Yeah...


0:48:22.7 S5: Yeah. Our team is really excited about launching all these new genes for all of these reasons. They're so complex, just learning how to assemble, evaluate, and really use all of this information for renal classifications has led to really long, really in-depth discussions to really just whatever is best for the patient, is what we... The information we need to find. So, you're right. Whether it's off-target phenotypes, whether it's penetrants, this is what... This is what our day is about, is just discussing all of these, all of these issues for these new genes, so we can get the best information out to our patients.


0:49:00.5 S1: Yeah. And you know... I was a fan of removing some of the genes that were just either... We took a stab at 'em, and they just didn't pan out. [chuckle] They were just... The literature just didn't evolve, or we just are unable to really classify mutations. They just add to more variants of uncertain significance, and more people getting results that they just don't feel confident with, and MBN was again, a big one for the breast cancer side, where it just is leading to the confusion. As many people know, it got dropped down from the recent NCCN guidelines as over the last few years, is something you wanna consider for breast cancer screening at least. So I think the new panel's gonna be really nice, and hope people find a lot of value for their patients with it. Great. So yeah, join us next week. We are gonna be talking... Or not... Sorry, not next week, March 1st [chuckle] is gonna be Dr. Richard Bolen, and yeah, that should be a really exciting one. Thank you again, Lauren, for helping set that up, because I think he's just such a great speaker, and it'll be fantastic to learn from him. And again...


0:50:16.7 S5: TJ, before we go, we have actually a case that maybe you wanna talk through in the chat. It literally just came through as you were talking.


0:50:23.6 S1: Oh, sure.


0:50:24.4 S5: There's a 41-year-old female patient with left ECIS breast cancer, mother with breast cancer, age 56 and 67, so it seems like two maybe separate primaries. Family history of bladder cancer, but no prostate cancer. Her BRCA STAT Panel is negative, then last night the update showed a pathogenic HOXB13 mutation. What are your thoughts? 


0:50:47.1 S1: Yeah. So yeah, interesting. And it's a woman. So I mean, you know... We think of HOXB13 as a prostate risk gene. I don't know, Rob. Do you wanna... Do you have any thoughts there? 


0:51:01.1 S4: I would just be interested to see if the men in the family have the HOXB13 mutation, for sure.


0:51:06.2 S1: Mm-hmm.


0:51:07.1 S5: Yeah, I've seen some of these come across my desk, actually for patients diagnosed with breast cancer having HOXB13, and at this point we only know that it's associated really with prostate cancer, so it is interesting, and I think just like some of these other genes and mutations, as we test more people and have things on panels, we're gonna find more that we maybe not have anticipated. So it's definitely something I've seen. It doesn't shock me that this came up, but it's interesting, 'cause she does have a pretty significant personal and family history.


0:51:40.7 S1: Mm-hmm. Yeah, and Rob, in the urology world, most of what you're testing obviously, is men affected with prostate cancer...


0:51:50.3 S4: Correct, yeah.


0:51:50.5 S1: Are you seeing a lot of HOXB13 pop up? 


0:51:53.9 S4: I wouldn't say a lot, but definitely a good amount. And we just say that it increases the risk for prostate cancer. There's no known link to more aggressive prostate cancer, just an increased risk to develop prostate cancer.


0:52:10.5 S1: Yeah. Yeah, so most likely a fairly incidental finding in your patient, but a lot to learn in general. But I haven't personally seen any association with breast cancer that I can think of, and others can chime in if they have.


0:52:28.1 S5: Now, Michelle is just, Michelle Knowles was just sharing recommendations that she had, that maybe the mom could be tested... Her mom had breast cancer twice, and she also shared that she had a patient that had breast cancer that came back negative for the known familial mutation. So it definitely happens. The incidents of breast cancer is high enough that it could happen, and the patient could not have the familial mutation, so that was just her commentary.


0:52:57.7 S1: Yeah. No, great, great question. So thank you, Rob, so much for coming on and presenting, thank you Lauren.


0:53:04.5 S4: Thanks for having me.


0:53:05.7 S1: Yeah, thanks Lauren, for running the chat.


0:53:07.5 S2: No, you were great Rob, thanks for preparing all that information, we covered a lot of ground.


0:53:13.6 S1: We didn't get into the Chromosome 3 Translocation, but...


0:53:14.3 S?: [chuckle]


0:53:14.3 S2: No one asked.


0:53:15.5 S1: So maybe another day. But I don't even have a lot to add. I'm mean... They're just, they're still odd to me, and I think we just need to learn more about how they contribute to hereditary renal cancer. And thank you so much, Amelia and Randy for coming on, giving a little background insight to some of the genes. Yeah, don't forget about the Krebs cycle. That was the lesson learned there.




0:53:38.8 S1: So, alright... And mitochondrial work. Who would think that would come up today? But it's always... Always good learning. So thanks everyone, and I look forward to hopefully seeing most of you March 1st. I'm very excited.