In this practical yet nuanced talk, gastroenterologist Aparajita Singh, MD, MPH, describes technological advances and dwindling barriers that are making tests for pathogenic gene variants more valuable and available than ever before. She discusses why getting a detailed family history is essential – but not the only factor – in determining which patients to offer genetic counseling; clarifies important terms regarding mutations; explains that certain cancer syndromes are far more common than we realize; and breaks down test options, including what UCSF and commercial labs offer. Bonus: Risk-calculating tools to use in everyday practice.
Thank you again for the invitation. Um, my name is Arajitha Singh, and I'm a gastroenterologist here at UCSF. I direct, uh, gastroenterology Quality Improvement Program, and I'm also the director of UCSF Lynch Syndrome Center, which is a newly launched center to provide comprehensive care for patients with Lynch syndrome. So, uh, a lot of my practice is seeing patients with a family history of, uh, GI cancers, and, um, and a lot of those are Lynch syndrome, uh, FAP, but her polyposis, or other GI cancer, even without a diagnosis of genetic syndrome. So, I'm very pleased to talk to you about uh genetic testing in primary care, and I try not to keep a lot of slides and kept the talk um very clinical and practical, and I'll be more than happy to answer any questions uh which I've been told in the end. So, let's get started. I have no uh financial disclosures. Um, just to add that I am a site PI for an NCI sponsored Lynch vaccine trial. So let me start with our patient's story. Um, it's something common in my practice, so it goes like, until my diagnosis, there were no less than 13 doctors who could have taken detailed family history from members of my family and referred them for genetic testing. It never occurred prior to the time I was diagnosed with the cancer. What I'm trying to convey here is it's, it's very, it's very common for patients to have high risk family history, and genetic testing or family history taking has not necessarily been part of medical school education or for that matter in in in residency or fellowship, and often not a priority for most of the patient encounters. So my objectives today are to convey to you when to think about genetic testing in your primary care practice and how to order genetic testing once you identify patients who, who should be tested, and then how to consult for genetic testing. So, Let me start with a question. Um, how common do you think is Lynch syndrome in the general population? Let's throw some numbers. 1 in 300, 1 in 1000, 1 in 5000, or 10,000? Any guesses? All right, so this is actually really common. 1 in 300 people in the general population are supposed to carry one of the Lynch mutations, so super common, and this is, you know, I'm a gastroenterologist, so a lot of my talk will be focused on, uh, you know, GI issues, but BRCA1, BRCA2 are equally common, in about 1 in 300 to 400, you know, individuals in general population carry that mutation as well. OK. So, Let's see. All right. So, a few words about familial versus hereditary cancers. So familial cancers, they mean that if you see a patient and they have a family history of cancers, but if they undergo genetic testing, no pathogenic variant is found. When I use the term pathogenic variant. It's something what we used to call in the past mutation, so we try not to use the term mutation as such. Um, the new way of saying that is a pathogenic variant, or you may see some reports saying that there's a likely pathogenic variant. They pretty much for practical purposes mean the same for clinical management. So, you know, it's a patient, they, they have their aunt, their mom, all with different cancers, and genetic testing is negative. That particular patient does have increased risk of cancer, but it's not hereditary because we don't know a gene. So I'll call that a familial cancer. And family history can be unreliable. Um, there is a condition called FAP, familial adenomatous polyposis syndrome. It's a rare one. I have several of those patients in my clinic, and in those patients, your patients can also have a de novo mutation, meaning they, they just, you know, that mutation happened during their embryonic phase, and so that's why their parents may not have any cancers or that mutation. And 25% of FAP patients are, are, you know, that's a de novo mutation. So, de novo mutation is more common in certain kinds of genes versus others, uh, so, I will, I can see a handful of patients who, uh, the story goes around, you know, they, they, they had blood in the stool when they were 18 years old, and they have no family history, and the colonoscopy shows hundreds and thousands of polyps, and then we found that they have FAP. It's a surprise to the patient. How come it happened if there is no family history? And those are classic examples of de novo mutations. So, uh, again, a word about the basics of mutations or pathogenic variant. It's important to know the difference between somatic and germline mutations. So somatic mutation, here is a cartoon to show you, if you can see my cursor, is a somatic mutation occurs in non-germline tissue, and they are non-inheritable. So any cancer, as you know, is a result of a mutation, right? So for example, if this cartoon gets a breast cancer, it's because there was a mutation in their breast tissue, and that led to the cancer. So that mutation leads to excess, you know. Cell division and there's a cancer. So since this happened in this person's breast tissue only, it's not in their germ line, meaning it's not in their sperm and eggs. They will not pass on this mutation to their children. So that is a somatic mutation. Um, and unlike somatic mutation, the second one is germline mutation, which is present in egg and sperm of the individual. So in this cartoon, this person's egg, uh, they that has a mutation. And when that embryo is formed with that egg, every single cell of that embryo will contain that mutation, and that will be this offspring here. So every single cell has that mutation, and this will be heritable, will be passed on to the offspring, and this is called germline mutation. So important to see when a patient comes to you with the result of genetic testing, uh, first thing you need to see is this is, um, you know, uh, a somatic mutation testing versus a germ-like testing. So, if a patient has, for example, um, uh, a colon cancer, and then they will undergo somatic mutation testing, which is done by our oncology colleagues to find some treatment targets. So based on what mutation that tumor may have, they can have some different kind of targeted therapy for them. And so in that, I have seen examples, let's say a patient has a tumor and the somatic mutation testing shows that they have APC variant in that, right? So, just in a somatic APC mutation, actually, it doesn't mean it's a germline. You need to do germline testing to confirm that, um, to see if it's in there. Oftentimes, APC mutation is seen in somatic cancers as well, as a somatic mutation as well, and if it's not present in germline, that is not familial APC, that's not like, you know, hereditary APC mutation, and that should not, should not be called FAP. So hope this conveys the point that first you need to see if that mutation is somatic or germline. Not all somatic mutations are also present in germline, so that needs a separate testing. Also, a key point is um to know that which mutations are monoalelic versus bi-alelic. So, for example, certain genes are, um, you know, just certain conditions and syndromes are autosomal dominant. Auto if they're autosomal dominant, and some examples here are APC mutation, so that leads to famil familial adenomatous polyposis syndrome. So here, if you see just one gene mutation, a monoalelic mutation, will be enough to cause the syndrome in that individual. So, Um, uh, uh, similarly, if you have MLH1, MSH2, PMS2, MSH6, uh, a single gene mutation in any of these genes will result in Lynch syndrome, and CVH1 is another example that results in hereditary diffuse gastric cancer. Um, I get questions asked like, oh, this patient just has one gene mutation, so they shouldn't have the syndrome. So take home is if it's autosomal dominant, single gene mutation or monoalelic mutation is all they need to have the syndrome. In reports, you can also see that mentioned as this patient is heterozygous for this condition. That itself means this is the syndrome based on the gene. And in contrast, it's important to know the autosomal recessive conditions in these, you have to have two genes to have the condition, and this is important because now genetic testing has become very common. If you are a physician, irrespective of your specialty, you're likely, you know, you're going to encounter. Um, uh, a patient will come to you with some genetic, uh, test results, or, you know, they may have family history that meets criteria. So, autosomal recessive conditions are important to know here because MUTYH it's actually 1% of the general population has single MUTYHG. So if your patient has one MUTYH mutation. It is not Mc polyposis. This is not a reason to worry about because you now know that this is an autosomal recessive condition. One gene of MUTYH will not cause mas polyposis, so, you know, they should get a counseling with the gastroenterologist. They will get, you know, uh, to discuss their, um, uh, colonoscopies, but this will not be a mass polypoosis. Their cancer risk is not much elevated than the general population. They would not make hundreds of polyps. Uh, but if they develop two MUTYH, that will be 100s of polyp and they get colon cancer, pretty significant, 70-80% lifetime risk. And there are some other genes here listed which are autosomal recessive. So take home is, first, when you see a mutation, the first thing you try to see is, is it a dominant condition or a recessive. So This is again an example here to show that, you know, when you find different genes, cancer risk, when we say that patient has Lynch syndrome, all Lynch syndrome patients are not alike. So depending on the gene mutation, their risk of cancers can be very different. So here, MLH1s, their risk is 40 to 60%. Uh, in contrast, let's look at PMS 2, their risk is about 80 to 20%. So this is close to, you know, um, it's, it's such a huge difference in the risk factor. So therefore, when you counsel patient, it really matters that. You know, I don't use the term lynch as an umbrella because which type they are, and the counseling and the age to start colonoscopies and the frequencies, they all vary over time. And for MSS 6 and PMS2, now the frequency for colonoscopies has gone down to every 1 to 3 years, so because those are less penetrant genes. So now, coming back to our question, in primary care, when to refer for genetic testing for GI indications. So, as I said, you know, for main common things, GI colon cancer is one. the second bucket is breast. I'm not gonna touch breast. I don't don't specialize in that. So, in, in, in breast, uh, in, in, in GI cancers, so if you see a patient and if they have a family history of colon cancer, and you're thinking, hmm, should I be sending them for genetic testing? So these criteria can be helpful to you. So first, you can do is look for NCCN criteria for lynch testing. Um, you can go to NCCN website and download their criteria. I do have some slides, we can talk, we'll talk about those. Uh, or you can go to, uh, uh, look for Prem 5. So if you just Google any search engine, if you put Prem 5, then you do get a nice link and a calculator that gives you, there are certain questions you can answer, and it's very nice and easy. It literally takes a minute to do and um that can tell you, it even gives you a cutoff and tells you that this patient meets criteria for genetic testing. So that's something simple, you can use that in your day to day practice, uh when you see someone with family history of colon, uterus cancer. Other things to think about are, um, if your patient, if they have made more than 10 adenoma, uh, in their colon, in their colonoscopies over a lifetime, so it's a lifetime, 10 or more adenomas, then that's a good time to discuss, uh, genetic testing. 10 to 20, we say consider, if it's more than 20, refer for genetic testing for sure. Or if they made 2 or more hematomatous polyps, this is kind of rare, um, uh, but definitely we see that. Or if you had a patient, if they had a tumor testing showed mismatch repair deficiency, so, even if they have no family history, they get, uh, you know, a tumor that's mismatched, repair deficient, they should undergo genetic testing. I will add here that this is a little bit older criteria. NCCN recently revised that if you have a person, if they have colon cancer, it doesn't matter what their family history is and what their tumor status is, and how old they are. If you're a person, you get a colon cancer, you should undergo germline testing. So made it very simple that um for any person with colon cancer, we should be doing genetic testing. And this is something we have had for pancreas cancer for the last many years. But if you have a pancreas cancer, it doesn't matter what your family history is, what your age is, and, you know, you should get drumline testing. And the same now we have for colon cancer as well. And of course, if you have a patient with family history of any genetic syndrome, you definitely want to send them for genetic testing. So before we talk about those NCCN criteria, let's, let's take a moment, you know, let's go back to my school days, um, and just talk about what do we mean when we say first degree, second degree, relative. So this is a pedigree or family tree. Um, our counselors are pretty good about making this. There are multiple programs that you just enter the family history and they generate this beautiful family tree known as pedigree. So, this is. So, um, this is a pro band, meaning this is your patient, the person of interest, uh, you're talking about. So, the circles are, um, uh, born female, uh, at birth, and then squares are people born male at birth. Um, so, let's see if these are. This person, their first degree relatives, will be number one here, directly related to them. So that will be their mother, their father, and brothers, sisters, and their children. So that one degree separation is first degree relative. And that's 2 degree separation becomes second degree relatives here. So here becomes their uncle, aunt, maternal or paternal grandparents on each side, and then their grandkids, and on here this side, nephews, nieces. And then when you start going to great uncles, uh, great aunts, then it's a 3 generations, uh, 3 degrees of separation, so that becomes distant 3rd degree relative. And I always like to think about this because NCCN criteria often refers to, you know, these degrees of separation. So, as I said, something that you can use in your clinical practice, day to day, uh, for Lynch Lynch syndrome prediction model is if you see patients with family history of colon and uterus cancer, is, um, um, go to this, you just search Prem 5, this link comes again. And this asks you a few questions. Here's a screenshot of that PRM 5 model, and um you just ask a bunch of questions on patient's sex, age, and their family history, and uh it will give you an output that says this person meets criteria or not very easy to use. And this is the big complicated NCCN criteria. I know it may be hard to read, and that's the purpose to show that, yes, NCCN makes it complicated to read, um, uh, and understand. So, this is a slide from NCCN 2023 version of patients. Whether they have colon cancer themselves or if they don't have cancer based on their family history, then you should be thinking about testing for Lynch syndrome. So this is a pretty busy slide, but I have the next slide where I summarize the, you know, something that will be practical for you. So, um, it's hard to memorize this, and even, even I have to, you know, go back and refer to this when I see patients, um, but just let's talk about it a little bit. So, first one we talk is, if you have a person now in 2024, if they get a colon cancer, think about germline genetic testing. Their family history doesn't matter, their age doesn't matter. Uh, it, you know, they should be undergoing genetic testing. So make a referral, um, if they did not have it already. Number one. And it's not part of the slides, but I'll throw in there, same goes for pancreas cancer. Any person with pancreas cancer, they should undergo online genetic testing. How about, let's see, um, uh, uh, so, other patients, you know, which is a well-defined. So they say if someone has a Lynch syndrome-related cancer, and any of the following. So, Lynch syndrome-related cancer means that Not just the colon cancer, there are several cancers that fall in the in the category of Lynch syndrome-related cancers, and those are ovarian, glioblastoma, small bowel, pancreas, gallbladder, kidneys, skin. It's a long list of tumors. Those are all Lynch syndrome-related cancer. So if they were diagnosed at age less than 50, then that person meets criteria for genetic testing. So how does that translate? I, so I said for colon cancer, uh, they say that definitively if you're less than 50, you should get germline testing for sure. It may sound confusing, but they say that for colon cancer, any age, you should consider germline testing. So, the way the interpretation now is for colon. Do at any age. For non-colon colon Lynch syndrome related cancers, so for example, if someone has, um, you know, a small bowel tumor, for, that's a Lynch syndrome-related cancer, and they, and that person is less than 50, so they're 45 years old, and they get small bowel tumor, it doesn't matter what their family history is, they meet NCCN criteria for referral for germline testing. Um, so if they even have like sebaceous skin tumor. And they are less than 50 years old. Based on this, they meet criteria for germline genetic testing. So there are certain, you know, some others listed here. I want to focus on the family history. So, something that you will see in your primary care, like a person comes, they do not have cancer, they come for a well person visit, but they do end up telling you that, you know what, my mom died of colon cancer when she was 45. So that person, you should be referring for jobline testing. Even that person is healthy and they have no other cancers, because here you can see family history of any of the following. So if they have one first degree relative with a colorectal cancer, uh, and then, or endometrial cancer. If any of these were diagnosed in their relative at age less than 50, your patient meets criteria for genetic testing. So that's an easy one. At the same time, they say, if they have family history of. Uh, one or more first degree relatives with colon or endometrial, and they also had a synchronous or mettaronous Lynch syndrome related cancer, regardless of age. So what does that translate in clinical practice? So let's say if someone has, uh, you know, had, um, uh, their mom had a colon cancer, and, uh, and they also had. And they also had stomach cancer, regardless of age. So that will make that a first degree relative, and they had two different kinds of cancers. Uh, so that person, your patient says like, well, my mom was 8 years old, but she had both stomach and colon cancer. So based on this criteria, that person, you know, should be tested, uh, should undergo germline genetic testing. And there are some others here as well, um, at 21st degree or 2 or more 1st or second degree relatives with Lynch related cancers, and then at 3 or more 1st or 2nd degree relatives with Lynch syndrome related cancers, regardless of age, and this is also I think commonly, if you start taking history is, you know, someone will have 3 of us. 3 1st or 2nd degree, so that includes your mom, your uncle, your grandparent, and you end up finding that one had stomach cancer, one had colon cancer, and the third one had, for example, endometrial cancer, and say patients will say, yeah, they all were old when they had it, but if you end up finding 3 of these, even if all of those were old, actually that patient met criteria for testing. So there's a common, you know, misunderstanding that, oh, if you have, you have to have genetic testing if you had family members with cancers at a young age, not necessarily. So, it's, it's, it's it's likely I confused you quite a bit, but just to show you that how complicated these are for someone, I literally have seen hundreds of patients, uh, with Lynch, it's hard for me to even spell it out to you. And to see that challenge, um, you know, I was like, OK, how do we make it easier for my primary care colleagues who have a million criteria to know for different body organs, uh, how, how can we just make it a little easier for them to use in their clinical practice? And then that's why I started this project, uh, just to make a calculator. This calculator will do this back end calculation for you. So I had the funding for Mount Zion Health Foundation, and this is a calculator you're getting a sneak preview here. It is not launched yet. Um, we have built it, it's working. We have done a pilot on about, you know, 100+ patients at UCSF. Uh, it's fully functional, validated, 100%. Accurate in its output. And what this does is it's built on Red Cap, uh, Redcap based calculator, and you just, once it's launched, I'll be more than happy to pass it along to, to your team. I'm guessing within a month we'll be able to launch this. And what happens is it doesn't have to be done by you. Of course you can do that. You can send it to your patients, and it simply asks them, it's designed to be filled out by a patient, and they can just say, it asks questions like. Your mom had this cancer. Did your grandpa, have, you know, this cancer, uh, you know, how many of these were? So literally, it's asking those complicated NCCN criteria questions, one at a time, and it takes 56 minutes, it's not taking super long for the patient. And in the end, this is the kind of output your patient will receive. So, it just says that you meet criteria for genetic testing for common hereditary cancer syndromes, and the beauty of this calculator is, it's designed not just for Lynch, also for HBOC, which is BRCA1 and 2. So, the most common cancers that, you know, that we want to target are if patients have family history of colon, uh, pancreas, prostate, breasts, right? These are the commonest cancers, um, that exist out there, and this calculator will capture that. So the difference between Prem calculator that I told you and this calculator that we have built is, uh, PREM is built by Dana-Farber, pretty well validated, but that will just target for uh colon cancer risk, GI cancer for Lynch, and this UCSF calculator that I built will, will, will cover, uh, breast BRCA 1 and 2 as well. Just to explain that this is not designed to, uh, you know, test for rare syndromes, we are not doing those, we're not testing for FAP or those things. This is for family history of common cancers for Lynch and BRCAs, which is like pretty, in the majority of the patients we should be capturing from general population and primary care, uh, this should be the focus. So stay tuned. And then this calculator actually is also built in the end to ask patients, are you interested in scheduling an appointment with the counselors? If they say yes, we have built an interface. Patients can enter their their insurance information, their phone number, and that information goes to UCSF contact center, and they can actually reach out to the patient that, hey, you said you want to see a counselor, uh, let's set you up. So that actually has been built. It also says for patients who do not live in California, it gives them a list, like, this is how you can find a counselor wherever you live, and then please reach out to them. So, we have tried to make it a patient-friendly photo. OK, so you're like, great, OK, now I have identified patients who should be getting genetic testing. How do I do? Well, one is, you know, if you have GI family history, you can send them to me. I'm a gastroenterologist. I also do genetic counseling and other testing. You can send them to a genetic counselor. They can do that counseling and testing as well. Both are the options. And the third one is, as a provider, you can order genetic testing. Uh, any person, any, any trained medical professional, um, uh, you know, as long as you understand the basics of genetic testing, it's just like ordering, you know, a CBC for you. So, um, so how can you order that? So first, have the basic concepts as we talked, and then make sure that your patient meets criteria. And I'll just say, you know, following this field, I have seen that with time, every single revision of NCCN we make it easier and easier for patients to get genetic testing. So you could argue that do you have to have some family history to go undergo genetic testing? Not really, you know, why does anyone have to have a cancer? For you to have genetic testing, why can't we just shift the paradigm and test you first so that nobody gets a cancer or we catch only for everybody. So, um, it's just a cost issue. I think if, if it becomes cheaper, it may be, you know, you may be just doing the way you do lipid panel for everybody. You may do genetic testing for common syndromes. I'm not saying the rarest one, Common like Lynch and BRCA's, uh, BRCs, you'll be testing, uh, you know, for everybody. There are a bunch of, uh, you know, states, for example, in, in, in Nevada, they had a healthy Nevada project. Anybody can just go to their website, and then just doesn't matter what your family history is, you just can get a kit and do genetic testing, uh, send a saliva sample, they'll do that. There's another state in, in, in this country is doing that. In Australia, um, there is a population based, large scale, like, let's just test everybody to see if they have Lynch and BRCA is going on. NIH here is doing a study as well for general population genetic testing, anybody. I think it's called All of Us is the name of the trial. I have seen some patients who tested through that and actually tested positive, then they came to see me. So, so overall, the barrier for genetic testing is actually, you know, it's going down with time. And if you're curious, you can afford, you understand. In my opinion, um, uh, you know, high risk genes can be tested in anyone. But for insurance purposes, you have to have these criteria. So, insurance will not pay just because your patient is curious or you're curious. Uh, but patients certainly can pay out of pocket. We'll talk. So first you make sure that patient meets criteria, then you have to consent. The consent can be a verbal consent after offering an appropriate counseling, and I strongly advocate that appropriate counseling is important, otherwise you can do harm to the patient, uh, and, you know, not be as helpful. Uh, and the consent in California, you can do a verbal consent and a counsel and document that the components of counseling that you have done. Uh, so I don't make patients sign anything as such. I'm not required to. I discussed with them, and I, that I did the counseling and I consent. They give me consent to order the genetic testing, and I document the whole counseling process and uh the consent, and that's enough. There's no signature needed legally as such. Uh, you certainly can. Uh, I'll show that some labs will ask you to, to make them sign a consent for genetic testing that they understand what it entails, but you're not required, uh, to have a signature, just oral, the verbal consent is fine. Uh, so, so now you, you decided patients who meet criteria, then you did the counseling, then you consented, and you're like, all right, great. How do I order it? What are your options? So, the options are, uh, certainly, I work at UCSF. I can tell you that UCSF providers can order genetic testing at UCSF just like I ordered CBC. It's the same way, one click, I ordered a large panel of genetic testing. External providers, yes. You can also send a requisition to UCSF Genetics lab, uh, for a large panel genetic testing for any of your patients, uh, as well. And then, there are a bunch of private labs. I listed a few, just for the sake of your information. Invite, Ambri, Myriad, uh, Gene DX, Chole Genomics, Prevention Genetics, Quest, and many, many others are out there. Uh, the names are listed here, just for your information. I do not have any financial, uh, uh, you know, uh, connection with any of these private companies. So, uh, genetic testing, you know, current status, as we said, it's very, it's actually with next generation sequencing, the change in technology, genetic testing is actually very, very affordable now. Most insurance companies will pay for it. A test that used to cost $4000 a couple of years ago is now like $200. Uh, so there's a huge advancement in technology. And a 150 gene panel um can cost you $250 and actually at, at UCSF it's just $200 out of pocket. So even if your insurance doesn't pay, um, you know, it's, uh, it costs less than a month of Starbucks supply for many of your patients. And if you have a patient who has a genetic mutation, and then let's say I see a patient and I diagnose them with Lynch, many labs say that, well, now we know that their family members are very high risk to carry those, right? So they will say they give like, they forgot like 1 or 2 month window that they will test their family members just for $50. So, it's pretty amazing, uh, you know, then we are like, telling their kids and parents to get tested for 50 bucks, very affordable. And as I said, it's covered by most insurance plans, and there is growing public interest in genetic testing. So there is a patient-initiated genetic testing as well. So, uh, a patient doesn't need your order to undergo genetic testing, doesn't need my order to undergo genetic testing. If they're informed, they can just go to many of those private commercial labs I mentioned to you, and then they have a patient initiated, uh, uh link. So, I'm not talking about those 23andMe or ancestry.com. Um, uh, those are, you know, I would not recommend any of those, just briefly for medical grade genetic testing for cancer risk, uh, management. Those are, their purpose is very, very different. They have a very tiny fraction focused on clinical cancer risk. So I will send them for these clinical grade genetic testing to the other labs I mentioned. Uh, patients can go to these labs I mentioned, like, you know, invite, Marriel, Ambry, UCSF, not UCSF. UCSF does not have patient initiated testing, it has to be through a provider, but commercial labs, patients can go to their website, you can Google any of those, and then, um, it will just, you know, it just, you order that kit, they send it to you, and they have their own network of. Providers and counselors who, who may just ask you a few questions, follow up with you, and they do the testing. And if it's positive, they even do part of their care, a genetic counseling to you as well. So this all can be handled by an informed patient without any contact with a provider. Not recommended, but it's possible. Uh, so just again, you know, part of genetic counseling, I said like before you order the genetic test, you have to do a counseling, right? It's not just, you know, uh, there has to be a documentation process. So you should be taking three generation details, family history, draw a pedigree. I'll be honest, I don't draw. Pedigree, it's like takes time, but I do take three generational family history and document that, uh, in the note, who had cancer, and also the age of diagnosis of the cancer, um, not when they died, like, so when the cancer was diagnosed. And then you take, I take a verbal consent and document in the note. Uh, and then in the counseling part, you have to discuss limitations of testing. So, and that should be that, you know, you have. Several members in your family with colon cancer, and we can test you for that, but we don't know all the genes that can cause colon cancer, so that's a limitation. We may find a VUS, which is a variant of uncertain significance, meaning, we may find a change in your gene, and that will be something that's different, but. We don't know uh the, the clinical consequences of those, and at the same time, we may find some changes, a variant of mutations in some other genes when we do a large panel testing, which have, which do not have a well defined penetrance. Or management plan. What that means is an example would be if you have a patient with breast cancer, or for example, colon cancer, and you do their genetic testing in a large panel, you may end up finding a mutation in a gene called, I'll just pick CDH1, which is increases risk of stomach cancer. But the exact penetrance is a little bit ill-defined, and what does it mean when we find that in a person who has no family history, which is an incidental finding, uh, it can generate some anxiety in some patients. So I actually do discuss with my patient. I actually ask them, are you a worrier? Do you like to worry if we find some unknowns? In that case, I will be like, well, let's do a smaller panel for you, or in those patients, you can do a single site testing, meaning a limited panel. Because the larger the panel, larger, you know, the higher the chance that you will find some VUS or some other genes. So, so you, so the panel that you choose, that's where I try to be selective. Many of my patients are scientists, well informed, uh, you know, people who understand science and they're like, no, I understand, I'll just refer to your opinion, whatever the findings are. So most of my patients, I end up going, uh, expanded panel, but a very small fraction, I respect their preferences and choose accordingly. And other things are to know about genetic discrimination that should be part of your counseling. So genetic discrimination, it's, it is a law that protects your patients from genetic discrimination, and it's called GINA, Genetic Information Non-Discrimination Act, which was passed by President Bush in 2008. So what GINA does is, it will protect your patients, you know, like, for example, an employer or a health insurance company. They cannot discriminate your patient based on their genetic diagnosis. But GIA does not cover life insurance, disability insurance, long term care insurance, and military personnel as well. So some states, um, you know, I tell my patients, well, uh, not life insurance companies will do that, but some, since there's no legal protection, if they find out today that you have lynch, they may charge you super high premium if you buy life insurance. Um, so I have had examples that, you know, I have a young man coming in, they have a family history of cancers, and I tell them I do this counseling before I order genetic testing. So they're like, all right, let me buy my life insurance, and I'll do this genetic testing after 6 months. I'm like, that's fine. Um, so that's where this counseling part is important. And then also it's important to counsel that a negative genetic test does not mean the risk is lower. You know, so patients should not get a false sense of reassurance that if they have 5 or 6 colon cancers in their family and the genetic test is negative, you know, their risk is just like any person, any other person walking on the street. Oh, they still have much higher risk than the general population, and they need to be managed, you know, they may, they may still need frequent colonoscopies, even if they didn't find a gene, uh, based on their clinical risk, so that counseling is important as well. And this is a screenshot I took for you for uh UCSF expanded hereditary Cancer panel, because that was one of the asks for this talk, like, how would you order that? So you go to UCSF Health, um, you know, clinical genetics and geno genomics website, you'll find this panel, which is a large panel for most common genes. The genes are all listed here in the bottom, and it's a pretty comprehensive list, and, uh, this, you can find on that. Web page, this is the link, you will find this requisition and you fill out uh all the information. There's an email ID and phone number for any questions, and you will be checking this box for, uh, which is a common hereditary cancer panel, which will cover for, you know, most colon, breast, ovarian, pancreas cancers, those all genes are in there. And then, here, there's a link of. Oh, I think if you go on this webpage, it also shows you the link for consent form. So if you send them a requisition for genetic testing, they'll ask you to send patients a signed consent form, um, as well, which, and that's can be taken care of. Similar process can be done at, you know, you can go to any of those commercial genetics labs I mentioned. You just create a profile with them. And anytime you need to do for a patient, you go to their portal, super easy, and you can enter that. I personally, as a physician, I use UCSF lab because I'm in the system, it's faster for me, but my counselors use both. They use many of the commercial labs as well that they have done, and the UCSF tests, you know, we have started using this year. So now, you counsel the patient, you place the order, what happens to the patient. So genetic test can be done just on simple saliva sample. Patient doesn't need a, you know, uh, a prick for a blood test. So it can be done on saliva, it can be done on a blood test, and, um, you know, buckle swab, uh, as well, like uh swabbing your cheek. And the other option is to do a skin biopsy, fibroblast culture. I've done it once in 1000 patients, super rarely, and that is done, you know, for patients who have a bone marrow transplant, um, uh, because if you have a bone marrow transplant, and they do a saliva or blood test, you actually are doing genetic tests on the donor, not on you. So in those situations, uh, you will need a fibroblast culture, super rare scenario, but most of these, you can choose whether your patient wants to go to the lab and give a blood sample, easy, uh, it's just a 4 cc of blood they take, or you can just click saliva in the order, and the labs will mail a kit to your patient, and it's a very simple, like, you know, tube, uh, just you spit in the tube, mail it back, super easy process. And we discussed, you know, single site versus multi-gene panel tests. So, the same, same way of asking that, do you just want to test hemoglobin or do you want to test the CBC, right? So, generally, we are so much in the habit of testing CBC or chem panel, right? We barely just order sodium. Uh, so similar process, uh, short answer is, in the interest of time, I'll say is we do multi-gene panel testing, that is the most recommended, unless a rare scenarios, you know, uh, we'll be testing single site for some, uh, reasons I mentioned. And then also, like, you know, important to know there are different labs, if you do a colon cancer panel, a prostate cancer panel, the kind of genes that are added in those panels, they, they may vary based on labs. So if my patients come to me and say, I had genetic testing done, I. My next question is, I need to see the report to see which genes were tested. Example will be, I literally saw a patient, she had breast cancer, uh, and had genetic testing 10 years ago. She was found to have BRCA positive, and she said, yeah, I have had genetic testing done. And then when I talked to her, she told me that her mom died of colon cancer at age 39. So, I was like, well, then, you know, BRCA uh is not a colon cancer gene, so you need genetic testing for colon cancer genes as well. Um, so, in that case, I asked for her genetic testing results to ensure that she has had all the genes tested. It's similar, similarly, like, you know, your patient comes to you that, and say, I have had blood tests done. You need to see like what was included in the test, and you can expand and change the panel, and that applies to genetic testing as well. Uh, all genetic testing is not the same. So testing results, you know, it can be positive, negative, or you can see variant of uncertain significance. So, important to know in the results, you can see positive mutation, or I said positive pathogenic variant, likely pathogenic deleterious, or suspected deleterious. Any of these things you see, all of these mean that this is a positive result for you, OK? If you see negative, self-explanatory. And if you see VUS variant of unknown significance, I have seen not infrequently, I see this being misinterpreted. A VUS means that it's not a maybe, it's not a touch of mutation, it doesn't mean that. It means that. There's a change in the spelling of the gene, and as of now, science doesn't know what that means. So what happens in the future? So 95% of these VUSs over time, as labs learn more data, they get reclassified as benign or negative, and 5% of these, they may get reclassified as pathogenic or, you know, positive. So, so, in clinical practice, in primary care, like, you know, uh, when a patient has a VUS, you should treat them as negative and managed patient according to family history. There's a nuance at the genetic counseling level. All righty. So, I think in the interest of time, I'm gonna, you know, I'll just be quickly here that, uh, when should the children, offspring, offspring be tested? So, we test children if their clinical care will be impacted, um, uh, by knowing the testing results. If not, we do not recommend testing children. Let children be children as long as they can be, right? So, Lynch syndrome, for example, I do not test children. I hundreds of Lynch patients, they do, they're curious. About the kids to be tested. I keep pushing them back, um, unless they turn into like 1718 years old, we do not test them. There are certain conditions, you know, where children do get polyps and cancer, and they're listed here. In those situations, I do test children, you know, that's around age 8 or something, when the polyps start forming. So if the clinical management is not going to change, do not test children, is my recommendation. OK, so conclusion. So, just, you know, I hope I was able to share with you that technological advances, they have made genetic testing very affordable and accessible, and about 1 in 280 individuals are estimated to have Lynch syndrome, and most are unaware of the diagnosis. If you say that you're a practicing provider, and you say that you do not, you do not have Lynch syndrome in your practice, my. Thought will be, you do have Lynch syndrome in your practice, you or patient just don't know that yet. Uh, and timely diagnosis of hereditary cancer syndromes can alter therapeutic options for the patients, and, and these are not just for the patient, their families as well. So, high impact, uh, for care. And in family history and referral to genetic testing. Should be a routine part of your practice. So take family history, identify patients, either be comfortable, uh, and do the testing. If not, make the appropriate referral, and, and, uh, that will go a long way for that patients and their family's management. Uh, this is one line club that at UCSF I have launched a UCSF Lynch syndrome Center. Uh, I direct the Center, it's a multidisciplinary care for patients with Lynch syndrome. We do genetic testing, we do colonoscopy, and we do endometrial biopsy at the same time at colonoscopy. We have a vaccine. The trial that I have started for these patients to lower their risk of colon cancer, uh, fascinating concept to see if vaccines can prevent cancers. There's a lot of stuff going on. Uh, you're welcome to check out. We'll be adding some more information and growing that site as well. It's a little bit new. And I think, uh, that's all I have for today. And if you have kids who like Ugly Duckling, I don't think I did a good job of cropping the image, but That's it for my talk today and more than happy to answer any questions.
