10 – Lynch Syndrome: An Inherited Disorder Associated with Increased Cancer Risk
June 20, 2023

Lynch syndrome is an inherited disorder associated with many different cancers including ovarian, uterine, pancreatic and, most commonly, colorectal. It is estimated that about one in 279 people are Lynch syndrome carriers, or about 1 million people in the U.S. Dr. Jordan Karlitz, Senior Medical Director at GRAIL, and Robin Dubin, Executive Director and Co-founder of AliveandKick’n – a patient advocacy organization focused on Lynch syndrome – join The Cancer SIGNAL to discuss risks associated with hereditary cancer predispositions, the need for tailored screening programs and how multi-cancer early detection could be used to look for cancers associated with Lynch syndrome.

AliveandKick’n: https://www.aliveandkickn.org/


Kim Thiboldeaux  00:17
Welcome to The Cancer SIGNAL, a new podcast presented by GRAIL where we discuss the impact of early cancer detection, the science behind multi-cancer early detection and insight into how this approach has the potential to shift the cancer paradigm. I’m your host, Kim Thiboldeaux. Today we are going to talk about Lynch syndrome, an inherited disorder that increases the risk of many types of cancer. I’m pleased to be joined today by two special guests who are experts in Lynch. Dr. Jordan Karlitz is a Senior Medical Director in Medical Affairs at GRAIL. He is also chair of the GRAIL Scientific Review Committee and has a strong interest in MCED research, including high risk populations. Prior to joining GRAIL, Dr. Karlitz was the chief of Gastroenterology and Hepatology at Denver Health Medical Center and a clinical professor at the University of Colorado School of Medicine.

Robin Dubin is the Executive Director and co-founder of AliveandKick’n, a patient advocacy organization focused on Lynch syndrome, hereditary cancer predispositions. She is a mom and entrepreneur and advocate and caregiver to her husband, David, a three-time cancer survivor and two Lynch positive sons. With an MBA in finance from NYU and a 25 year healthcare career, she has shaped AliveandKick’n to focus on providing resources for Lynch syndrome patients, and developing innovative tools like The HEROIC Registry to further research. Welcome to the show, Jordan and Robin.

Dr. Karlitz  01:49
Thanks. It’s great to be here.

Kim Thiboldeaux  01:50
Excellent. All right. Well, let’s jump in. We have a lot to cover today. Let’s just start by taking a moment for our listeners to get to know each of you a little bit better. Jordan, please tell us a little bit about yourself, about what brought you to GRAIL. Give us a little bit of background.

Dr. Karlitz  02:05
Yeah, no, absolutely. And first off, I just want to say it’s great to be on the podcast with Robin. So I’ve known Robin and Dave for years. And I’ve been involved with AliveandKick’n, and we’ve been working together on the National Colorectal Cancer Roundtable. So a pleasure to see Robin and Dave who’s probably listening again, so. So a little bit of background on me. So I’ve been at GRAIL for about eight months now. I’m an academic GI doctor. And I actually started off my career at Tulane in New Orleans, which is really where I first started getting interested in Lynch syndrome. And I think there’s an interesting story behind this.

So when I first got to Tulane, I’d heard stories from providers in the Acadian region of Louisiana, which is home to the Cajun population, that there were very high rates of cancer in this area. And for those that don’t know, the Cajun population came from southern Louisiana in the 1700s, from Nova Scotia, Canada, and the Cajun population has actually what’s called a genetic founder population. So in founder populations, hereditary disorders, including colorectal cancer, for example, and Lynch syndrome, can actually be magnified compared to other populations. And so given this, I actually approached our state SEER tumor registry and designed a study looking at colorectal cancer incidence rates in this Acadian region. And to better define this region, we looked at French language census data and ancestry data. And we discovered that in areas with the highest concentration of those with Cajun ancestry, colorectal cancer rates were among the highest in the US and significantly higher than other parts of Louisiana.

So we hypothesized that this may be due to a genetic cause for colorectal cancer in this population, potentially Lynch syndrome, although clearly additional research would be needed. And this actually led us to a second study, which was a smaller pilot study in which we performed genetic analyses directly on colorectal cancer specimens in Cajun patients. And we did in fact find a signal for Lynch syndrome and also a suspicious change in another gene called the APC gene, which could also be associated with colorectal cancer. So we’re really hoping these results will fuel larger studies to better understand the genetic risk in this population. But it was really this immersion in studying the Cajun population that got me interested in Lynch syndrome. And based on these experiences, I actually translated this into the clinic. And I ended up starting a hereditary GI cancer program at Tulane, where I, with a strong focus on Lynch syndrome patients and family members. And we actually drew patients from all over Louisiana and Mississippi.

I did end up transitioning to University of Colorado where I was, as I mentioned before, a professor and chief of GI and Hepatology at Denver Health Medical Center, which is a large safety net hospital. But I will say that much of my clinical career has actually focused on expanding clinical access to underserved patient populations. And I really think there’s a critical need for this. In genetic testing, and even other newer technologies, including multi-cancer early detection tests, or MCEDs, that we’re going to speak about today. And finally, you know, I ultimately moved to GRAIL after being introduced to the company by my colleague in Medical Affairs, Whitney Jones, so definitely wanted to mention his name. The multi-cancer screening approach at GRAIL really sparked my interest and gelled with my prior work in Lynch syndrome, which as we know, has a multi-cancer test. A lot of people associate Lynch syndrome with colorectal cancer, but there are a spectrum of cancers associated with Lynch syndrome. So that was really how I ended up transitioning, a bit of a long story, but somewhat interesting.

Kim Thiboldeaux  05:25
Now it’s, it’s great background, Jordan, I appreciate you sharing that. And you’re probably not surprised that you got a little bit of my attention with the Louisiana reference. My recent DNA testing showed a little chunk of Acadian with my last name in our roots in southern Louisiana French settlers. So you certainly got my attention with some of that background. So thanks for sharing that. I love to learn about the research that kind of brought you to this work. Robin, please tell us a little bit about your background and about the organization that you founded, AliveandKick’n.

Robin Dubin  05:56
Sure. So that leads perfectly what Jordan was discussing about Lynch syndrome and it not just being colon cancer, because my husband, Dave, had colon cancer for the first time when he was 29 years old. And it was 1997. So back then, very few people were talking about genetics. We knew there was a family history, but we didn’t know much more than that. He, our oldest son was about 15 months old at the time, and he, it was stage three. So he had surgery, he had chemo and we kind of went on with our lives after that. He was getting screened fairly regularly. But we didn’t know anything yet about Lynch syndrome. And it wasn’t until 10 years later with a second colon cancer diagnosis, and then a kidney tumor a few years after that, that he had genetic testing and we learned about Lynch syndrome. And he had been getting involved with kind of the colon cancer awareness world. And as we started to learn about his Lynch diagnosis, we started to recognize that it was more than just colon cancer, and that there were obviously hereditary aspects about it.

So it encompasses more than just the individual patient, but the entire family and we looked around and we didn’t find any real patient advocacy resources, support, education about it. And so that’s how just a little over 10 years ago, we came to launch AliveandKick’n as a patient advocacy nonprofit. And I’ve been running it ever since then. We have since then had all three of our ch- who are now mostly adult children tested and two out of three of our sons are positive for the MLH1 gene that my husband has. And they’re called previvors. So they have the hereditary predisposition, but they’ve never had cancer. And part of that is because we make sure they get all of their annual screenings to catch things early, and things like that. But we have also been, I’ve been building up the organization. We started it from scratch. Jordan is actually on our board of directors. So it’s been really valuable having his expertise in supporting and helping to grow the organization.

We have put together things like our patient registry, which is a registry where patients put their own medical data into our database. And it allows us to really connect with the research community and help further research into various aspects of having Lynch syndrome. And we have put together with our partner, the Colon Cancer Coalition, our annual Living with Lynch Patient Workshop, where we bring a small group of patients together in a different city every year for patient education, advocacy training and awareness activities and an opportunity for them to meet others with Lynch syndrome. So for many of the people that attend, it’s the first time they’ve met someone outside of their family that has Lynch syndrome. So it’s a kind of an opportunity for kind of an emotional connection with others that are going through similar things to them.

Kim Thiboldeaux  09:43
Right, Robin, thank you for sharing and thank you for that background and congratulations on all the great work that you’re doing to support patients and families. I want to dive in for our listeners, Jordan, I want to start with some basics. Please tell us, what is Lynch syndrome and what are the cancers for which it is elevates one’s risk? Robin pointed out it’s not just colorectal cancer, it’s many cancers. So Jordan, can you give us a little bit of that medical background?

Dr. Karlitz  10:06
Yeah, absolutely. So Lynch syndrome is an inherited disorder that can be associated, as we just mentioned, with a number of different cancers. The disorder is autosomal dominant, which means there’s a 50% chance of inheriting the disorder. And the most common cancer associated with Lynch is in fact, colorectal cancer. Again, it’s important to stress that there are multiple other cancer types that can be associated, including ovarian cancer, uterine cancer, pancreatic cancer, and there are actually a number of other types as well. There are also several different genes that could actually underlie Lynch syndrome. And the rates of cancer development over one’s lifetime could vary depending on what gene you’re carrying. So for example, rates of developing colorectal cancer by age 80, could be as high as 61%, depending on the mutation type, and rates of uterine cancer could be as high as 57%, and ovarian cancer as high as 38%.

And then there are other cancers as well that have higher lifetime rates. Importantly, in some families, there may actually be no history of colorectal cancer at all. So for this reason, it’s really important for patients and providers to be aware of all the different cancer types that are associated with Lynch so that we can help identify Lynch syndrome. And identifying Lynch syndrome is really critical so that we can implement tailored screening and surveillance programs. So for example, colonoscopy, which can obviously be lifesaving. And I will say and I think Robin probably agreed with us that one of the best times to update once family history may be during the holidays, right? So this is a time when everyone may be together and really spending a few minutes to find out any new developments in a family member’s medical history can be really helpful.

Kim Thiboldeaux  11:42
Okay, so no real no religion, no politics at Thanksgiving, but we can talk about healthcare and Lynch syndrome, right?

Dr. Karlitz  11:48
Even if it’s a few, even if it’s a minute, you know, just what any updates are. And if everyone’s kind of gelled and on the same page, like it could be helpful over time.

Kim Thiboldeaux  11:55
I love it. No turkey until we talk about –

Dr. Karlitz  11:57
Yeah, exactly.

Kim Thiboldeaux  11:59
[Laughs] I love it. Jordan, tell us how is Lynch syndrome diagnosed? And who should get tested? You talked a little bit about risk and family history. I mean, do we know how many people have Lynch in our country?

Dr. Karlitz  12:10
Yeah, so it’s thought that about one in 279 people are Lynch syndrome carriers. In the United States, this would amount to over one million people. So it’s a very large number. But unfortunately, the vast majority of those carrying a Lynch syndrome mutation are unaware. And there are really two main ways that Lynch can be diagnosed, it can be diagnosed through a personal history of cancer or a family history of cancer. And obviously, in many cases, there’s going to be both a simultaneous personal and family history of cancer. So I’ll kind of divide this up. So in patients presenting with cancer, there’s certain tests that can be done that directly look at the tumor tissue, for example, colorectal cancer to look for evidence of Lynch syndrome. So these tasks, I’m just kind of throwing these terms out there as people may hear them. One test is called microsatellite instability testing, abbreviated MSI, and the other is immunohistochemistry testing, abbreviated IHC. And the National Comprehensive Cancer Network recommends universal testing in those with colorectal cancer and uterine cancer.

So universal testing means like anybody developing this type of tumor, regardless of age should undergo this tumor screening. There’s also something called multi-gene panel genetic testing, which may be blood or saliva test that may be recommended in patients with cancer. So multi-panel gene testing, in contrast to the tumor testing, looks directly for changes in the DNA to confirm the presence of Lynch syndrome, or even to pick up other hereditary conditions. So this multi-gene panel testing could be done as a second step. So for example, after abnormal tumor testing, or potentially even as a first step in some higher risk patients, including younger patients. So the other situation may be a patient presenting with a family history of cancer. So I will mention that there are online risk calculators that actually allow easy calculation of one’s risk of carrying a Lynch syndrome gene mutation based on both cancer family history, and potentially a personal history of cancer if a patient has a personal history of cancer. These risk scores can really be used to make decisions on whether genetic testing and counseling are needed.

And I think a really good example that listeners could, they could actually look up this score online. It’s called the PREMM score. So it’s P-R-E-M-M, and you could just Google this, just Google PREMM and it will come up. It was developed at Dana Farber and Harvard. And what you do is you just, it’s very quick, you could fill this out in a minute or two, and it will you put in your family history of cancer and your personal history, and it will click out a percentage chance and that threshold can be used to determine whether or not you meet criteria for genetic testing or counseling. One other last thing I should say about this is that there unfortunately there are a number of studies showing challenges in identifying patients with Lynch syndrome. And I’ve actually been involved in some of these when I was at Tulane. So in one study, we actually looked at statewide tumor testing rates with as I mentioned before MSI and IHC testing in young patients under 50, with colorectal cancer in Louisiana, and unfortunately found that only 23% of these high risk patients underwent tumor testing. And that should really be 100%. So that’s a major missed opportunity for identifying Lynch syndrome in a large population.

Kim Thiboldeaux  15:18
Got it. That’s great background. Jordan. Thank you. Thank you. I want to get with Robin to some of the family issues and challenges. Obviously, this is an inherited genetic disorder. So, Robin, obviously, there are challenges and issues that patients with Lynch are facing themselves. I imagine getting diagnosed, getting screened, getting treated, but also challenges and having these family conversations and family communication. Robin, tell us a little bit about that. I’m sure you have a lot of experience in talking with families about these issues.

Robin Dubin  15:48
Right. Yeah. So that is a lot of what we do as an organization is to try and help educate people. And help them understand the best way to kind of navigate a lot of these challenges. And there’s, there’s so many different aspects of it that are challenging. There’s everything from just getting that diagnosis, like Jordan said, a very small percentage of people that have a Lynch syndrome predisposition even are aware they have it. So there’s educating, you know, the general public about understanding their family history and what it might mean, to try and get more people tested for Lynch syndrome before they have cancer. But right now, many of the people are often getting their Lynch syndrome diagnosis with a personal or family cancer diagnosis. And so that kind of complicates the it even more, because you’re in the middle of cancer treatment, and suddenly finding out that you have this hereditary condition, that’s going to put you at increased risk for a variety of cancers in the future, again, and often those are at a very young age.

So there’s the aspect of understanding what it means to have a Lynch syndrome diagnosis separate from a cancer diagnosis and treatment, what you need to do to get screened for it properly, how to find the right clinicians and doctors to manage your care. Where do you get that care? A lot of sometimes that depends on geography and where you live. There are quite a number of cancer centers that have cancer genetic clinics, that specifically help to manage the care for Lynch syndrome patients. But if you don’t live near one of those, you have to essentially manage your own or navigate through your own care and screening on your own. So we kind of help patients to understand by trying to educate them about what the guidelines recommend in terms of cancer screenings, how often and what types of screenings, and then there’s everything from well, how do I? When do I get my kids tested and things like that? Do I need to have risk reducing surgeries because guidelines do actually recommend risk reducing hysterectomy and bilateral single oophorectomies for women once they’re past childbearing ages. So that is a very, very big decision to make. At what age do you, do you have a risk reducing surgery like that happen? If people are aware they have Lynch syndrome, before a colon cancer diagnosis, it’s often recommended that they get a total colectomy versus a subtotal colectomy or another type of surgery. Jordan can probably talk more about that. But you know, there’s a lot of decisions that have to be made in terms of managing your care and managing the care of your family members.

Kim Thiboldeaux  19:25
Right. Right. So a lot of, sounds like really strong sense of self advocacy, Robin, because sometimes the answers are not right there at your fingertips and where you live really matters where you’re getting care, maybe getting second opinion really matters as well. And then also all of the family issues and family dynamics that you’ve talked about I think are so complex we could probably talk for days you know about that. I want to, in our few remaining minutes together guys, I want to pivot a little bit to multi-cancer early detection MCED and chat about that for a moment. Jordan, as it relates to, to multi-cancer early detection, how could we potentially be thinking about MCED testing for people with Lynch? What studies are necessary? What research programs are necessary for us to understand this and its potential?

Dr. Karlitz  20:15
Yeah, no, that’s a great question. So as we’ve discussed several times, now, Lynch is a multi-cancer syndrome, so at risk for colorectal cancer and a multitude of other cancers, so think multi-cancer, early detection tests, or MCEDs, for example, Galleri, could be a potential screening tool in those with Lynch syndrome. I think clearly, clearly, we wouldn’t want to replace Lynch syndrome standard of care screening and surveillance. But I think MCED testing could be used as an adjunct really to assess for cancers associated with Lynch, including cancers that are particularly challenging to screen for. So there are a number of cancers that can be harder to detect, in comparison to colorectal cancer, for example, in which we have colonoscopy, which is a very good test. So along these lines, we’re really looking into developing research protocols at GRAIL to help understand how MCED testing could be utilized in these populations, and also in other high risk populations, including other syndromes and other high risk populations, including cancer survivors and other groups. And I’ve been working with someone named Guneet Walia, one of my colleagues in clinical development, I definitely wanted to call out her name on these types of research initiatives. So that’s an active area that we’re currently working on.

Kim Thiboldeaux  21:29
Great, I think, a lot, a lot of questions, a lot to learn. So we appreciate the focus on that. Robin, let me get your thoughts on that. Do you think that MCED has the potential to be added to screening protocols for people with Lynch? How do you believe we should be thinking about this into the future?

Robin Dubin  21:45
I definitely think it’s something to pursue in terms of, of adding to the screening protocols. Like Jordan said, you know, there are some screenings like colonoscopy that are so high quality that, that I doubt that we can replace them anytime soon. But this is certainly something for some of those cancers that, that don’t really have great screening tools that we could add as an addition to the current guidelines. Assuming we can get tests that are high enough quality to specifically, you know, be of use to this high-risk patient population.

Kim Thiboldeaux  22:38
Right, so important questions that we need to be asking in the research and thinking about the potential for MCED for folks with Lynch. Before we go, Robin, can you tell our listeners your URL, and how folks can find your organization if they want to learn more?

Robin Dubin  22:53
Sure. AliveandKick’n is at aliveandkickn.org. And that is spelled a-l-i-v-e-a-n-d-k-i-c-k-n dot org. We have a lot of patient education and resources for patients on our website. We have a Facebook page. And we have things like videos that we have produced with patient stories and other information from our previous Living with Lynch Patient Workshops. We have, we just launched our 2023 virtual patient community discussion series. First live, virtual patient community discussion will be coming up in May. And we’ll have I think three – May, June and July – patient community discussions on specific topics. And you can go to our website and sign up to and register for those. We are working on organizing our 2023 Living with Lynch Patient Workshop in the fall of 2023. We’ve got marathon, New York City marathon runners this year for the first time, and where, we have a lot of resources, including things like links to the PREMM risk assessment model that Jordan mentioned, we have that on there. We have links to the NCCN screening guidelines, and several other outside resources. And then we have all our own resources, including the ability to sign up for the patient registry and provide your information into our registry and things like that.

Kim Thiboldeaux  24:39
Right. Wonderful. Robin, thank you so much. Robin Dubin, Dr. Jordan Karlitz. I want to thank you both for joining on the podcast today. This is The Cancer SIGNAL presented by GRAIL. I’m Kim Thiboldeaux. Please rate our podcast or leave a review and subscribe to learn more about the impact of early cancer detection on future episodes.


Important Safety Information
The Galleri test is recommended for use in adults with an elevated risk for cancer, such as those aged 50 or older. The Galleri test does not detect all cancers and should be used in addition to routine cancer screening tests recommended by a healthcare provider. Galleri is intended to detect cancer signals and predict where in the body the cancer signal is located. Use of Galleri is not recommended in individuals who are pregnant, 21 years old or younger, or undergoing active cancer treatment.

Results should be interpreted by a healthcare provider in the context of medical history, clinical signs and symptoms. A test result of “No Cancer Signal Detected” does not rule out cancer. A test result of “Cancer Signal Detected” requires confirmatory diagnostic evaluation by medically established procedures (e.g. imaging) to confirm cancer.

If cancer is not confirmed with further testing, it could mean that cancer is not present or testing was insufficient to detect cancer, including due to the cancer being located in a different part of the body. False-positive (a cancer signal detected when cancer is not present) and false-negative (a cancer signal not detected when cancer is present) test results do occur. Rx only.

Laboratory/Test Information
GRAIL’s clinical laboratory is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and accredited by the College of American Pathologists (CAP). The Galleri test was developed, and its performance characteristics were determined by GRAIL. The Galleri test has not been cleared or approved by the Food and Drug Administration. GRAIL’s clinical laboratory is regulated under CLIA to perform high complexity testing. The Galleri test is intended for clinical purposes.