Intro: Welcome to Precision Pathology Podcast, featuring interviews with authors and global thought leaders who are at the forefront of technological advances in precision diagnostics and therapeutics. Your host is Dr. George Netto, the Simon Flexner Professor and Chair of Pathology and the Laboratory Medicine at the University of Pennsylvania's Perelman School of Medicine in Philadelphia. Here is Dr. Netto.

George Netto, MD (Host): Greetings from Philadelphia. It's such a pleasure to welcome my guest today, Professor Matija Snuderl, Professor of Pathology at NYU Langone Health. He serves as the Director of Molecular Pathology in that great institution. More importantly, he's a leader in the field of neuro-oncology with the molecular aspects of neuro, where his team was really instrumental in describing many subtypes, novel subtypes of brain tumors based on molecular classification.

As you all know, the WHO is moving that direction and, really, CNS tumors are the lead besides heme-path and these molecularly defined. Matija and his team has been tremendous in that regard. He's also an expert on methylation profiling where he contributed to the use of that classification in CNS tumors, and also branching out. We were discussing before that we went live on his paper around the role of these classifications, even in renal cell carcinoma. So, these fields just keep going. And today, I wanted to welcome him to discuss a recent publication. So, thank you, Matija, for accepting my invite.

Matija Snuderl, MD: Thank you, George, for inviting me. It is the second time we've talked together about the research, and it's always a real pleasure to be back and talk science with you. I'm excited about that today.

Host: Wonderful. So, we're going to talk today about your September 2025 publication on the role of TERT promoter mutation in meningioma in terms of predicting prognosis. It's, in my opinion, the kind of study that is potentially practice-changing. So, I would like to start by giving us a little background about TERT promoter mutation in meningioma. What's the gap and why did you do this study?

Matija Snuderl, MD: Thank you for focusing on this paper, because many people forget that meningiomas are some of the most common CNS tumors. And in terms of pure numbers, they outnumber primary gliomas. And although many meningiomas are low grade, just because of the sheer number of patients with this disease and morbidity associated with it either requiring surgery or radiation, they claim a high number of lives. And TERT promoter, obviously, I'm sure it's familiar to most of the listeners for this podcast. Because really, it's one of those mutations that is across melanoma, gliomas, and also meningiomas. And it's been a few years now that people in neuropathology community have been trying to figure out how to best utilize the presence of TERT promoter mutation for more accurate diagnosis and grading. I would say really it started with the gliomas. But then, eventually, with the most recent WHO, trickled into classification and grading of meningiomas. and that really was the beginning of our journey, trying to understand better what is the role of TERT promoter mutation in meningioma.

Host: So currently, if I understood correctly, I have a tremendous interest in TERT promoter. I'll add bladder cancer because that was during the work with our team at Hopkins, we realized that was the most common alteration in non-invasive bladder cancer and has the potential for early detection and what have you. But I did not know, because I don't do brain tumors every day, that TERT promoter now is part of the grading. Can you expand a little bit on that? How does it play currently?

Matija Snuderl, MD: So,I always say that mutations are a little bit like a real estate in New York, right? It really depends what is the location, right? What is the tissue in which mutation is happening? And I often go back to one of my teachers back in medical school, who in my first year of medical school told every one of us that the worst career that you can do as a medical student is to become a pathologist. That was in the late '90s, right? Early 2000s. So, he was actually a visionary because he believed that, one day, there will be machines that will be able to sequence every tumor and we will not need pathologists and their silly microscopes. We'll just need to know what the mutations are and, based on that, we'll classify all the cancers.

So, he was right in the technological aspects. We now have the machines to sequence everything. But he was terribly wrong, I would say, in the implications of that because we know that TERT promoter, as you mentioned, and BRAF is another example I often talk about, you can have a TERT promoter in oligodendroglioma, which is a very low-grade CNS tumor, everything considered. And you can have it in a glioblastoma, which is the most malignant CNS tumor. And you can probably give multiple other examples across the human body.

And when TERT started emerging as a biomarker, there was several studies that identified TERT promoter mutation in aggressive meningiomas. And I'm sure we're going to talk a little bit like selection bias and how these studies come to light and how they have impact on classification. But before the last WHO, there seemed to be a good body of evidence saying, "Look, TERT promoter occurs in high-grade meningiomas." And WHO has really made this, I think, an incredible leap to say we need to incorporate molecular testing into the grading. Histology alone may not correctly represent how the tumor will behave, and decision has been made to incorporate TERT promoter mutation as one of the two molecular biomarkers, that would automatically upgrade tumor into grade 3.

It was a big leap of faith, I would say, considering all the studies and that has happened. So basically, then we started seeing tumors that had these mutations. We found these mutations. And then, what do you do with them when the rest of the tumor, when you look at it, it's completely low grade? That was really the driver behind the study.

Host: Very well put. I love it. And we actually can do a whole episode talking about why your teacher was wrong about how the revolution, the third revolution in pathology is really making it more relevant. And you just have to look at the number of applicants that want to go into Path. From Penn alone, last year, we had six students who went into pathology. Four of them stayed with us, and two went somewhere else, which is an incredible number considering a class of 150. Smart people are going into Pathology. But also, we need smart people in every specialty. But really, we're up there.

Back to the paper, you touched upon one of the questions because after-- and I don't want to ruin and tell the end of the movie story here before we watch it-- but the reality is it seems to be like, "Why were they wrong?" And you touched probably the structure of the studies, how big the studies was, where the biases that led to the premature incorporation of this.

So, let's talk about what I'm pretty sure is a very solid study, that's why we picked it. Tell us what's the material and method section basically in your study?

Matija Snuderl, MD: So, biomarker studies, I just want to preempt, are hard. The problem is, as you know, George, probably better than me, like when you have multi-institutional studies, very few people, unless they did it themselves, realize what an incredible effort it is to herd all the cats trying to do a big multi-institutional study. But they're absolutely critical, because there is so much bias that comes from cherry-picking cohorts from single institutions, right? So, I would say one of the main factors of this study is when we started discussing how should we do it, I was like, "Okay, the number one thing is it has to be big number. It has to be a lot of patients, so we don't have a bias, and it has to be really diverse across many different institutions because practice of neurosurgery and how patients do really influence the outcomes of patients." So, you have a surgery that is not aggressive and they don't remove all the tumor, tumors will recur more easily. Then, you have another institution where surgeons are very aggressive. Those tumors will not recur. And we have to have it really well-controlled.

The beauty of this study is really-- you have 14 institutions. They really span Europe and North America. You have almost 1500 patients that are included in the study. And most importantly, you have it across all the histological grades.

I think the poison in that decision to incorporate TERT into the WHO grading was that most of the studies were, in retrospect, it's easy to say it now, there was a selection bias. They sequenced tumors that were more aggressive; therefore, they were more likely to find TERT promoter mutation, and therefore they decided that all TERT promoter mutant meningiomas are aggressive. It turns out that when you really expand your study to all the histological grades, you realize that that's actually not true. That is really a selection bias. And I think it's an important study. And an important point of a study is to keep in mind, you really need to think your biomarker studies very carefully because the conclusion of those studies can impact management of patients down the road. Design size, diversity of institutions really matter on what conclusions you're going to be able to derive from the study.

Host: Excellent. So clearly, 1500 patients, that's an amazing number. I like it. Clearly, the question-- and then you stated that from the beginning-- the question that you were trying to address, is this association due to really TERT or is it because there are some confounding factors? Those who are TERT promoter-positive may have other molecular alterations. So, tell us what you found in that regard.

Matija Snuderl, MD: Yeah. If I circle a little bit back to our very beginning of our discussion, right, how does a project like this even start? And I think that's where really pathologists play a critical, critical role. Because this project in a big part originated because I've been looking at these cases, and I am fortunate to do molecular and neuropathology practice, and our neuropathology group is-- I just call us molecular neuropathology. I think every one of our neuropathologists is basically molecular neuropathologists. They all know molecular. All my colleagues practice with molecular in mind. And you look at these tumors that look grade 1, they have a low Ki-67, like 2%. And then, it comes back with a TERT promoter mutation. And you just feel it's wrong to call this tumor grade 3, knowing that this will immediately trigger radiation of a patient who had a total resection, has every other factor that's low grade. And that's what drove this idea. It's like, "Okay, we should really look if these are really grade 3, are these really aggressive tumors?" And we want to make sure that we control for all the variables.

I mentioned the clinical variables. Clinical variables are incredibly important, but we also wanted to control for other variables and, most importantly with them, was the other high grade biomarkers, CDKN2A/B homozygous loss, which was also in WHO, proposed as a high-grade biomarker. And that's something that I don't want to go into details. It's called the integrated grading, right? Integrated molecular grading. When you look at the copy numbers together with the histological grade Ki-67, you integrate everything together into the risk stratification, right? And once you put everything together and you do the analysis, it turned out that TERT was not the culprit, more like an innocent bystander, often in a bad circumstances, but not a primary culprit of aggressive behavior.

Host: To summarize the way I understood it, and correct me if I'm wrong, because most of our audience is going to be people like me who don't do these types of tumors every day. You focus on the TERTp mutant cohort, you looked at their overall survival, recurrence-free survival and turned out to be around 50% and 27%, respectively, which is really not dissimilar from those who are grade 3 and TERT wild type. Then, when with what's happening there, you realize that there is a very high rate of 1p loss. And these other markers that you mentioned, CDK through 8 was around 40% and 1p loss were around 70%. So, that's probably what's happened, is just marking those high rates of the  CDKN2A. And when you focus on that and you did multivariate, it turned out to be the cyclin-dependent kinase 2A is the one really that is associated with high risk. It sounds like the HR was around 3 for overall survival and five times more likely to recur. So, the recurrence-free survival was very poor in that cohort. That's, I imagine I'm stating correctly what you found and that's why you're coming into the opinion that we shouldn't be using TERTp now.

Matija Snuderl, MD: Your summary is absolutely correct. What basically it turned out is that if you looked at grade 1 meningiomas with TERT promoter, there was really no difference between grade 1s with TERT promoter mutation and without TERT promoter mutations. So, grade 1s or grade 2s, once you started adding other molecular aberrations, then it turns out that those are more malignant tumors and that's when the CDK-8 really kicks in and the 1p loss and so on.

So yeah, it's really a combination of different factors. But the major point is really, you should not be using TERT promoter mutation as a biomarker to upgrade tumors, right? And it's not just an academic discussion like, "Oh, did we do this or that?" It has really serious implications for management because if you call a meningioma grade 3, you don't really give a radiation oncologist an option. You're basically telling them you need to radiate this patient, because otherwise you're dealing with a very bad disease. So, it plays an incredible role what kind of grade we assign to these patients.

Host: It's exactly why pathology is important. We're exposing that person to radiation through the skull. And really, that's not something trivial. So, we have to do it right. And, incidentally, and I'm sure you know that, is we're going right now through the WHO, working on the sixth edition of the CNS literally this week. We launched it. And I'm going to be a proponent based on your paper that this needs to change back. So, that's the kind of seminal studies that really drive the evolution of the field. So, I'm really grateful for your study and for your leadership as a pathologist, herding cats, as you mentioned-- especially when the cats are Mass General and many major institutions, Yale and others is not easy, Brigham. And it's not easy to convince people to come around the table and do a study like this. So, this is wonderful.

I wanted to give you a chance to make a really poignant comment on the first author of the study.

Matija Snuderl, MD: So, I'm really glad you mentioned it. So, this paper is really a labor of love between three people. It was me; my co-author, Dr. Bi from Brigham and Women's who really spearheaded a lot of great work in meningiomas. But it was this medical student who actually came Boston, Karenna Groff, who was the first author on this study, who has really worked years putting together this incredible cohort, working with all these institutions and did just an incredible amount of analysis.

And unfortunately, this paper is both incredible accomplishment of this group of people, but also a sad story because, unfortunately, Karenna passed away tragically before publication of this paper. And it's the best we can acknowledge her contribution to this, is really to keep working in the same way as she always did with an incredible degree of enthusiasm, professionalism, and dedication to patients with brain tumors.

Host: God bless her soul. This is such a sad story. And really, kudos to you and the team for carrying out her work and making sure that this publication, this seminal publication that sounds like she contributed tremendously to its success, made it to Lancet Oncology after her passing.

Matija Snuderl, MD: It's one of those pleasures of academia, as you know better than me, is meeting incredible, talented young people who want to make a difference, and then really making that difference. And it is sad when you don't see them enjoying the fruit of their labor. But it was a great team effort. Everybody was incredibly dedicated, including Lancet Editorial Office, to see this paper come to light in her memory.

Host: An impact she left for sure. Thank you all for listening. It was really a pleasure, Matija, to discuss with you this seminal study again. I look forward to your future work. I'm sure there's going to be a third time on a podcast. It won't be that long, knowing how productive and how dedicated you are and the great team that you work with.

For our audience, see you next time and please feel free to send us input on this episode or any episode, how we can do better. We hope you were engaged and learned a lot from this podcast and future ones.

Matija Snuderl, MD: Thank you so much for having me on the podcast. Appreciate it.

Outro: We would like to extend our sincere gratitude to today's guests for their valuable contributions and thoughtful perspectives. We also wish to thank our dedicated production team and the technical team at DoctorPodcasting. Special thanks to Jennifer Vepler for her dedication and skill in coordinating our episodes.

Please note the opinions expressed by our speakers are their own and do not necessarily represent the Perelman School of Medicine or the University of Pennsylvania. Thank you for listening, and we look forward to welcoming you back for future episodes.