Intro: Welcome to the CGA-ICG podcast series, brought to you by CGA's Education Committee and made possible through the generous support of our sponsor, Lynsight. Each episode aims to bring you an in-depth discussion related to emerging data, clinical challenges, and unique perspectives in the world of hereditary GI cancers.

Before we start, we'd like to remind you that the content of this podcast is not intended to replace professional medical advice, diagnosis, or treatment, and the content reflects expert opinion at the time of recording. Keep listening to find out more about this episode's Host, guest and featured topic.

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Emma Kiel (Host): Hello, and welcome to the CGA-IGC podcast. My name is Emma Kiel. I'm a Genetic Counselor at the University of Chicago, and I will be your host for today's episode. This is the third and final installment of our research collaboration series. Today I have the pleasure of welcoming Melyssa Aronson and Lucy Stengs, who work at the Hospital for Sick Children in Toronto.

Melyssa is a Genetic Counselor, and Lucy is a Clinical Research Project Coordinator. Today they're going to tell us about their experience with the International Replication Repair Deficiency Consortium. Their group published findings from their cohort study in Lancet Oncology in May of 2024. The CGA-IGC Education and Research Committees reviewed this paper in our first 2025 webinar Impactful Papers of 2024.

So be sure to check this out on the website as well as episodes one and two of our research collaboration series. I want to hand it off now to Melyssa and Lucy. Could you guys please introduce yourselves and tell us about your roles in this consortium?

Melyssa Aronson, MS, CGC: So I'm Melyssa. Thank you so much for having us, Emma. I'm a longtime CGA member, so it's exciting to be here. I am a Genetic Counselor, as you mentioned. I work at two registries really, one at Mount Sinai in the Zane Cohen Center, and I manage that registry, and then I'm the lead counselor at the International Replication Deficiency Consortium at SickKids, and my role is really to work on anything clinical.

So I review all the families to see if they meet criteria for CMMRD. I'm involved with sort of clinical studies, looking at surveillance, looking at diagnostics, looking at GI issues and also interacting with patients. So counseling patients, speaking to other clinicians about their patients from around the world. So that's kind of my role in this.

Lucie Stengs, BSc: And hi Emma. My name is Lucy Stengs. Very nice to meet you and thanks for having us on. So as you mentioned, my role is Clinical Research Project Coordinator. I'm actually employed through the Hospital For Sick Children or SickKids, specifically under Dr. Uri Tabori, who's the PI of our study the International Replication Repair Deficiency biobank, and now consortium and a hundred percent of my time is dedicated to the consortium. So, I essentially bridge the gap between our lab-based discoveries and the clinical impact that these can have on patients and families and doctors who are dealing with C

So, a lot of the goings on includes emailing back and forth, sample acquisitions, a lot of administration, and just coordinating all that needs to be done with a large rare disease registry.

Host: Great. Thank you. It's great to have you both. Now, this is a massive collaboration. Can you guys tell me about how this got started and what your primary objectives were?

Melyssa Aronson, MS, CGC: So I'll take this one since I was there from the beginning. So it really started with two hospitals, as I said, Mount Sinai Hospital in Toronto and across the street is the Hospital for Sick Children, where if you're under 18 you get treatment at SickKids and then adults move on to the adult clinic.

And so normally we wouldn't see kids at Sinai. But in 1980, Dr. Zane Cohen and Dr. Steve Gallinger started a registry to follow hereditary GI cancer families at Sinai. So we were already seeing kids with Polyposis, FAP and JPS, and by the late nineties, early 2000s, we had maybe five families with C-M.

In the meantime, at SickKids, there was a very large brain cancer registry where they were collecting samples on brain cancer. They were absolute experts at it. Dr. Uri Tabori and. Dr. David Malkin, Dr. Eric Bouffet. And they were noticing C-M-M-R-D coming up in the Brain Cancer group, which is a little different than the hereditary GI group.

And so originally we came together, Dr. Tabori, Uri and I, and our team and Carol Jarno, who's a pediatric gastroenterologist and said, let's try and all work together. So we started by collecting all the samples at in the Mount Sinai registry for the kids. And the objective was really to try and learn more about C-M-M-R-D. It was such a rare syndrome. We wondered how common it was. We wondered how many families there were. And we also wanted to invite families internationally to send us information so that we could get a better handle and understanding about C-M-M-R-D.

Emma Kiel (Host): You mentioned these samples. What were you collecting and what were you doing with these?

Melyssa Aronson, MS, CGC: So we were collecting blood samples and also tumor samples. And we had a biobank at Mount Sinai, so we were storing them there. And I was basically almost single handedly recruiting all the families, entering all the data, going through every screening, which is a lot when you have CMMRD, you have scopes every three months or so, and they get a lot of polyps.

So I was gathering all the data and eventually it did come to be that it was a little bit too overwhelming for us to do it at Sinai because, we just weren't set up to follow, the brain cancer. We have to really think about what data you're collecting, how your database is set up, and the biobank.

And we were set up for hereditary GI mostly, but Uri is the expert at brain cancer and we actually thought it was a much better fit just to have SickKids take the lead on the registry or consortium. So, maybe around 2010, 2014, we ended up transferring all the data over to SickKids and they began what started as a B-M-M-R-D consortium at the time it was called.

And they hired some more staff. They hired a coordinator. They designed their own database. They had their own biobank there, and they started collecting more samples through SickKids. So it was a very interesting evolution from our registry to SickKids and why we had to do that.

And sometimes you have to realize this is outgrowing what we're able to do and changing the focus of our already very busy GI cancer registry. So we need a dedicated group to do just C-M-M-R-D at the time, which has now grown again into all replication repair deficiency syndromes because there is a gray line in kids, some assume are CMMRD, some really have Lynch, some have P.

And so that also grew to be much bigger than we thought. So Lucy probably can talk about what samples they get now, because I'm sure it's evolved since our early days.

Lucie Stengs, BSc: I think the biggest evolution, in moving from F-G-I-C-R and the Zane Cohen Center over to SickKids was, the fact that it went from being a Canada based study to this international scale.

We had our neuro onc leaders who had a lot of connections in lower middle income countries like Pakistan and all across the Middle East. And we were seeing that this, autosomal recessive disorder was very frequently seen in these communities. And so, we had to be able to execute storage and shipping and all of the administration on an international level and be able to store these biological samples and clinical information longitudinally, in a database and in a biobank, as Melyssa alluded.

So, it just became necessary to have this biobank to facilitate the research, that now is foundational to the consortium.

Melyssa Aronson, MS, CGC: Like, I think one example was, I think at the beginning we got, you know, purple top tubes from people locally. And now we needed to figure out how do we ship blood from around the world. It's probably not stable enough in just your regular old EDTA purple top tube. And so Lucy and the whole team had to figure out how do we do this? How do they ship it in areas where it's much more challenging? How do we get genetic testing done in other countries where it's maybe not as available?

How do we get all of the records from pathology because they have such a big team of doctors. So it ends up being a huge collaborative group and a lot of coordination from the team.

Emma Kiel (Host): Got it. So I mean, this really started locally and then grew. So how did you recruit collaborators from around the world?

Melyssa Aronson, MS, CGC: So at the very beginning when we began, we really wanted to know sort of how common it was. And we were fairly well known at the F-G-I-C-R and Uri and the neuro-oncology group was really well known at SickKids. And we basically just said we have this many families. We probably started with five or 10 families.

I think we published pretty early on some of the findings that we had. So there were some publications to show our interest and then people started sending families to us because we were very interested and we did a lot of other things, and I think Lucy can probably elaborate, but there was a big symposium where we invited people internationally to Toronto in 2017 just to talk about the consortium and what our aims might be as a very large group. We are also incredibly collaborative. So if there's a study that wants to be done in Jordan, or a study that wants to be done in Egypt, or a study that wants to be done in the states or a case report, we always ensured that we were collaborating with all of the co-authors and all of the primary sites so that everybody gets to be on the publications.

And that's why our authorship lists are usually gigantic because there's a lot of people involved from around the world.

Lucie Stengs, BSc: Exactly. I think Melyssa made a really good point about how it kind of became this self proliferative network where by word of mouth it would travel. You would have one doctor at a hospital who was aware of the consortium and they would tell their colleagues upon diagnosis or suspicion of C-M-M-R-D, that we were in existence and that we were willing to help.

One thing that really helped was having a funding source so that the burden of cost of testing or cost of shipping or, even the burden on patients of what exactly we were collecting, was very low. So it was very feasible for people to become involved in our study and to send us samples.

There was also the addition of novel therapies. So the consortium is kind of involved in two arms. We have a diagnostic role where we're helping genetic counselors and doctors confound the CMMRD diagnosis. We're doing functional assays, we're reviewing genetic test results and so on. But we also are managing tumors.

And, a big thing that came about in the process, was immunotherapy and access to immunotherapy. And so, if we could provide testing for a doctor anywhere who had no means of validating that their patient could benefit from this therapy and get access to that therapy through insurance or what have you, the consortium could serve that effort and assist in that way.

And that became, I think, a huge insight and benefit to doctors becoming involved in the consortium along with publications as, Melyssa shared. But yeah, as soon as we started identifying new tools and implementing these new projects, people became very interested in their involvement because they could see the benefit for their patients and for their centers in general.

Melyssa Aronson, MS, CGC: I think we were also invited to speak at different conferences. So, when we went and we always were willing to do that, submitting abstracts, publishing papers, doing presentations. You know, we basically presented our data to show here's what we're doing. And, the team there came up with a test that was able, a functional test to see if someone might have CMMRD.

And as you might know, it's quite a complicated diagnosis. It's not completely clear just through germline. So we often will get emails to say, my patient has a VUS and a pathogenic variant. Do you think they might have C-M-M-R-D? And so we're able to offer this functional test for free and we're able to work with the family.

So people also came to us for help with their families. They came to the team at SickKids to say, okay, this is a tumor. What do we do? What immunotherapy, how long should they be on immunotherapy? Do you give immunotherapy to healthy patients? All of those questions are things that the team at SickKids were always willing to reach out and talk about with families.

So, I think being a collaborator and a support to clinicians knowing that they're in charge of their patients, and that's not our role, but we're here to support them and do whatever we can to support their family, makes it a much more collaborative effort because they feel more part of our team, and then we can support them in any way that they need.

Emma Kiel (Host): That's really cool. I guess I wasn't aware of what a great resource this was for patients around the world. Tell me about funding and support. How did you get money to do all of this?

Lucie Stengs, BSc: So obviously we are a large study. We have required several funding sources over the years, and actually each of our individual research projects or research interests requires individual funding or several forces of funding combined.

And so it's always a struggle at reporting time to decide which projects are associated with which cost center. But, we make it work. So, the biobank and sequencing costs is kind of one thing. We have foundational supports, the coordinators, the salaries of all the people involved. Most of these come from either large or small scaleable funding organizations or patients, even families who are supportive of our initiatives. So to shout out a few, we have the Meagan Bebenek Foundation, the Live Wise Foundation, the Harry iac, Hall Foundation, and all of these have provided us with the funding to get through our daily operations.

And then, of course, on a research grant level, we have large funding agencies who we are reapplying and renewing with kind of big government ones that you'd be able to recognize, to do this project.

Emma Kiel (Host): Now, Lucy, you're responsible for a lot of the administrative part of this project. Tell me about oversight, data use agreements, how this works with IRB.

Lucie Stengs, BSc: Yeah. So, the various aspects of our consortium all have, like I said, kind of different costing sources and funding sources. And they also have individual IRB approvals. So this allows us to advance each project at a different rate, whether it's focused on diagnostics, on treatments, on surveillance; they all have independent goals and individual requirements from patients and in research ethics

 As you know, we run one of the largest biobank in the world for RRD patients. And this itself has its own IRB. So, we're frequently working with the IRB to make sure that we're doing everything in a manner that is respectful and considerate of patient autonomy.

With this, we actually work with our patient advocacy group who are very well informed on the matters of patient ethics and they can ensure us that the patient perspective, particularly the C-M-M-R-D patient perspective, is incorporated into our research questions. We understand that surveillance is already very burdensome.

A lot of them are already dealing with a lot of appointments and a lot of blood draws, and a lot of tests going on. They're not only registered to our study, they may have a clinical trial or other things available at their local hospital. And so, when we need to make amendments to our study protocol or renewals to our IRB, we increasingly involve the patient advocacy group to make sure that what we're asking, the frequency of samples, the frequency of studies are all in line with.

And that makes our approvals obviously go a lot smoother. When we need to work with other institutions, so that's like our material transfer agreements, MTAs or DMTAs; there's a lot of back and forth that happens understandably. We make sure that the protocol is consistent between our hospital, our center, and the one with which we're working.

This can often be problematic because different places have different standards and different language that they use. And so it's a lot of legal. We have a legal department here at SickKids that reviews all of our agreements. And so oftentimes it's kind of out of our hands and waiting for signatures.

But we do a lot of the initial drafting. When we run into challenging times, we don't get thrown off. We just kind of figure it out. Follow up emails are very important to making sure that we're doing things like in a timely manner and that everyone is happy with the results. But definitely navigating regulatory requirements in different regions is very challeng.

And to those who are thinking of starting a consortium of their own on an international scale, I would just say not to be discouraged because ultimately your goal and the goal of these agreements is to protect patients and protect their information. And so it's all in good faith. And when it gets through, it'll be worth all the time and effort and follow up, that it took.

Melyssa Aronson, MS, CGC: I'll also just add that we really encourage collaboration with other centers. So if they have an idea for a study and wish to use our biobank, samples or our data, we certainly want to work with other people, so we do have a lot of people approach us with their own study ideas. And I'm sure at the beginning it was people writing me or Uri saying, Hey, I'd like to look at this. What do you think? And then we would work on, you know, IRB with them. Now there's an advisory committee. So if people submit ideas to us, there's a group of advisors that would have to review the submission and we take a vote on whether we approve it or not, based on the scientific merit of it and whether we have available, biospecimens for them and so forth. So there's a much more tailored way of approving studies now than I'm sure there used to be back at the beginning days.

Lucie Stengs, BSc: I'll also just add on the note of the biobank that there are published guidelines for biobanks. So we use the CTR net guidelines, and so we are routinely checking in with them to understand the storage, and the processing are all meeting those guidelines.

Because ideally we want this to be a resource for centuries. And so in order to do that, we have to make sure that we are following the guidance of those who have done the research and know exactly how to build such a amazing foundation.

Emma Kiel (Host): Now you mentioned, hosting some symposiums in the past, and I know that, a lot of the idea of this consortium was kind of mutual collaboration, but how else did you keep people involved?

Lucie Stengs, BSc: So I've already mentioned our patient advocacy group. They are amazing. They are four women, two of whom are, you know, direct familial relation kin to C-M-M-R-D patients, and two who are actually just from the kind of brain tumor world. And they play a huge role in outreach and writing letters of support for our funding. One of them has her own foundation through which she collects independent funding from the consortium and uses that funding to attend various PA conferences and provide her perspective. And she ends up meeting a lot of people in that way. And that's actually how we get a few patient centered referrals to the consortium. We do educational seminars.

So we try to run these twice a year in cycle with our newsletter. So, first quarter we'll do a newsletter. Third quarter we'll do a newsletter. And second and fourth we'll do a seminar. This is usually a virtual format. We open it up to physicians and families, with the aim of presenting research findings, but also doing it in a way that patients and families can feel comfortable, understanding and asking questions and being mindful of course, that the data that we're showing is, you know, optimistic and presenting things in a positive light rather than survival curves and these things that can be very daunting.

And, as well, we were aware that, we're not working on it through the consortium, but we were aware of kind of circles outside that exist on social media, where patients are finding one another, supporting one another, and going through what is now becoming very frequently a transition into adults with C-M-M-R-D and supporting each other and perhaps independently advocating for themselves amongst a new set of doctors in a new hospital as they age out of the pediatric setting.

Melyssa Aronson, MS, CGC: I think also as a genetic counselor, I'll recognize things that I have a lot of questions about. So for example, early days I used to wonder how common with small bowel cancer. We didn't see that as often in CMMRD. So we did a study on that and we didn't have great diagnostic criteria, so we actually formed a big collaborative group to come up with the diagnostic criteria for C-M-M-R-D. I remember giving talks at CGA about, how you could have a VUS and or two VUSs or even just one pathogenic variant and still have C-M-M-R-D, or there's atypical CMMRD where people are presenting as adults. And so giving these presentations at CGA, I would have a lot of people come up after going, I think I have a case like that.

Let me talk to you about that after. And then they would get in touch. So, being curious ourselves and then, trying to answer questions that we think other clinicians would know or would want to know about surveillance. Right now, I have a lot of questions about brain cancer in kids and is it really Lynch syndrome or is it really C-M-M-R-D?

And I'm sure a lot of clinicians would like to get an answer. We're, did a big project on that. Also, just I'm now looking at incredibly complicated cases with Lucy and we're like, we don't know how to call this. It is giving us different information and it's not clearly CMMRD, but it's also not, clearly not, and it would be nice to actually present those cases.

So there were things that were looking at and we're like, okay. If we're questioning and struggling, I bet there's a lot of others. And it's true. When we go to the conferences and present these, that also, brings a lot of interest. And then we also send newsletters out to say, here's everything that we've learned so that you're up to date, as much as we're up to date on all of the information in C-M-M-R-D and other replication repair deficiency syndromes that we now do.

Emma Kiel (Host): You've mentioned this question about small bowel cancer in patients with C-M-M-R-D and some of these other complex cases. Tell me a little bit about some of the ancillary studies and kind of secondary objectives that have come out of this.

Melyssa Aronson, MS, CGC: I would say at the very beginning, our goal was really to look at how common or rare this was, what they really looked like, what the cancer risk was, and is there any genotype, phenotype correlations? Have there ever been MSH2 CMRD which there have have, there have been mlh1 and there have, or EPCAM, and there have. So at first we're sort of looking at that.

It then moved into how do we try and help diagnose people who are unclear, the 33-year-old who presents, which never used to happen. How do we diagnose and figure out if that's really CMMRD or not? And moving more into sort of complex things, now that our patients are in their twenties and thirties, what cancers are they at risk for?

How do we screen for them? We just met a family the other day and we're still trying to understand, as our patients are getting older, what that means. Looking at surveillance in countries that don't have all of the tools, so they might not have capsule endoscopy or MRE to look at the small bowel.

So how do those countries screen their C-M-M-R-D patients? And then as Lucy said that we're also moving into other things, looking at treatment and immunotherapy, can you give preventative immunotherapy, which you can't, but there are studies looking at that and expertise looking at that.

So I would say those are some of the areas that we're moving into. And you might know more, right, Lucy?

Lucie Stengs, BSc: Yeah, so I think when it comes to developing new tools, particularly in diagnostics, this is something that has always been at the root of the consortium. You know, as I mentioned earlier, we have this huge population of patients in lower middle income countries, and the availability for next generation sequencing, it's getting more frequent, but it's not something that every patient is getting.

And it's also deals with social stigmas. Like not everyone there wants genetic testing. And so we offer tools that are based on low read, low coverage, genetic sequencing that can be very informative in the context of C-M-M-R-D, but might not might not find things that they don't want to find.

We have a tool called Logic that looks at microsatellites specifically. So we know that, mismatch repair has a microsatellite signature and we've been able to produce an algorithm that goes off one X genome. So a normal genome is 30 x, a normal exome is, you know, 200 to 250 x. So we're looking at very, very low coverage sequencing and we've been able to find a threshold that we can accurately detect C-M-M-R-D in blood or R-R-M-M-R-D in tumors.

And that has been hugely, hugely beneficial to the consortium in corroboration with things like immunohistochemistry to deduce whether a patient or tumor is mismatch repair deficient. And, in our Lancet paper, which, you mentioned earlier, we looked at the effect of missense versus frameshift variance.

And that was a huge interesting finding for us as well in terms of identifying possibly new mutations that could be causative in mismatch repair.

Melyssa Aronson, MS, CGC: I think also with the advancement of molecular signatures in tumors and doing molecular work on tumors, we're also looking at cosmic signatures, tumor mutation burden, molecular profiling of the tumor, and seeing what is common in C-M-M-R-D patients versus a POLE patient versus a Lynch patient to say, okay, this brain cancer is much more typical for C-M-M-R-D or not usually seen in CMMRD. And it gives us, not necessarily a diagnosis, but a hint that this might be, and sometimes we need all these hints because the family isn't completely clear cut for us. So there was a day where we thought, you know, a 10-year-old with a glioblastoma and an MSH6 mutation, there's no way that's Lynch syndrome.

Now we know it. Yeah. It, it is Lynch syndrome and we've only been able to figure that out by using every tool in our toolbox and our experience in seeing enough patients, which you would never see unless you're in a big consortium that invites people from around the world. You just don't have the experience that you would need to get in one clinic with one patient.

Emma Kiel (Host): Do you guys foresee a vaccine trial in C-M-M-R-D patients in the future?

Lucie Stengs, BSc: So, yes, thank you for the question. It is absolutely the frontier of where our research is going right now. The consortium, and I should say Dr. Uri Tabori's lab. You know, we have a lot of Master's and PhD students here through the University of Toronto who are focusing on this project.

So, t through the consortium, we have this massive collection of patient tumors, right? And what we know about these tumors is that 99% of them are ultra hyper mutant. That is, they have a massive amount of mutations in their genetic material. And so now our question has become okay in cases where immunotherapy has been responsive to the cancer, how can we prevent a cancer, from recurring or possibly ever occurring in the first place. And so to do this, we're looking at common mutations between all of our tumors and then testing these in mouse models and in tissue culture. We're co culturing vaccinated immune populations with tumor cells and we're looking at whether the tumor cells are dying and what's the immune response.

So definitely something that we are hoping to accomplish and I think we'll know in the next three years whether this is something that's really feasible. And Melyssa can comment, it's something that they're doing in Lynch syndrome.

Melyssa Aronson, MS, CGC: I mean, you probably know this too, Emma, there's research studies looking at vaccine in Lynch syndrome and, whether that's going to be clinically possible of some of those data hopefully will be coming out soon, but it looks promising.

The same idea in C-M-M-R-D. I think whenever we talk about immunotherapy and vaccines, we always balance the benefits and, and limitations, especially for immunotherapy. We want to make sure people don't have autoimmune response that we're not going to be able to give them immunotherapy because their immune system's already attacking their colon, their heart, their pancreas and other areas.

We don't want to cause more harm. So, one of the things that we have to balance is the harm versus benefit. And I think we actually have done a lot of work in the consortium using animal models and fish and other things like that Zebra fish to look at, how these genes and mutations impact, to see if we could bring it to trial. But that is the hope of the consortium for sure.

Emma Kiel (Host): Wow, that's really exciting and it's going to be huge for these families to have that, possibility in the future. I want to switch gears a little bit and talk about lessons learned and kind of unforeseen issues that came up with this and how you went about fixing those.

Melyssa Aronson, MS, CGC: I think the first and biggest lesson was when it was at Mount Sinai in our registry and the growth, the exponential growth that occurred, which was maybe we should have foreseen it, but we didn't. So just knowing, you know, there was only so much that I could do running an already very busy F-G-I-C-R, and then figuring out what is our needs?

 What staffing do we need? What database do we need to create? How do we do this? What is the ethics for even talking between our two hospitals, we need an MTA and a DTA just to go between Mount Sinai and SickKids. And how do we do that in a way that's ethically sound? Figuring out consent forms, which at the Hospital for Sick Kids is daunting.

They have very big consent forms. And sometimes also figuring out how do we recruit people into more than one registry, as Lucy said. They're sometimes bombarded with more than one, but sometimes they fit into the adults GI Cancer Registry and the C-M-M-R-D registry. So, those were some of the initial questions that we had.

And then diagnostic became a big problem. We didn't really know how to call C-M-M-R-D, which we needed to be able to do in order to analyze so that we actually created a diagnostic criteria, which has been very successful for us. We needed tools to figure out, okay, if we're on the fence, we were mostly using germline and IHC, and that wasn't enough.

So we needed to develop a new tool, which we've used for logic now. So all of those things had to be learned and the team has really grown at SickKids. I mean, it is huge. Now with more neuro oncologists, you need people from all different disciplines, gastroenterology, neurology and now breast cancer, gynecology, urology, because this syndrome can impact so many different organs of the body.

And then the patients, you know, at the beginning I remember patients would say, is there anyone I could talk to? And there, wasn't really, because the kids all passed away young and the parents were all in mourning and how do I do a support group for grieving parents? And that really became very educational that the parents wanted, at whatever stage it was.

I always used to worry, what if someone has a child going through this and they're going to go into a support group and everyone has just lost their children? And maybe that's not a healthy group for them to be in. And luckily we have now, so many more patients that we're able to match them a little bit more appropriately.

And we can also learn a lot from patients. So the patient advocacy part, which maybe we didn't do 25 years ago, as much as we do now, that takes us a long way in patients saying, you may have thought that that would be hard for us, but that is what we want. And so knowing those things have been great learning experiences.

So I would say from the clinical part, that's some of the things, and there's still unanswered questions clinically that I'd like to know. So I just continue working on, when I'm curious about something, I figure everybody's going to be curious about it too.

Lucie Stengs, BSc: Then from the kind of administrative side, unforeseen circumstances, I mean, our first REB was approved for a hundred patients.

Like we thought this was a rare disease and our most recent amendment is for 800 patients. So that I think, speaks volumes to how we thought this was a rare condition. We were focused on, we called it B-M-M-R-D, we were focused on one syndrome, and now we use the International Replication Repair Deficiency Consortium, it's an umbrella term.

It includes all forms of inherited or totally somatic or treatment induced Replication Repair Deficiency. We're a lot bigger in terms of the spectrum or the scope of cases that we accept or review or investigate in the consortium. I think also, when it comes to the testing, we've learned that there is of course, like a difference between what's considered a clinical test and what's considered a research test.

And when we are working with genetic counselors, we need to make sure that they have access to both, and that they have an honest and transparent understanding of what we were able to offer and how we're able to offer it. So a lot of the tests that we do are in the process or have been CLIA approved, but not all of them.

So when we are offering someone, for example, a logic test on blood that is still, considered a research test. And we'll follow a research timeline. DNA will be extracted in a research lab. It'll sit in a sequencing batch that has to be of a certain size.

It might take six months for them to get a result. And so if they're looking for a clinical answer, if they're looking for something that they can act upon and initiate treatment with we have to give them that realistic expectation and suggest an alternate pathway. So, because we're based at SickKids, we have relationships with clinical pathologists here.

And so, in coordination with them, we're doing all the CLIA approvals for our tools, but we also use them as our touchpoint. So we say, you know, this is how long it's going to take. And if. you are looking for our faster results suggest you send it clinically to this person, and they'll be able to get you a nice signed report that says at the bottom, this is a clinical report and you can store it with your patient files and use it diagnostically.

And then I think the last thing I wanted to touch on in terms of lessons learned was with regards to surveillance. So what we're asking is obviously very technologically advanced, and when we're saying a whole body MRI or a PET CT, these are not available everywhere in the world.

You know, here in Toronto, we are lucky to have first of all, a, a very accessible healthcare system and a very technologically advanced facility, and that is not available everywhere in the world. So kind of learning how to modify surveillance across various regions and in various disciplines.

Melyssa, if you want to expand on that.

Melyssa Aronson, MS, CGC: You bring up some really interesting points. So, first of all, first surveillance. I remember when we wanted to do a study looking at, colon cancer and polyp burden and small bowel. We literally got every single pathology report for every single scope and made sure we didn't miss one to review them all.

Count the adenomas, count the serrated polyps, count hyperplastic. I mean, it was a huge undertaking and when we say to people, you know, are they screening? Do they have polyps? Certainly people aren't giving us the tiny minute details that you would need to report that, and it would be virtually impossible to get all those medical records that aren't even in English in many times.

Many times we get reports that we don't understand. Somebody writes in English somewhere that this is, you know, something. So it is actually quite a challenge that you can't always compare apples to apples in the different groups. And I think it's also a good point about, clinical germline testing versus research testing.

There's been many times where I'm reviewing a family and I'm like, this is research. But did they validate it? Do they called it likely pathogenic? But according to gene reviews, it's a, a V-U-S. So that makes a big difference in the evidence that I would need for a diagnostic.

And Lucy and I have often changed the database to say, okay, we used to just say, here's the germline results. Now we need to clarify was this germline results by clinical test? Was this germline results by a research test? Updating the database has also been something that's constantly ongoing.

Also, things like NF1 features. So we would say, you know, let us know if somebody has NF1 features. So if they didn't say anything, does that mean they don't have NF1 features? And if they say they don't have NF1 features, is that because a clinical geneticist looked at them and said they don't have NF1 features or just like, you know, the surgeon says, no, we don't see anything.

So again, it's very hard to do studies with accurate data when we may not be getting completely accurate data. And so we know we have to ask these very specific questions. Do you see Cafe au lait macules or not? If you do, have many? Who found them, like, so then we at least have a sense of were they examined, who examined them, how many are there?

And it gives us a starting point to compare to everybody else. And we've changed our database many times to reflect all of these things, which is something that you're constantly doing in a consortium to keep the data accurate.

Emma Kiel (Host): Now for the people listening to this podcast who may have a patient that sounds like they have a replication deficiency or simply want to collaborate with you guys, how do they contact you?

Lucie Stengs, BSc: So when it comes to reaching out about a patient, I would suggest reaching out to the doctors who lead the consortium. That's Dr. Uri Tabori, or Dr. Anna Bandas. They are co-leads. We have a central inbox that's monitored by myself. Which is replication. Repair@sickkids.ca. And, I will, translate your email into our weekly rounds and make sure that you're responded to as quickly as possible.

When it comes to collaborations, you can follow a similar platform. We also have a website, replicationrepair.ca and there we have a contact form where you can submit your project proposal. And this will be eventually reviewed by our advisory board, which Melyssa sits on amongst many physician scientists.

And, we review those kind of on a regular basis and we look at how we can help each other. So it's encouraged, obviously, to use our biobank. We need to make sure that it's in the scope of something that we also have interest in and have understanding in, because we have a lot of things that aren't published and a lot of things that are on the back burner.

And that might be contradictory or that might be very complimentary. So it's important that we have a chance to understand and review, and Dr. Tabori and the team are very open to Zoom calls at all hours. So, yeah, you just contact us and we'll talk to you. And, Melyssa's obviously the best contact for patients and diagnostics so.

Melyssa Aronson, MS, CGC: If someone contacts me and they'll say, how do we get into the consortium? They might have questions for me as the genetic counselor. But then of course I always loop in Lucy and Anban and Uri and the rest of the team. They do rounds each week to review cases, and if people send in brain MRIs, they'll also review all of those.

I mean, they're really, really good at sort of sharing their expertise after reviewing all of these hundreds. We have hundreds now, CMMRD patients, so, they're welcome to get in any way they want, but we talk to each other all the time too in Toronto. So we'll get ahold of each other and get them to the right people.

Emma Kiel (Host): Excellent. Thank you both. As we wrap up, are there any last minute comments or pieces of wisdom for our listeners?

Melyssa Aronson, MS, CGC: I think it seems daunting at this stage where we are right now with hundreds of patients and all these grants and big things. But remember that we started as a small thing. We started with five families, probably or less, and had to learn. And had to grow. So if you're a center that wants to grow and learn about different rare conditions, I think it's fair to reach out. I mean, I know the last podcast was on gastric cancer and I'm glad that people reached out to me to say, do you have gastric patients that you can include, because we also have a lot, I think we really all have to work together. These are rare conditions and in order to really understand it. And that's what the patients want us to do. We need the numbers to look at enough people to say, these are the cancer risks, these are the screening, and this is where we need to go.

And C-M-M-R-D was certainly a condition that needed that international push to all collaborate together. And I will say the Europeans also have a very big group and we also, speak to them, of course. And so I think it's really important. We are all working with rare conditions, even Lynch syndrome.

Not so rare anymore, but I still think it's somewhat rare and not as understood. And I think it's really important to get to know the people in this area. I have never met anyone, first author on a paper who hasn't been willing to write me back and talk to me. You think that they're untouchable? They're not. They're often so friendly and kind and we're always welcome for people to reach out to us. As we said, we like, we'll literally call anybody anytime. So I think, if you have an idea, reach out to see how you begin, reach out to see if there's, any way we can help collaborate or have families like that.

There's enough rare syndromes that we all need to work together, I think. And, you just start small and start growing from there.

Lucie Stengs, BSc: And I would just add the note that if there are any parents or any families or anyone affected by this condition or a similar condition, or anyone who participates in a registry, we are so grateful for your involvement and for your contribution and everything that we do every single day is with you in our hearts.

And e wouldn't be able to publish in high impact journals or develop new therapies or diagnostic tools if it wasn't for consortiums and research studies and biobanks. So the next time someone approaches you with a form, I hope you consider it wholeheartedly and do your independent thought process of is this something I'm comfortable with, but also know that you are benefiting society overall and science overall by contributing.

So we thank you so much and wish you the best.

Emma Kiel (Host): Wow. Thank you both so much for telling us about this consortium today. The scope and timeline is incredibly impressive, so we really appreciate you both taking the time. With that we'll end the final iteration of the CGA Research Collaboration podcast series.

Please be sure to check out the first one on the Lineage Consortium and the second one on the CDH one multicenter study. And be sure to tune into webinars in May and July. Thank you.