 Good afternoon and welcome to our lecture series start today. My name is Charles Routime and I am the scientific director for the foundation right at NIH and I'm really You know glad today and happy to introduce our only named lecture series at our Institute the Jeffrey trained lectures in cancer research and I'm going to say you know a couple of sentences about Dr. Trent and he was going to come on and you know say a little more about his himself and and and his work Dr. Trent is president a research director of the translational genomic research Institute teaching in Phoenix, Arizona You know prior to forming teaching in 2002 Dr. Trent served for ten years as a scientific director of the National Human Genomic Research Institute and Under his guidance our division of interim rural research Became an internationally recognized research center in human genetics. So Dr. Trent Thank you Well, thank you very much. Dr. Routime. What a wonderful Opportunity to be able to share with you today at this seminar I would have hoped that this would have been an opportunity to see everyone in 3d rather than the 2d We've become so accustomed to but nevertheless I'm particularly delighted to be part of Dr. Plon's lecture as her work actually aligns perfectly with What nearly 20 years ago? I gave Francis Collins who was then the NIH director as a reason why I was choosing to leave the the mothership to leave the NIH In order to start a fledgling organization like TGen and that was Recognizing that the power that the NIH could bring forward for a common good project like the human genome project was one thing But bringing genomic information into clinical practice That is literally being on the forefront of bringing clinical genomics into the care stream Seemed to me to be something where industry academia and government were going to be involved in a Cooperative fashion and a nonprofit Institute would be best positioned to help the patient sitting in front of us today That's my departure to TGen which is now part of the city of hope So let me just stand by saying again at the reason that I believe Dr. Plon is the perfect individual to highlight her work today is As hard as it is to believe for some on this This video 20 years ago. We really were looking at one gene at a time and for the better part of a decade Most clinical groups were satisfied with small panels of genes All the while knowing that we needed to look at every gene and ultimately every base pair if we wanted to maximize information for our patients so as you'll hear from Sharon she has Led the use of comprehensive genomic profiling for childhood cancers And in that regard she is both a world leader and a true kindred spirit So again, thank you dr. Rotimi and thank you Sharon for giving this lecture Thank you, Dr. Trench and I'm going to see just a little more about Professor Sharon Plon She's a both certified medical geneticist and the long-standing career cancer genetics researcher Her research has led to the discovery of new cancer susceptibility genes and Implementation of genomic testing in medicine She holds the Dan L. Duncan comprehensive cancer center professorship at Baylor College of Medicine in the Department of Pediatrics Immatology oncology molecular and human genetics and human genome sequence center She was the co-PI of the end is your NCI funded basic three clinical trial on the incorporation of exome sequencing Into the care of newly diagnosed childhood cancer patients a study that Expanded into diverse patient populations across Texas She has served for almost a decade as one of the PIs of the clinical genome clean gene resource and cheers the clean gene heritory cancer cancer efforts She's currently co-chair Our co-chair in the gem line reporting Effort of the national cancer Cog pediatric match precision oncology trial Dr. Plon is also working on a population-based study to understand the association between bed difference and cancer risk in children I serve with Dr. Plon on the board of director of the American Society of Human Genetics and There she also served on the and NIH human genome In the research advisory council So I the title of our talk today is evolution of gene line cancer genomics From rare disorders to precision oncology trials. Thank you. And it's a wonderful pleasure to have you today Thank you very much. And as I share my screen I just wanted to remind folks that if you have questions, please use the Q&A I'm going to try to finish in enough time To allow us to have some good questions at the end So you've already heard all about me. So which I just incredibly honored to have this and as Jeffrey Dr. Trent said he and I work in kindred spaces. I've had the pleasure of participating in the TGEN pediatric cancer genomics meeting before the pandemic and admire his work so Okay, I Have I don't have any disclosures so I'm not going to talk much about rare disorders because I wanted to have enough time to talk about what's gone on in the last 10 years But where were we in 2010? So as you heard I'm a medical geneticist and Prior to 2010 the way we figured out which cancer patients got genetic services were particularly in pediatric realm If a child had specific birth defects and a childhood cancer diagnosis Hemie hypertrophy things like that. Obviously, you're all aware of the work predatory breast ovarian cancer lynch syndrome so individuals with personal and family history of cancer There's an increasing number of cancers that we recognize that that cancer diagnosis alone is associated with a high likelihood of genetic predisposition Retinoblastoma being the classic one but medullary thyroid cancer and many others and then Unfortunately, if a person developed more than one malignancy and all of those things would get your referral to a cancer genetic service You'd get a full genetics evaluation. You'd have pre and post test Counseling and testing and as was mentioned by Dr. Trent, we would often do genetic testing one gene at a time But patients who didn't meet these criteria Really didn't get any genetic services. So it was sort of an all or none and that was something that always really worried me What were we missing in the individuals who did not have that? I? Did just want to pull up one of Jeff's many Papers in this area and just in this paper was published in Nature around 2010 and really highlighted sort of the revolution in research genomics that was going on and even back then He and his colleagues Kevin Brown and others were already doing whole genome sequencing of pro bands looking for new Cancer susceptibility genes and this is the classic paper that identified the MITF variant and familial melanoma But at Baylor what we really started to think about was the question of precision on oncology and precision medicine And so precision oncology is defined as the tailoring of cancer prevention and treatment based on the characteristics of each patient This was a slide my colleague will Parsons put together many years ago Of course, it's not a new concept oncologists have been doing that for decades But the code words here when you refer to prevention Typically you're talking about germline analysis and for treatment you're talking about tumor analysis And what we started to talk a lot about at Baylor was the fact that to do precision oncology You had to have clinical grade genomic testing you had to implement it You had to put it into the medical record and report it back to physicians and patients in order to actually have precision oncology work So one of the nice things about being a physician scientist is you have different parts of your careers And one of the really sort of fabulous things I got to participate in Was the early work starting in late 2010 early 2011 at Baylor to take the the research exomes and translate them into the clinic So Christine Ang and Richard Gibbs really led the effort Yapping Yang and Donna Musney did a huge amount of work And a group of us and we called ourselves sorry the management team met every Friday for two hours for about two and a half years To develop our clinical exome test And we first applied it really clinically we made it available to physicians to order and We had the privilege of publishing our first 250 patients in the New England journal and around that time as I'll mention in a minute The clinical sequencing or CSER consortium RFA came out and that really changed much of my career trajectory But of course on the germline side we went on by 2014 to publish our first 2000 exomes and then Jennifer Posey which many of you know through the Gregor program actually when she was a fellow worked with me and did the analysis on our first adult who had exome sequencing So the availability of that test and our rapid translation to a tumor exome really In our work was really are the onset of clinical cancer genomics and we were able to ask the question and many others as well What happens when all cancer patients children or adults have access to genetic or genomic testing So as I mentioned NHGRI was at the forefront of this they put out what eventually became known as CSER the clinical sequencing exploratory research RFA Eventually under the genomic medicine division and I did just want to do a shout-out to Terry Minolio Who's head of that division for being awarded the presidential rank award yesterday? But we well Parsons and I with the group I just showed you said, you know, let's do this for pediatric cancer. Let's take that clinical exome test and offer it to every child Tumor and germline and really explore what's going to happen And we were one of the early CSER sites along with the unit and there were two others actually doing tumor normal sequencing University of Michigan doing children and adults with rare tumors predominantly sarcomas and the Dana-Farber doing adults with advanced malignancies and So our project as you heard was called basic three Well, Parsons was co-PI with myself and Amy McGuire and her Center for Medical Ethics and Health Policy played a major role throughout And we called it basic three really basic cubed But that's because I was an MIT nerd But everyone first it is basic three and what we proposed to do was essentially take all comers all newly diagnosed Solid tumor patients not leukemia lymphoma, but with both brain and non-CNS solid tumors Do the blood exome to do a blood sample for the germline exome tests? I just mentioned we developed a tumor exome tests attracting the germline and reporting That so every patient had a clear certified germline exome report somatic mutation report Those went into the electronic medical record and I'm talking back in late 2011 They were shared with their pediatric oncologist and our study genetic counselors with the oncologist shared them with families So we return results from the beginning and then we followed the patients for two years and our study objectives Of course, we're number one to see could we really do this? At Texas Wilkins Cancer Center and then evaluate the impact on both the physicians and the families and I should just say the oncologists have been subjects in our trial and have been amazing research Participants and stakeholders as well as the families that have participated in our studies So the methods have all been published a number of years ago But I'm going to give you sort of the final results of the study. This paper came out when we were about halfway through so first of all because there's a lot of emphasis now on Diversity and race and ethnicity Houston of course is considered the most diverse city in the country and Texas Children's Hospital is one of the primary Caretakers of children in the in the city. And so we were committed from the beginning to Enroll all of our patients and we provided everything in Spanish and English And this paper they came out in 2014 for the first hundred patients I've now updated to the whole study and again there were no statistical differences at all in who enrolled or declined to enroll and So our study in the end was about almost 50-50 Self-described Hispanic and non-Hispanic. This is all self-described information and by race Approximately 10% or African American. There's a few more percent African American in Individuals with more than one race and that very much represents what the state of Texas looks like So this really was representative of our city and of our state We also Made what I think at the time was a fairly brave decision to return lots of types of results So on the tumor side we returned all Sematic mutations and on the germline side we returned Pathogenic unlikely pathogenic in V us related to the patient's cancer and we included any cancer susceptibility gene Or if they had another phenotype We this predated actually the ACMG Secondary findings, but we had our own initial list and then we adopted that list of other medically actionable findings We had a small pharmacogenomics set of genes and we actually returned all pathogenic variants in recessive In recessive Omens genes, but I'm only going to talk about the results related to cancer So again, I mentioned that we had a diverse patient population and because this was started in 2011 We had a lot of variants one certain significance But we were able to look whether that varied by race or ethnicity And this was really some or some of the first data to show that we really had no difference in the number of us Reports or median number of us is on the reports between Hispanics and non-Hispanics But as has been reported by many others, we did have significantly more for individuals who self-described as African-American In terms of diagnoses this was one of the early studies That showed that approximately 10% almost exactly 10% of the patients in the study had a molecular diagnosis and by that what I mean is they had a pathogenic or likely pathogenic variant in a Dominant cancer susceptibility gene or they had biolealic variants in Autosomal recessive. I'm not including here patients who had a single recessive variant So let me talk about the recessive first my early career. I spent a long time studying rare recessive disorders like Rothman-Thompson syndrome I'm disappointed to say that less than 1% of our patients. We only had one patient, but biolealic variants in a recessive gene And in fact, I'll show you data later about other studies But I can just say now that all of them have reported the same thing that if you look at solid tumor patients Much less than 1% of those individuals appear to have a recessive cancer susceptibility disorder It probably is higher for leukemia lymphoma patients because of diseases like vanconi anemia If you have one of those disorders like Rothman-Thompson syndrome You have a very high risk of cancer, but they make up a very small proportion of the pediatric cancer population The other surprising results were that even though we only had 26 dominant Disorders that made up 19 different genes only p53 and VHL had three Gene three patients each all of the other genes only represented one or two individuals And the other surprise which as I'll mention has now been repeated by at the same time and subsequently by many others Is that we found many patients who had a molecular diagnosis, but a gene not previously associated with that child's tumor And I highlight BRCA1 and BRCA2 and pal B2 here because I'll raise that again later But you can see it was a wide variety of genes that we didn't think were necessarily related and we didn't know We're related to the tumor but smart gave four is a good example This is a patient at neuroblastoma complete loss of heterozygosity and since we published this case There are at least three or four additional patients and a group of us I mean across many studies and a group of us are writing this up to suggest that perhaps neuroblastoma is Part of this so we may be expanding the phenotype for some of these genes Of course as a geneticist the question is always could we have predicted who was positive so age in adult genetics is the classic Feature that's associated with cancer predisposition. That's not true in children children diagnosed at very young ages We're as likely there's absolutely no statistical significance here Based on the age of diagnosis We also again could compare Hispanic versus non-Hispanic because again, we're almost 50 50 And again, there was no statistically significant difference And there was actually no difference. Sorry that didn't come out right between CNS and non CNS tumor types I Don't have a slide here, but I can also say for every patient in the study We said at entry so prospectively based on what we know about the patient age of diagnosis Tumor type anything in the electronic medical record would we have recommended genetic testing? And then we went back and looked for these 28 individuals and for 40% of them We did not recommend testing for the gene in which we found the mutation So that's about all I want to say about basic three except for to say that of course We weren't alone in this and these are three other early studies The first one is the other Caesar study from the University of Michigan also reported ten percent also reported than many of the patients Had no family history again wide variety of genes the large st. Jude retrospective study that was published in the Nolan journal 1,100 patients of course eight and a half percent again wide variety of genes again Brca2 came out of that and then a large study a couple years later again Retrospective almost a thousand patients again seven to eight percent germline findings and again They actually get a statistical analysis and showed that actually brc2 was overrepresented in their population so And all of these studies and many others have commented that many of the germline positive patients do not meet the current criteria for genetic testing This of course applies to adults as well I have the honor of being part of the TC GA germline Analysis and again paper now published a number of years ago. We showed that eight percent again carried Pathogenic variants in cancer susceptibility genes and there have been many many such studies in adults You may note that some of those studies have higher numbers those often are studies that are including single Recessive variants and about six percent of cancer patients carry one of those so that explains some of the differences in numbers across studies So of course everyone especially my clingent hat are interested in the issue of variant reanalysis So we have followed these patients and Sarah skull and our lead counselor and I were reviewing these results for this talk The largest number of variants that were reclassified are actually in that group of secondary or incidental findings And we had three pathogenic variants that were downgraded This is primarily in very early patients in the study this predated the exact database or no matter Of course predated that as well and it also actually predated the Richards at all 2015 classification rules which really tighten up How do you call what evidence do you have to evaluate to call something pathogenic? So we've actually had three of those downgraded. I did just see that I was supposed to see I didn't see the patient one of those patients for a different reason yesterday and I noted that despite the Revaluation and the fact that we had informed everyone she was still having echocardiograms and so it sort of highlights that Once you have a label a genetic label that it can be hard to change practice We did have one patient had a negative West who through the work of my colleagues at Baylor actually was found to have a And had intellectual disability and congenital anomalies Actually was one of three patients where they described a new and published a new Genetic disorder not related to their cancer And we had one patient with a cancer diagnostic finding that was downgraded and that was in DKC1 Discaritosis congenital gene that patient had completely normal telomere length And in fact that variant is now likely benign in ClinVar and we had one upgrade So it's just to say that among 300 patients We had a fair number of changes and I think this highlights a point that my colleague Heidi Rehm And I made in an editorial a couple years ago, which particularly people that had genetic testing early 2010-2012-14 is the group where you really need to reevaluate some of those variants because of these subsequent developments So just let me briefly mention of course, that's one of the goals of ClinGen not going to talk about ClinGen today This is the last year of the CSER consortium So I thought it was a good time to focus on that But of course ClinGen is really focused on the relevance of genes and variants for precision medicine and research And I hope that last slide kind of pointed out why that's so important And we have a large number of ClinGen expert panels I co-lead the hereditary cancer efforts with my colleague Doug Stewart On many genes that are relevant to both adult and pediatric cancer And we have a number of new ones planned as we've just entered five additional years of funding But with regard to the CSER consortium There was a second round of funding and we applied again But we expanded our team now across much of the state of Texas So we called that study Texas Kids Can Seek and we learned that it's good to have a logo for your study So we now have a logo and we were fortunate to be selected for funding We've increased the diversity even further So now we have a diversity of clinical sites and includes a small clinic on the Rio Grande border in McAllen, Texas A large private hospital, Cook Children's in Fort Worth, and then other academic centers in Texas And again Expanded to an even greater proportion of medically underserved families as well as of course diversity with a focus on Hispanic individuals We also expanded the entry criteria to include not just newly diagnosed patients But children who had recurrent or relapsed solid tumors As well as lymphomas and rare histiocytic disorders and we've just completed enrollment Of over 630 patients all six sites did participate And we overall have greater than 65 percent diversity based on the CSER criteria So we did things a little bit differently and kids can seek and I'll just show a little bit of data since we haven't finished reporting everyone out First of all Obviously the field has changed Jeff Trent mentioned that as well Targeted cancer panels are a very important tool And we are directly comparing for every patient the results of a targeted cancer panel that was designed for pediatric cancer patients at Texas Children's Hospital With more extensive genomic testing by EXO And we were going to do more pilot work with genomes, but I have to say on covid sort of got the way of that On the tumor side one of the other things we learned sorry From basic three is that pediatric oncologists really do follow Evidence-based medicine And if the patient has a tumor that what they know they can treat with current therapy They will not generally diverge based on genomic findings And so we really limited the tumor analysis to patients in this high risk group So people that have a very bad diagnosis or prognosis even at diagnosis like a glioblastoma Or children that have relapsed or recurred And the other reason the panel was so important for that reason and I want to highlight ancient boy Roy here Who is a molecular pathologist started as a fellow in basic three and now is our lead molecular pathologist for kids can see Is that his laboratory at Texas Children's Turns the panel around in about 10 to 12 days So that they can use that tumor information very rapidly to make treatment decisions And in that arm of the study we are the children in the high risk arm We are comparing not just to exome because we also learned from basic three that you really need to look at the RNA of the tumor And I should say this panel on the tumor side is a dna RNA panel We're comparing it to exome RNA seek an array That's being run at the genome center clinical lab donna musny is the manager of that lab with richard gibbs and others of course And we will be able to compare directly the outcomes of these two types of tests So I can't give you summary data, but I just wanted to give you a couple of stories So one tumor story. This is a paper that just came out in case reports and This is a patient who had an appendemoma But was discovered through the RNA dna panel to actually have an n-trek fusion Appendemomas can be quite serious and this patient presented with widely disseminated This is the tumor But these little marks on the x-ray point out the fact that it had already spread down the spinal cord and quite surprisingly Is okay quite surprisingly The rna analysis showed that this patient actually has an n-trek fusion And n-trek fusions are one of the you know miracles of genomic medicine They are highly tumors with these are highly responsive to larytrectinib to FDA approved for that indication They're almost never seen in appendemoma So our colleagues will Parsons and Stephen Mack and others did research methylation profiling And in fact appendemomas are generally found in the little circle to the left or to the right But in fact the arrow points out that this patient the little black dot Actually from a methylation profiling looks more like an astrocytoma But like other patients this patient has been highly responsive to larytrectinib and you can see That there was great Diminate Can't say that word today Both the main tumor and the spinal cord lesions and as far as I'm aware the patient actually continues to do well In terms of the germline side Very similar to what we saw in basic three are these unexpected results in patients who don't meet criteria So this is a 15 year old Previously healthy male very large oropharyngeal spindle cell arcoma has been treated with chemotherapy and radiation No family history and so would not have warranted a referral to cancer genetics or any genetic testing based on current guidelines However, when angshamoy reported out the tumor panel There was a myo d1 Driver mutation which is seen in these tumors But there were actually pathogenic variants in two different cancer susceptibility genes Both of which have been reported in clenvar is germline And both of which were actually pretty close to a 50 percent Variant allele fraction, which is what we often see in cancer susceptibility genes So there was concern that one or the other of these might be germline in fact And when the germline exome and the panel they both agree with each other came out In fact, it was the dicer one variant So this is an example of a patient who would have had no testing But because of the study in fact was found to have dicer one syndrome Actually, it wasn't inherited variant and other members of the family are now having dicer one screening guidelines as recommended by duck steward and others So the other thing that I really haven't had a chance to talk at all about is that there's a Big team of folks that are really looking at the implementation part of all of this Since I just want to shout out to sarah skullan our lead genetic counselor When we design kids can seek we realize there's no way with we were aiming for 600 to 1,000 patients at the time That we would have enough genetic counselor Time to do disclosures for every patient Um, and so sort of based on our results We uh, and we used to and one of the things we did in basic three we continued But in a structured templated way Which is the oncologists are notified by email and this is the treating oncologist when the germline results are available in the electronic medical record And we provide them a structured summary of what we think we meaning myself and genetic counselors But the germline results mean And what the plan is for disclosure and whether there are any recommendations that we would recommend you do for the patient And we're trying to model what some groups use as an e-console in this finding If the patient has a significant finding they have an in-person or telemedicine visit by the study genetic counselor And of course because of covet it was really good that we set it up this way because we were able to continue Disclosures by telemedicine throughout throughout the pandemic We now are back to offering in person although most of the families do select telemedicine And that's if you had a diagnostic finding of any type Secondary findings or even carrier status even someone found to be cystic fibrosis carrier gets an in-person visit They the family is then and those are in English or Spanish at the parent preference And then they're provided the letter packet following the disclosure If you don't have a significant finding So we call those non significant findings and we do include any report with only v us's in the non significant findings They get a letter packet only it has a counseling letter They have a copy of the test results as educational materials That have been developed through the stakeholder working group of the caesar consortium They're mailed to the family in English or Spanish and we emphasize in multiple places in the letter That they have access to a genetic counselor for questions. They can email us. They can call us actually very few families do So what sarah has been leading and she presented this work last month at nsgc And this is an initial evaluation of the first about 150 parent surveys Is every parent gets a post disclosure survey and there are a set of questions that have to do with actually the mode of return of results So the first piece of data here is would you have preferred to receive your child's genetic test results in a different way? And in fact, if they got to meet a genetic counselor 90 percent said no If they only got the letter packet still 70 almost 75 percent said no But of course there this difference is statistically significant almost a quarter of them would have preferred a different way Probably more important is we ask about their subjective understanding. We're not giving them a genetics test We're just asking them how well do they think they understood the results And again, you see there's a significant difference here The ones who met with the counselor said very well or well Or somewhat, but if you now look at the ones who got the letter It's only 60 who said very well or well And in fact, you now start seeing even 12 that said a little or not at all So the conclusion from the this part of the study so far Of course, we'll get more data as we just finished the disclosures The majority of the parents are satisfied with all three modes This did include a few in person and mostly telemedicine and letter However, parents receiving results by letter certainly had lower perceived understanding and more unanswered questions That was one of the other questions on the study and had a stronger preference for an alternative mode Interestingly, there were no significant differences in satisfaction or understanding by ethnicity and language Whether they preferred English or Spanish and whether there was a v us on the report or not So our data suggests that disclosure might Mail was sort of passive Access to genetic counseling may not be adequate and may need some form of active support Even if that's just a phone call a week later by the clinical genetics team I should say in contrast I've just evaluated this evidence and submitted to america in the american college for next spring Is that the structured email to the physicians does seem to be sufficient to really mediate their sort of downstream physician recommendations What they do with the patients So I do just want to do a shout out Part of the reason I think there's been no difference between english and spanish preference is really sort of the amazing work of Amanda Gutierrez All the racinos and many others in our study But Amanda really starting with basic three when she was I think right out of college said, you know, we've got all these Disclosure visits that are recorded and you've used interpreters Let me really look at what how the interpreters interpreted exomes And her first paper was really looking at the language that they used and actually made some recommendations Subsequently she's led an analysis of really looking how medical interpreters made bridge socio cultural gaps And now in the second phase of the cesar consortium working with uh, nonville lindberg and many others There's now a whole team this paper. I think just came out With recommendations from cesar on how to create accessible spanish language materials And sort of the lessons that have been learned from these studies So fortunately in january of 2020 We had a team meeting And this was all of us together Of course the data lives on and so the basic three and kids can seek data are available for use by the larger genomics community basic three the exomes tumor germline and any research transcriptomes are in db gap and that data is actually being used right now in clingent For a pediatric cancer hotspot analysis We submitted variants to cling var and we're doing even more of that with kids can seek the kids can seek exomes are going into anvil And we were selected as part of the gabriela miller kids first project To have whole genomes of the basic three parents and children And we're now actually part of a long read pilot and that data is all available in tibatic We of course ourselves have done more research and just to sort of highlight a paper from a few years ago Based on a single basic three patient. We are able to identify led by angshamoy roy and will parson's internal tandem duplications that are the most common driver mutation in this very rare home of the kidney I mentioned our one recessive diagnosis has turned out if we Collaborate it with two other groups and describe three patients with this new deficiency syndrome and a high risk of hepatocellular carcinoma and graduate student That disappeared. Yes a graduate student in my lab is analyzing the whole genomes From the basic three trios and for example has identified a tandem duplication that he's now trying to interpret whether this in some way may have driven the appended moment in that patient So the second study I wanted to talk about and I'll probably end with that is Okay, so this was all put it in the medical record provide the information To the oncologist and let them decide how to use it particularly in the patients who relapse Would that make them eligible for a clinical trial or not? But with the data from basic three and from the st. Jude's data and many others That data was really used to motivate that the pediatric match trial which was Modeled after the adult match precision oncology trial would in fact include germline reporting So really in this trial we're answering the question Can we implement tumor germline reporting in a national treatment trial? So pediatric match which is cosponsored by the national cancer institute and the children's oncology group Is a single-stage phase two trial of genomically directed therapies for children with refractory solid tumors So these are tumors that have failed all current treatments. They get biopsied and sequencing at Relapse they identify actionable mutations. They're selected into a study agent arm And then those individuals are assessed for a response Uh relies on the children's oncology group which has over 200 research sites throughout the united states Unlike pediatric cancer Almost 90 of children diagnosed with cancer in the united states are treated and over 100 I think 120 sites from cog are participating in the match trial So for match, there's tumor and blood sample sequencing for every patient Using the ffp tumor samples at relapse. They're processed in the biopathology center They're using a platform similar to adult match, which is a targeted panel on combined DNA and RNA mutation fusion panel It's got over 140 genes And they really identify through their software analysis pipeline mutations of interest Uh and the sequencing is performed at those centers for the blood Analysis the reporting is being done by two labs baler genetics and children's hospital la They do a lot of germline reporting And this was not done for the adult match trial There was no germline analysis in adult match and this will obviously provide information on genetic susceptibility to cancer In terms of that, we've actually been able to collect blood samples for more than 99 percent of the patients at entry Um, the analysis focuses the tumor analysis as I mentioned focuses on actionable changes So mutation hot spots loss of functional meals Match does not report deletions or splice site variants unless it's a known hot spot For the splice sites and the match germline Reportings reflect what was found on the tumor report So we identify the genes on the report that are likely to be cancer susceptibility genes that's shown here There's a variant on the tumor report. We then know immediately whether it's found in the blood or not We've been doing this now for I think three and a half years. We made every Tuesday afternoon And we get online and we review the study data through the matchbox platform So for the tumor you can see the copy number for all the genes On the on the panel as well as if there are any genetic changes identified the red and green little boxes here Tell you if they match a treatment arm And this is a patient if you can't see it that has two NF1 Loss of function variants and an msh6 So all three of these could have been germline and related to cancer susceptibility And in fact one of the NF1 Variants was a patient with no neurofibromatosis and you're essentially seeing the second hit in the tumor Conversely, we have patients who have tp53 alleles This again is a known variant that can be germline or tumor The allele frequency is 0.976. So clearly there's loss of heterozygosity But the concern was still whether this might represent the fraumini syndrome in a patient with a sarcoma And under the blood result. It says no variant data. So this variant was not found So I reported an acr an interim analysis when we've completed 868 patients overall seven percent essentially 6.8 percent Are positive for such a germline finding and it's an interesting step down panel if you Pattern if you look at the 868 patients about a quarter of them Have a finding on the tumor report that would be That could be suggestive of cancer susceptibility. So tp53 or msh6 or NF1 I just wanted to point out that the proportion of patients with a finding in their tumor that's found in the germline does vary by gene And so in fact what you can see here is surprisingly there are 22 patients And this is when we were about two-thirds of the way done Who had NF1 findings about a third of which actually have neurofibromatosis? Again for rb1. It was about a quarter p53 is clearly the big player in terms of variants in the tumor that could be Obviously of concern and there it's only about 16 15 16 percent that are actually in the germline Interestingly, there are 20 patients without Missense variants that are associated with familial neuroblastoma None of those have been in the germline so far similarly for p10 But for BR BRACA mutations and here I sort of cheated I combined four genes BRCA1, BRCA2, Palbitu and Chectu Similar to what we saw in basic three and have been seeing in kids can see Actually, if you see those in a pediatric tumor almost all of them are germline So in fact these represent patients with these hereditary breast cancer mutations so um, I And I just wanted to I think I will sort of finish here because I'd like to leave time for questions. So If you think about it what match has sort of told us is that you can do paired tumor normal testing For precision oncology trials. It's really the first national trial to perform prospective match tumor blood analysis With the germline status returned to oncologists and patients and I say that every every Patient in the trial gets a germline report. You don't only get a report if there's a finding It obviously allows us to rapidly delineate germline status. Uh, when you see it in the tumor We've identified susceptibility syndromes and children and their family members that would be missed by current guidelines And you know a point that my colleague Steve Jaffee who co-chairs the committee with me has made many times is that We are providing useful information for the families in the trial even if a treatment arm is not available um An interesting finding of the results being 7 and I'll just highlight that again is an underestimate because we're not reporting deletions We're not reporting splice sites But it's still comparable to what's been seen in other other studies So it does suggest that pediatric cancer patients with recurrence or relaxed tumors Have similar germline findings to studies of unselected pediatric cancer cohorts. So overall Bad tumors don't seem more likely to be germline I I will just say we do have some data that in specific tumor types That may not be the case and here because of the problem with my slides I am just going to skip first of all, sorry I don't want to skip that I want to acknowledge the huge number of people that have made the nci cog pediatric match study possible in particular need of sible from nci and will parson's And getting the data I shared today is all data that's in our abstract from a acr and the I'm going to skip all this and just come to This last slide that as hg this year We looked specifically at a study. We published last year at rabda master coma. We then uh, bailey graduate student in Bailey martin gf cologne a graduate student in philip lupo's lab one of my collaborators I did a really nice analysis that looked at overall survival and event free survival This study was also done with the children's oncology groups and we do have really good treatment data And in this case what we found in rabda myosarcoma Is again, it's about seven percent of the patients all comers have a germline variant If you've limited to embryo rabda myosarcoma, it's about 10 And the group that have germline findings actually do significantly worse in terms of overall survival or event free survival And this is important because embryo rabda myosarcoma is actually thought to be the better acting rabda myosarcoma And so the germline status in this setting may help us to identify patients at diagnosis Who actually have a poorer survival might Eventually down the road need alternative treatment. Um, and these are patients who don't have the packs Three or seven foxo one fusion that drive unfavorable outcomes in the alveolar form So with that, I hope I've sort of convinced you that 10 years after the first tumor exome We have the early realization of precision oncology for childhood cancer and much of the same works being done in adult Cancer multiple studies suggest that eight to ten percent of pediatric and adult cancer patients have a monogenic cancer predisposition syndrome Current testing guidelines miss a substantial fraction of these findings And really I hope I've sort of convinced you that one path forward may be offering germline testing to all pediatric cancer patients I didn't have time to talk about brca2 But our prior assessment of adult versus pediatric cancer predisposition genes clearly needs to be reevaluated There's much more overlap in that than I think was expected I hope I've convinced you that we demonstrated the ability Much with the support of the cesar consortium To conduct and with the match trial to conduct precision oncology treatment trials that efficiently provide tumor germline reporting And this may serve as a model for how to do rapid reflex testing for tumor only test results And my last slide was trying to convey that there's increasing evidence that germline Data may provide important information for outcome for cancer patient or eligibility for targeted trials And with that I will stop sharing and turn it back over to my NHGRI colleagues Very impressive presentation of clinical genomics and precision oncology in action So i'm paul liu the deputy scientific director of NHGRI So i'm happy to moderate the question answer session for this lecture So the first question comes from dr. irie green the director of NHGRI And he says sharon thanks so much for giving this year's trend lecture and for giving such a fabulous presentation You're truly a role model as a physician scientist you'll work on rare diseases and kinds of genomics Clearly illustrates the changing landscape in terms of the use of genomics in medicine And he has two questions first one is What are your thoughts about how medical schools are training future physicians in terms of knowledge and awareness Of how genomics will influence the practice of medicine in the coming years Yeah, it's a great question. And I just finished lecturing actually on cancer genetics, but of course it was this year by zoom I would say that I think medical schools are trying It's a very tough question And there's still a lot of focus on sort of classic cancer genetics retinoblastoma and things like that on board exams And so that sort of translates into it. I will say baler has had a unique pathway And a shout out to lori pataki schwannadar and others we have a we have a An essentially an interest group where medical students Can who are interested in genetics can do a number of additional genetic activities and get a certificate for that I think that medical students are very interested in precision medicine But they're not necessarily seeing it modeled when they do their rotations And I think that's where we're likely to have the biggest input whether that's doing sample cases Or that kind of thing. I think we really they really need to see it influencing patient care to sort of Drink the kool aid Do you think the faculty need to be strengthened in this area too? I guess well, I think that that's I mean you need the faculty to be strengthened and applying it in order for you know, the students to buy into it, but I I do think You know, perhaps all the emphasis on coven and mr. Dr. RNA and vaccines will in and of itself Create some additional interest in this area Okay, that's second question from Eric is um, are you keeping pace with the opportunities in genomic medicine that you describe in your talk? Oh, I haven't applied for the genomic medicine rfa if that's what he means, but I've encouraged Sarah skullan to do so and Hopefully I'm keeping pace. I think I'll leave it at that Okay, all right. Here's one from an anonymous attendee when calling the biallelic recessive cases. Did you include Trans compound pedozygous What would you uh, what would yes, but we yeah Well, so this is one of the advantages of doing exomes with kids, which is that we got samples from parents And so any pathogenic variants and recessive genes the lot if there were two the lab would Test the parents so we could set phase Um, we have had a couple of patients who have V us is in cancer susceptibility genes in both genes and you can maybe argue about that But as I said, there've now been a number of studies that have tried to look They're very few. I mean, they exist certainly in team. You presented someone with a taxi to lentic Asia There's you know, it's just they don't make up a large proportion of childhood cancer patients Yeah, seems like very few Uh question from last piece occurred earlier in the talk you show the finding of surprising German line variants in genes not predicted by the patient's tumor Does that have implications for secondary findings in patients with pediatric cancer? Yeah, and so the slides I skipped over the best example that is brc2 so We only reported one in basic three, but in our rhabdomyocercoma study We reported six patients out of 600 so one percent and it was clearly one of the only Non rhabdomyocercoma genes that was significantly over represented in controls My graduate student adam Weinstein has really reviewed the world's literature on this There are at least four other studies that have showed that brc2 is over represented in pediatric cancer And specifically brc2 not brc1 and a couple of studies have showed pal b2 Which is the partner brc2 is over represented So I think that's an example Where we may think of it as a secondary finding where in fact it may be playing some role and we're certainly interested in doing adam is working his thesis on that question So based on this probably we should look at more kind of broadly Rather than limiting to only genes relevant to certain cancer Yeah, and so for example the original pediatric cancer panel At texas children did not include the mismatch repair genes and then it became clear not only is the the rare recessive condition Which we have diagnosed one of those patients and kids can see But in fact, um michael walsh first reported and we have a paper under review That about a half to one percent of pediatric cancer patients appear to have lint syndrome So that's another example where we added the miss. I mean not me, but uh, dr. Roy's team Added the mismatch repair genes back to the pediatric cancer panel. So I do think limiting the panels Can will prevent us from learning about some of these relationships Look at the next one. Hopefully a short question from yi yi lu For the match trial. Do you report variants with uncertain significance? Uh, generally we don't and that's because the max spot the matchbox pipeline does not call Does not call them out on the tumor report There's a few cases where something on the tumor report is actually a v us in germline status And those are the only ones reported Okay Uh, next one from lea cunning. I hope I read this correctly. I got one for talk I got the sense that your statement back tumors quote-unquote don't seem more likely to be germline Pertain primarily to solid tumors and not liquid tumors. Is that your statement? Yeah, and I should I should have I should have had a caveat from the beginning that I Did not show any data related to leukemia today Um, there definitely are examples in leukemia and I tried to show the example in rabbi the monster combo We're having germline status is a poor prognostic feature I think we went into match thinking That okay, everyone in the study had to have failed treatment That we might have a much higher rate of germline findings than uh, Then have been reported in Just unselected patients and there we don't see it But they're definitely individual tumor types and leukemia is a good example Where germline status can be a poor prognostic factor Right, and also your umronic. Yeah RMS. Of course. It's an example. So, um, we're running out of time But there are still some very good questions and dr. Altar Blanket altar What is the cancer significance of a single mutation? For example in brca2 in the child with cancer versus two mutations of brca2 Equals funcone anemia with a specific cancer spectrum Well, hello, dr. Altar um, and I I avoid to say anything about single fanconey alleles today, but the um I think it's sort of what I said in answer the other question We initially thought in fact, I think we even wrote in the basic three paper that this was probably a coincidence I would say there's enough data now that suggests single pathogenic brca2 variants are not a coincidence But they have been reported in mesoloblastoma Rhabdomyo sarcoma lymphoma and osteo sarcoma. So that is a different pattern than you see in the fad1 patients But happy to talk to dr. Altar about that That's good one last question Then we'll have to finish although you mentioned that there was not a correlation of age with germline mutations in pediatric cancers as a group As an age correlation appeared when considering individual pediatric cancer categories Well, I mean, of course, there's some classic ones like retinoblastoma where it's well reported but there are other examples, uh, gail tomlinson's reported that hepatot Hepatoblast Hepatoblastoma in patients with apc or not not necessarily younger the patients with germline finding So I think there are some other individual tumors where age diagnosis has not been a good predictor in pediatric cancer Very nice. Thank you very much for, you know, all the answers for the questions. Well, thank you again for the great Great questions and the great honors Thank you very much