High-sensitivity Approach for Detection of Tert Promoter Variants in Shh-activated Pediatric Medulloblastomas

High-sensitivity Approach for Detection of Tert Promoter Variants in Shh-activated Pediatric Medulloblastomas | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article High-sensitivity Approach for Detection of Tert Promoter Variants in Shh-activated Pediatric Medulloblastomas Laura Giunti, Milena Guidi, Valentina Cetica, Abramo Ponticelli, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7527596/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 10 You are reading this latest preprint version Abstract TERT promoter ( TERT p) hotspot variants − 124C > T (C228T) and − 146C > T (C250T) are recurrent in various central nervous system tumors and serve as established prognostic markers in many cases. Among medulloblastoma molecular subgroups, TERT p variants are most frequently observed in adult SHH-activated (Sonic Hedgehog) medulloblastomas and are traditionally considered mutually exclusive one another. However, their prognostic significance remains unclear and appears to be subgroup-dependent, being associated with improved survival in SHH-activated tumors but poorer outcomes in Group 4 medulloblastomas. We investigated the presence of the C228T and C250T hotspot variants in TERT p using high-sensitivity droplet digital PCR (ddPCR) in ten consecutive pediatric SHH-activated medulloblastomas (nine desmoplastic/nodular and one extensively nodular) with sufficient residual material available for analysis. Both variants were detected in all tumors, with variant allele frequencies (VAFs) ranging from 0.14% to 61.7% for C228T and 0.06% to 44.6% for C250T. Notably, only the two patients aged ≥ 10 years exhibited high VAFs. Additionally, we compared the results of 5 out of our 10 cases, which were also analyzed by Children’s Brain Tumor Network (CBTN; PedcBioPortal) through Whole Genome Sequencing (WGS). In all five cases, the CBTN analyses yielded negative results. In conclusion, our findings indicate that the two TERT p variants may co-occur; they are ubiquitously present at low VAFs in younger children, while higher TERT p variants VAFs increase with patient age. Larger cohorts are required to validate these findings and to elucidate the prognostic significance of TERT p variants at low and high VAFs in SHH-activated medulloblastomas. Biological sciences/Cancer Biological sciences/Genetics Health sciences/Oncology TERT TERTp variants medulloblastoma digital droplet PCR desmoplastic pediatric Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 29 Jan, 2026 Reviews received at journal 27 Jan, 2026 Reviewers agreed at journal 19 Jan, 2026 Reviews received at journal 12 Jan, 2026 Reviewers agreed at journal 12 Jan, 2026 Reviewers invited by journal 07 Jan, 2026 Editor assigned by journal 06 Jan, 2026 Editor invited by journal 16 Sep, 2025 Submission checks completed at journal 10 Sep, 2025 First submitted to journal 10 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7527596","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":571470766,"identity":"a33ceff2-4e62-4d3f-907a-99fe8248569b","order_by":0,"name":"Laura Giunti","email":"","orcid":"","institution":"Meyer Children’s Hospital IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"Giunti","suffix":""},{"id":571470771,"identity":"ee390d0a-753d-4d55-a6b2-7923df211a74","order_by":1,"name":"Milena Guidi","email":"","orcid":"","institution":"Meyer Children’s Hospital 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Medulloblastomas\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"TERT, TERTp variants, medulloblastoma, digital droplet PCR, desmoplastic, pediatric","lastPublishedDoi":"10.21203/rs.3.rs-7527596/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7527596/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e \u003cem\u003eTERT\u003c/em\u003e promoter (\u003cem\u003eTERT\u003c/em\u003ep) hotspot variants \u0026minus;\u0026thinsp;124C\u0026thinsp;\u0026gt;\u0026thinsp;T (C228T) and \u0026minus;\u0026thinsp;146C\u0026thinsp;\u0026gt;\u0026thinsp;T (C250T) are recurrent in various central nervous system tumors and serve as established prognostic markers in many cases. Among medulloblastoma molecular subgroups, \u003cem\u003eTERT\u003c/em\u003ep variants are most frequently observed in adult SHH-activated (Sonic Hedgehog) medulloblastomas and are traditionally considered mutually exclusive one another. However, their prognostic significance remains unclear and appears to be subgroup-dependent, being associated with improved survival in SHH-activated tumors but poorer outcomes in Group 4 medulloblastomas. We investigated the presence of the C228T and C250T hotspot variants in \u003cem\u003eTERT\u003c/em\u003ep using high-sensitivity droplet digital PCR (ddPCR) in ten consecutive pediatric SHH-activated medulloblastomas (nine desmoplastic/nodular and one extensively nodular) with sufficient residual material available for analysis. Both variants were detected in all tumors, with variant allele frequencies (VAFs) ranging from 0.14% to 61.7% for C228T and 0.06% to 44.6% for C250T. Notably, only the two patients aged\u0026thinsp;\u0026ge;\u0026thinsp;10 years exhibited high VAFs. Additionally, we compared the results of 5 out of our 10 cases, which were also analyzed by Children\u0026rsquo;s Brain Tumor Network (CBTN; PedcBioPortal) through Whole Genome Sequencing (WGS). In all five cases, the CBTN analyses yielded negative results. In conclusion, our findings indicate that the two \u003cem\u003eTERT\u003c/em\u003ep variants may co-occur; they are ubiquitously present at low VAFs in younger children, while higher \u003cem\u003eTERT\u003c/em\u003ep variants VAFs increase with patient age. Larger cohorts are required to validate these findings and to elucidate the prognostic significance of \u003cem\u003eTERT\u003c/em\u003ep variants at low and high VAFs in SHH-activated medulloblastomas.\u003c/p\u003e","manuscriptTitle":"High-sensitivity Approach for Detection of Tert Promoter Variants in Shh-activated Pediatric Medulloblastomas","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-09 13:48:14","doi":"10.21203/rs.3.rs-7527596/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-29T07:56:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-27T19:13:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"49299088311288044014506275892691685638","date":"2026-01-19T18:20:57+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-12T13:41:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"73718644276370142951700838846721786356","date":"2026-01-12T12:59:05+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-07T16:40:30+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-06T11:32:41+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-16T09:00:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-10T11:42:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-09-10T11:39:06+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a3ad0af8-ee2f-4933-b04f-6b9c44df9ed1","owner":[],"postedDate":"January 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[{"id":60882861,"name":"Biological sciences/Cancer"},{"id":60882862,"name":"Biological sciences/Genetics"},{"id":60882863,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2026-03-09T06:39:42+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-09 13:48:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7527596","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7527596","identity":"rs-7527596","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}