Multi-omic profiling identifies distinct MAPK-centric subgroups in BRAF- and PTPN11-mutant IDH-wildtype glioblastoma

Multi-omic profiling identifies distinct MAPK-centric subgroups in BRAF- and PTPN11-mutant IDH-wildtype glioblastoma | 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 Research Article Multi-omic profiling identifies distinct MAPK-centric subgroups in BRAF- and PTPN11-mutant IDH-wildtype glioblastoma Tim Vladimirov, László Bárány, Sebastian Jeising, Oliver Schnell, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9415669/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The role of MAPK pathway alterations in IDH-wildtype glioblastoma remains incompletely defined, particularly for BRAF and PTPN11 mutations. Methods We performed an integrated analysis of publicly available glioblastoma datasets (n = 641; IDH-wildtype n = 588), including 25 BRAF-mutated, 22 PTPN11-mutated, and 537 double-wildtype tumors. Clinical, genomic, transcriptomic, and epigenetic features were compared across subgroups. Results Clinical characteristics and overall survival did not differ between subgroups (global log-rank p = 0.60). In contrast, molecular analyses revealed distinct architectures. PTPN11-mutated tumors showed strong enrichment of RTK–RAS–MAPK signaling (OR 22.77, 95% CI 12.79–40.53, FDR < 0.001) with additional PI3K–AKT–mTOR and cell cycle activation, frequently co-occurring with NF1 alterations (68%). BRAF-mutated tumors also demonstrated MAPK enrichment (OR 4.09, 95% CI 2.21–7.56, FDR = 3.55 × 10⁻⁵) but with a more diffuse co-mutation landscape. Transcriptomic analyses identified a hyperactivated state in BRAF-mutated tumors, marked by proliferation, inflammatory, angiogenic, and metabolic programs, whereas PTPN11-mutated tumors clustered closer to double-wildtype glioblastoma. Conclusions BRAF- and PTPN11-mutant glioblastomas define distinct MAPK-centric subgroups without survival differences but with divergent molecular architectures, supporting pathway-informed stratification and therapeutic targeting. Glioblastoma BRAF PTPN11 Multi-omics Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. 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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-9415669","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":628361710,"identity":"e37bd2ee-728d-4238-be2f-2370da8602fd","order_by":0,"name":"Tim Vladimirov","email":"","orcid":"","institution":"University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg","correspondingAuthor":false,"prefix":"","firstName":"Tim","middleName":"","lastName":"Vladimirov","suffix":""},{"id":628361711,"identity":"b83665ef-c2f2-44fe-b120-63383c8e7636","order_by":1,"name":"László Bárány","email":"","orcid":"","institution":"University 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Erlangen-Nürnberg","correspondingAuthor":true,"prefix":"","firstName":"Dieter","middleName":"Henrik","lastName":"Heiland","suffix":""}],"badges":[],"createdAt":"2026-04-14 12:53:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9415669/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9415669/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108182727,"identity":"d1229461-288d-4d2d-8486-aa8a418a9cda","added_by":"auto","created_at":"2026-04-30 08:59:31","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1277581,"visible":true,"origin":"","legend":"","description":"","filename":"ManuscriptV2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9415669/v1_covered_fc2d535c-e5c3-45be-89cf-c59b4fe1b58d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Multi-omic profiling identifies distinct MAPK-centric subgroups in BRAF- and PTPN11-mutant IDH-wildtype glioblastoma","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Glioblastoma, BRAF, PTPN11, Multi-omics","lastPublishedDoi":"10.21203/rs.3.rs-9415669/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9415669/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe role of MAPK pathway alterations in IDH-wildtype glioblastoma remains incompletely defined, particularly for BRAF and PTPN11 mutations.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe performed an integrated analysis of publicly available glioblastoma datasets (n\u0026thinsp;=\u0026thinsp;641; IDH-wildtype n\u0026thinsp;=\u0026thinsp;588), including 25 BRAF-mutated, 22 PTPN11-mutated, and 537 double-wildtype tumors. Clinical, genomic, transcriptomic, and epigenetic features were compared across subgroups.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eClinical characteristics and overall survival did not differ between subgroups (global log-rank p\u0026thinsp;=\u0026thinsp;0.60). In contrast, molecular analyses revealed distinct architectures. PTPN11-mutated tumors showed strong enrichment of RTK\u0026ndash;RAS\u0026ndash;MAPK signaling (OR 22.77, 95% CI 12.79\u0026ndash;40.53, FDR\u0026thinsp;\u0026lt;\u0026thinsp;0.001) with additional PI3K\u0026ndash;AKT\u0026ndash;mTOR and cell cycle activation, frequently co-occurring with NF1 alterations (68%). BRAF-mutated tumors also demonstrated MAPK enrichment (OR 4.09, 95% CI 2.21\u0026ndash;7.56, FDR\u0026thinsp;=\u0026thinsp;3.55 \u0026times; 10⁻⁵) but with a more diffuse co-mutation landscape. Transcriptomic analyses identified a hyperactivated state in BRAF-mutated tumors, marked by proliferation, inflammatory, angiogenic, and metabolic programs, whereas PTPN11-mutated tumors clustered closer to double-wildtype glioblastoma.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eBRAF- and PTPN11-mutant glioblastomas define distinct MAPK-centric subgroups without survival differences but with divergent molecular architectures, supporting pathway-informed stratification and therapeutic targeting.\u003c/p\u003e","manuscriptTitle":"Multi-omic profiling identifies distinct MAPK-centric subgroups in BRAF- and PTPN11-mutant IDH-wildtype glioblastoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-24 12:36:40","doi":"10.21203/rs.3.rs-9415669/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6508d7b4-1bff-428a-8d7e-b10cdde73956","owner":[],"postedDate":"April 24th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Rejected","date":"2026-04-29T14:26:04+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-29T14:40:33+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-24 12:36:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9415669","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9415669","identity":"rs-9415669","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}