Construction of a Survival Prediction Model and Molecular Subtype Analysis Based on TARGET Osteosarcoma Multi-omics Data

Construction of a Survival Prediction Model and Molecular Subtype Analysis Based on TARGET Osteosarcoma Multi-omics Data | 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 Construction of a Survival Prediction Model and Molecular Subtype Analysis Based on TARGET Osteosarcoma Multi-omics Data Qiang Wang, Shiming Huang, Ying Li, Daohua Chen, Dongfeng Chen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8201160/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background Osteosarcoma is the most common malignant bone tumor in adolescents and young adults, characterized by high heterogeneity and poor prognosis. Despite advances in multimodal therapy, reliable prognostic biomarkers and molecular classifications remain limited. Methods Multi-omics data (RNA-seq, miRNA expression, CNV, DNA methylation, and clinical variables) were obtained from the TARGET osteosarcoma cohort. After normalization and batch effect correction, prognostic features were identified using univariate Cox regression and LASSO-Cox modeling. Prognostic risk scores were constructed and validated with time-dependent ROC, C-index, Brier score, and calibration analyses. Consensus clustering and multi-omics factor analysis (MOFA) were applied to define molecular subtypes. Results Transcriptomic features exhibited the strongest prognostic performance (C-index = 0.726), outperforming clinical-only or integrated multi-omics models. A minimal LASSO-Cox gene signature stratified patients into high- and low-risk groups with significantly different survival outcomes (log-rank p < 0.001). Consensus clustering identified two robust molecular subtypes, which displayed distinct survival patterns, clinical characteristics, and multi-omics profiles. Mechanistic analysis suggested that dysregulation of PI3K/AKT, Wnt/β-catenin, and TGF-β signaling, combined with an immunosuppressive tumor microenvironment, underlies poor prognosis in the high-risk subtype. Conclusions We developed a robust prognostic model and identified biologically distinct molecular subtypes in osteosarcoma using integrative multi-omics analysis. These findings provide new insights into tumor heterogeneity and potential precision therapeutic strategies. Osteosarcoma Multi-omics integration Prognostic model LASSO-Cox regression Molecular subtypes TARGET database Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 04 Feb, 2026 Reviewers invited by journal 09 Dec, 2025 Editor assigned by journal 06 Dec, 2025 Editor invited by journal 05 Dec, 2025 Submission checks completed at journal 05 Dec, 2025 First submitted to journal 28 Nov, 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8201160","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":557843461,"identity":"7cef66b4-db07-4462-be44-2394885d1bfb","order_by":0,"name":"Qiang Wang","email":"","orcid":"","institution":"Longyan First Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qiang","middleName":"","lastName":"Wang","suffix":""},{"id":557843462,"identity":"90cd353f-6af9-40a7-9902-970b2b781fb4","order_by":1,"name":"Shiming Huang","email":"","orcid":"","institution":"Longyan First Affiliated Hospital 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Data","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":"bmc-musculoskeletal-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmsd","sideBox":"Learn more about [BMC Musculoskeletal Disorders](http://bmcmusculoskeletdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://author-welcome.nature.com/12891","title":"BMC Musculoskeletal Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Osteosarcoma, Multi-omics integration, Prognostic model, LASSO-Cox regression, Molecular subtypes, TARGET database","lastPublishedDoi":"10.21203/rs.3.rs-8201160/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8201160/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eOsteosarcoma is the most common malignant bone tumor in adolescents and young adults, characterized by high heterogeneity and poor prognosis. Despite advances in multimodal therapy, reliable prognostic biomarkers and molecular classifications remain limited.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eMulti-omics data (RNA-seq, miRNA expression, CNV, DNA methylation, and clinical variables) were obtained from the TARGET osteosarcoma cohort. After normalization and batch effect correction, prognostic features were identified using univariate Cox regression and LASSO-Cox modeling. Prognostic risk scores were constructed and validated with time-dependent ROC, C-index, Brier score, and calibration analyses. Consensus clustering and multi-omics factor analysis (MOFA) were applied to define molecular subtypes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eTranscriptomic features exhibited the strongest prognostic performance (C-index\u0026thinsp;=\u0026thinsp;0.726), outperforming clinical-only or integrated multi-omics models. A minimal LASSO-Cox gene signature stratified patients into high- and low-risk groups with significantly different survival outcomes (log-rank \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Consensus clustering identified two robust molecular subtypes, which displayed distinct survival patterns, clinical characteristics, and multi-omics profiles. Mechanistic analysis suggested that dysregulation of PI3K/AKT, Wnt/β-catenin, and TGF-β signaling, combined with an immunosuppressive tumor microenvironment, underlies poor prognosis in the high-risk subtype.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eWe developed a robust prognostic model and identified biologically distinct molecular subtypes in osteosarcoma using integrative multi-omics analysis. These findings provide new insights into tumor heterogeneity and potential precision therapeutic strategies.\u003c/p\u003e","manuscriptTitle":"Construction of a Survival Prediction Model and Molecular Subtype Analysis Based on TARGET Osteosarcoma Multi-omics Data","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-15 15:36:37","doi":"10.21203/rs.3.rs-8201160/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"130249595769506482890446132539673828407","date":"2026-02-04T17:16:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-09T20:20:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-06T14:52:36+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-05T11:07:35+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-05T10:56:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Musculoskeletal Disorders","date":"2025-11-28T07:34:54+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-musculoskeletal-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmsd","sideBox":"Learn more about [BMC Musculoskeletal Disorders](http://bmcmusculoskeletdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://author-welcome.nature.com/12891","title":"BMC Musculoskeletal Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6f323444-4bfe-47ee-8eeb-64737d53ccfc","owner":[],"postedDate":"December 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-12-15T15:36:37+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-15 15:36:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8201160","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8201160","identity":"rs-8201160","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}