TP53 Mutations as Drivers of Chordoma Progression and Hallmarks of Aggressive Chordoma

TP53 Mutations as Drivers of Chordoma Progression and Hallmarks of Aggressive Chordoma | 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 TP53 Mutations as Drivers of Chordoma Progression and Hallmarks of Aggressive Chordoma Szymon Piotr Baluszek, Paulina Kober, Michał Wągrodzki, Jacek Kunicki, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7374485/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Dec, 2025 Read the published version in Acta Neuropathologica Communications → Version 1 posted 9 You are reading this latest preprint version Abstract Introduction: Dedifferentiated (DC) and poorly differentiated chordomas (PDC) are rare, aggressive chordomas with a significantly worse prognosis than conventional chordomas (CC). The molecular mechanisms, driving them, remain poorly understood. Methods: Matched primary CC and recurrent DC cryopreserved samples from one patient were analyzed with whole-exome sequencing (WES). Targeted sequencing of cancer-related genes in three additional DC cases, one PDC. Furthermore, 102 CC cases - 32 novel and 70 from literature were analyzed. Functional and survival analysis was performed. Results: WES revealed striking genomic changes during progression from CC to DC, with the number of somatic mutations increasing from 211 in primary to 430 in the recurrent DC; recurrence acquired TP53 and BRCA1 deleterious mutations, along with copy-number alterations, including loss of 6q containing the TBXT locus. Targeted sequencing identified TP53 mutations in 4/5 DC&PDC cases compared to 1/102 cases in combined CC cohorts (p=2.7×10-5, OR=162.9). In 3 recurrent DC samples with TP53 variant, presence of the mutation was assessed in primary CC sample and in neither this variant was found. Literature review revealed TP53 mutations in 9/23 (39\%) DC&PDC cases versus 5/445 (1.24\%) CC cases. Survival analysis demonstrated that TP53 mutations confer a significantly worse prognosis in DC patients (p = 0.03). Conclusion: TP53 mutations are acquired during chordoma progression and are associated with an aggressive phenotype; TP53 sequencing could serve as a prognostic and potentially predictive biomarker in aggressive chordomas. Full Text Additional Declarations No competing interests reported. Supplementary Files STable1.xlsx STable2.csv STable3.csv Cite Share Download PDF Status: Published Journal Publication published 19 Dec, 2025 Read the published version in Acta Neuropathologica Communications → Version 1 posted Editorial decision: Revision requested 28 Oct, 2025 Reviews received at journal 27 Oct, 2025 Reviewers agreed at journal 11 Oct, 2025 Reviews received at journal 22 Sep, 2025 Reviewers agreed at journal 08 Sep, 2025 Reviewers invited by journal 23 Aug, 2025 Editor assigned by journal 19 Aug, 2025 Submission checks completed at journal 19 Aug, 2025 First submitted to journal 14 Aug, 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. 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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-7374485","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":518957273,"identity":"37329ff1-e9e1-4214-9d6e-8c40f6501e70","order_by":0,"name":"Szymon Piotr Baluszek","email":"","orcid":"","institution":"The Maria Sklodowska-Curie National Research Institute of Oncology","correspondingAuthor":false,"prefix":"","firstName":"Szymon","middleName":"Piotr","lastName":"Baluszek","suffix":""},{"id":518957274,"identity":"2ecda89d-d2ec-46ca-bd9c-df7efb2d6003","order_by":1,"name":"Paulina Kober","email":"","orcid":"","institution":"The Maria Sklodowska-Curie National Research Institute of Oncology","correspondingAuthor":false,"prefix":"","firstName":"Paulina","middleName":"","lastName":"Kober","suffix":""},{"id":518957275,"identity":"38f6c167-9d4e-430c-a2d9-e47834ef08d8","order_by":2,"name":"Michał Wągrodzki","email":"","orcid":"","institution":"The Maria Sklodowska-Curie National Research Institute of Oncology","correspondingAuthor":false,"prefix":"","firstName":"Michał","middleName":"","lastName":"Wągrodzki","suffix":""},{"id":518957276,"identity":"6d259ad2-6e83-4838-af29-65e08c0d32f8","order_by":3,"name":"Jacek Kunicki","email":"","orcid":"","institution":"The Maria Sklodowska-Curie National Research Institute of Oncology","correspondingAuthor":false,"prefix":"","firstName":"Jacek","middleName":"","lastName":"Kunicki","suffix":""},{"id":518957277,"identity":"41794b86-86aa-4df5-921e-f7c9bd8d13df","order_by":4,"name":"Bartosz Wojtaś","email":"","orcid":"","institution":"Instytut Biologii Doświadczalnej im. 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Chordoma","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":true,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"acta-neuropathologica-communications","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anec","sideBox":"Learn more about [Acta Neuropathologica Communications](https://actaneurocomms.biomedcentral.com/)","snPcode":"40478","submissionUrl":"https://submission.springernature.com/new-submission/40478/3","title":"Acta Neuropathologica Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7374485/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7374485/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIntroduction: Dedifferentiated (DC) and poorly differentiated chordomas (PDC) are rare, aggressive chordomas with a significantly worse prognosis than conventional chordomas (CC). The molecular mechanisms, driving them, remain poorly understood.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethods: Matched primary CC and recurrent DC cryopreserved samples from one patient were analyzed with whole-exome sequencing (WES). Targeted sequencing of cancer-related genes in three additional DC cases, one PDC. Furthermore, 102 CC cases - 32 novel and 70 from literature were analyzed. Functional and survival analysis was performed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResults: WES revealed striking genomic changes during progression from CC to DC, with the number of somatic mutations increasing from 211 in primary to 430 in the recurrent DC; recurrence acquired\u0026nbsp;TP53 and BRCA1 deleterious mutations, along with copy-number alterations, including loss of 6q containing the TBXT locus. Targeted sequencing identified\u0026nbsp;TP53 mutations in 4/5 DC\u0026amp;PDC cases compared to 1/102 cases in combined CC cohorts (p=2.7×10-5, OR=162.9). In 3 recurrent DC samples with\u0026nbsp;TP53 variant, presence of the mutation was assessed in primary CC sample and in neither this variant was found. Literature review revealed TP53 mutations in 9/23 (39\\%) DC\u0026amp;PDC cases versus 5/445 (1.24\\%) CC cases. Survival analysis demonstrated that TP53 mutations confer a significantly worse prognosis in DC patients (p = 0.03).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConclusion: TP53\u0026nbsp;mutations are acquired during chordoma progression and are associated with an aggressive phenotype;\u0026nbsp;TP53 sequencing could serve as a prognostic and potentially predictive biomarker in aggressive chordomas.\u003c/p\u003e","manuscriptTitle":"TP53 Mutations as Drivers of Chordoma Progression and Hallmarks of Aggressive Chordoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-25 13:25:50","doi":"10.21203/rs.3.rs-7374485/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-28T04:23:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-28T02:26:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"216738398010435184845444303756952138201","date":"2025-10-11T19:05:55+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-22T20:26:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"206088988088850146913129501489982962755","date":"2025-09-08T23:09:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-24T03:16:35+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-20T03:12:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-20T03:12:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"Acta Neuropathologica Communications","date":"2025-08-14T13:39:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"acta-neuropathologica-communications","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anec","sideBox":"Learn more about [Acta Neuropathologica Communications](https://actaneurocomms.biomedcentral.com/)","snPcode":"40478","submissionUrl":"https://submission.springernature.com/new-submission/40478/3","title":"Acta Neuropathologica Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"672b6687-0b23-4ba3-9092-6d9bf2b00c52","owner":[],"postedDate":"September 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-22T16:00:00+00:00","versionOfRecord":{"articleIdentity":"rs-7374485","link":"https://doi.org/10.1186/s40478-025-02180-z","journal":{"identity":"acta-neuropathologica-communications","isVorOnly":false,"title":"Acta Neuropathologica Communications"},"publishedOn":"2025-12-19 15:57:19","publishedOnDateReadable":"December 19th, 2025"},"versionCreatedAt":"2025-09-25 13:25:50","video":"","vorDoi":"10.1186/s40478-025-02180-z","vorDoiUrl":"https://doi.org/10.1186/s40478-025-02180-z","workflowStages":[]},"version":"v1","identity":"rs-7374485","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7374485","identity":"rs-7374485","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}