A minimal transcriptomic signature predicts intravascular tumor extension in renal cell carcinoma

A minimal transcriptomic signature predicts intravascular tumor extension in renal cell carcinoma | 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 A minimal transcriptomic signature predicts intravascular tumor extension in renal cell carcinoma Christopher Mao, Ramiro Ramirez, Hanzhang Wang, Wasim Chowdery, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9042174/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Renal cell carcinoma (RCC) with venous tumor thrombus, termed renal intravascular tumor extension (RITE), is associated with aggressive behavior and poor clinical outcomes. Yet, its underlying molecular determinants remain incompletely defined. We analyzed RNA sequencing data from three independent RCC cohorts comprising 721 samples. Two cohorts included matched samples of index tumor, tumor thrombus, and normal adjacent kidney tissue. Analyses integrated dimensionality reduction, differential gene expression, interpretable machine learning, and gene ontology approaches. Principal component analysis revealed that only these two cohorts exhibited a coherent RITE-associated transcriptional structure. Their sequencing depth was sufficient to delineate 6,317 differentially expressed genes that distinguish RITE from non-RITE tumors. SHAP-based feature attribution across logistic regression, random forest, and XGBoost yielded a robust 29-gene consensus signature, which was further distilled into a compact 13-gene panel that preserved maximal classification performance. These genes converged on biological themes, including loss of distal epithelial identity, dysregulation of ion transport pathways, and consistent enrichment of mitochondrial processes such as oxidative phosphorylation. Together, these findings define a newly discovered and uniquely refined molecular signature of venous tumor extension in RCC and highlight mechanistically relevant pathways that may inform biomarker development and future translational strategies for predicting or mitigating RITE progression. Health sciences/Biomarkers Biological sciences/Cancer Biological sciences/Computational biology and bioinformatics Health sciences/Oncology Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 10 Mar, 2026 Editor assigned by journal 09 Mar, 2026 Submission checks completed at journal 09 Mar, 2026 First submitted to journal 05 Mar, 2026 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-9042174","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":601360482,"identity":"e1ecd6a3-cce5-4e65-bc13-e7d0c5a44ed7","order_by":0,"name":"Christopher Mao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtUlEQVRIiWNgGAWjYLCCDwwMCVAmM3E6GGcwGJCohZmHJC267YcPfrZt+5Mn33784QeGCuvEBkJazM6kJUvnthkUG5zJMZZgOJNOhJYDOWbMQC2JGyR4GCQY2w4ToeX8GzNmS6CW+TPYH/9g/EeMlhtAWxiBWhpuMJhJMDYQpeVZsmTPOePEDWdyzCwSjqUbE+Gw5IMffpTJJc5vP/74xocaa1mCWlBBAmnKR8EoGAWjYBTgAgBEST7XwzukjwAAAABJRU5ErkJggg==","orcid":"","institution":"University of Texas Health Science Center San Antonio","correspondingAuthor":true,"prefix":"","firstName":"Christopher","middleName":"","lastName":"Mao","suffix":""},{"id":601360483,"identity":"01018cb9-9780-4cf2-b77b-042599971a37","order_by":1,"name":"Ramiro Ramirez","email":"","orcid":"","institution":"University of Texas Health Science Center San Antonio","correspondingAuthor":false,"prefix":"","firstName":"Ramiro","middleName":"","lastName":"Ramirez","suffix":""},{"id":601360485,"identity":"67cd7550-82cb-4481-9618-44690e3dd86d","order_by":2,"name":"Hanzhang Wang","email":"","orcid":"","institution":"Brown University Health","correspondingAuthor":false,"prefix":"","firstName":"Hanzhang","middleName":"","lastName":"Wang","suffix":""},{"id":601360487,"identity":"dfc3b50f-3b63-4aa5-b4b0-83e095206c35","order_by":3,"name":"Wasim Chowdery","email":"","orcid":"","institution":"The University of Texas Health Science Center at San Antonio","correspondingAuthor":false,"prefix":"","firstName":"Wasim","middleName":"","lastName":"Chowdery","suffix":""},{"id":601360488,"identity":"e1e23e7d-5d41-4d83-bc56-a1005d327d76","order_by":4,"name":"Dharam Kaushik","email":"","orcid":"","institution":"Houston Methodist","correspondingAuthor":false,"prefix":"","firstName":"Dharam","middleName":"","lastName":"Kaushik","suffix":""},{"id":601360489,"identity":"a33f8b83-d037-4ae2-af59-45a74108031d","order_by":5,"name":"Ronald Rodriguez","email":"","orcid":"","institution":"University of Texas Health Science Center at San Antonio","correspondingAuthor":false,"prefix":"","firstName":"Ronald","middleName":"","lastName":"Rodriguez","suffix":""}],"badges":[],"createdAt":"2026-03-05 15:54:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9042174/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9042174/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104062974,"identity":"bcee5335-3228-4c40-89ea-b3a911d6a4f2","added_by":"auto","created_at":"2026-03-06 10:03:59","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2482141,"visible":true,"origin":"","legend":"","description":"","filename":"RITEforScientificReports.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9042174/v1_covered_6c135e15-7c18-40ae-b414-036a44f7999f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A minimal transcriptomic signature predicts intravascular tumor extension in renal cell carcinoma","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"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":"","lastPublishedDoi":"10.21203/rs.3.rs-9042174/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9042174/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Renal cell carcinoma (RCC) with venous tumor thrombus, termed renal intravascular tumor extension (RITE), is associated with aggressive behavior and poor clinical outcomes. Yet, its underlying molecular determinants remain incompletely defined. We analyzed RNA sequencing data from three independent RCC cohorts comprising 721 samples. Two cohorts included matched samples of index tumor, tumor thrombus, and normal adjacent kidney tissue. Analyses integrated dimensionality reduction, differential gene expression, interpretable machine learning, and gene ontology approaches. Principal component analysis revealed that only these two cohorts exhibited a coherent RITE-associated transcriptional structure. Their sequencing depth was sufficient to delineate 6,317 differentially expressed genes that distinguish RITE from non-RITE tumors. SHAP-based feature attribution across logistic regression, random forest, and XGBoost yielded a robust 29-gene consensus signature, which was further distilled into a compact 13-gene panel that preserved maximal classification performance. 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