Characterizing selection signatures in coding and noncoding regions of 14,886 cancer genomes

Characterizing selection signatures in coding and noncoding regions of 14,886 cancer genomes | 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 Characterizing selection signatures in coding and noncoding regions of 14,886 cancer genomes Jian Yang, Mengyue Zheng, Xiwei Sun, Junren Hou, Minmin Guo, Xinran Liu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5500973/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 Clonal selection drives cancer development, but quantifying selection on noncoding somatic mutations remains largely unexplored. Here, we introduce dNdS-Fun, an extension of the dN/dS framework to quantify selection of both coding and noncoding somatic mutations, thereby enhancing the discovery of driver genes. Applying dNdS-Fun to whole-genome sequencing data from 14,886 cancer patients across 31 cancer types, we identified 196 genes under positive selection across multiple cancer types or datasets. Of these, 83 were previously unrecognized as drivers, and 56 were identified solely through noncoding mutations. Additionally, we observed widespread negative selection throughout the genome, particularly enriched in essential or cancer-dependent genes. Twenty genes exhibited an overall signature of negative selection but showed positive selection in noncoding elements, indicating both their conserved functions and adaptive regulatory roles in tumorigenesis. Our study reveals pervasive selection signatures of non-coding mutations, providing important insights for future research on their roles in cancer progression. Health sciences/Diseases/Cancer/Cancer therapy/Targeted therapies Biological sciences/Cancer/Cancer prevention Full Text Additional Declarations There is NO Competing Interest. Supplementary Files dNdSFunSuppFigures22Nov2024.pdf Supplementary Figures 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. 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-5500973","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":390075854,"identity":"3fbf2595-01de-42a7-a15f-fbaae9ea0dea","order_by":0,"name":"Jian Yang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEUlEQVRIiWNgGAWjYBACxmYYi70BRFowSIAoHqK08BwAEgkShLUggEQCkVqY25mfPWBss8uTj3xj+PDnDwl5yfYGxgdv2xjkzXE6jM3cgLEtudjwdo6xMU+ChOFsngPMhnPbGAx3NuD0i5kEYxtz4sbZudukgQ5jnCeRwCbN28aQYHAAlxb2b0At9YkbZ57d/vNHgoT9PPkH7L/xa+EB2XI4cb4E7zYGoMMSZ0swsDET0FImkXDueOIGnvzP0jxpEskzexKbJeeckzDcgEOLYf/xbRIfyqoT57cfS/z4w8bGdsbxwwc/vCmzkcdliyEoWBLZGBiQFDCCxCSwqwcCeTD5B8howKlmFIyCUTAKRjoAAMknVfQI80mpAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-2001-2474","institution":"Westlake University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jian","middleName":"","lastName":"Yang","suffix":""},{"id":390075855,"identity":"c4cab51b-599f-4d94-9eea-43e95cbff1d2","order_by":1,"name":"Mengyue Zheng","email":"","orcid":"","institution":"College of Life Sciences, Zhejiang University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mengyue","middleName":"","lastName":"Zheng","suffix":""},{"id":390075856,"identity":"207a59be-49cb-4eb2-a272-3da24dacd538","order_by":2,"name":"Xiwei Sun","email":"","orcid":"","institution":"Westlake University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiwei","middleName":"","lastName":"Sun","suffix":""},{"id":390075857,"identity":"94a207aa-1360-420f-807a-1ff94e99a33a","order_by":3,"name":"Junren Hou","email":"","orcid":"https://orcid.org/0009-0009-7016-707X","institution":"School of Life Sciences, Westlake University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Junren","middleName":"","lastName":"Hou","suffix":""},{"id":390075858,"identity":"8c5bfe96-11f9-47f8-b9dc-fdab3be98664","order_by":4,"name":"Minmin Guo","email":"","orcid":"","institution":"School of Life Sciences, Westlake University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Minmin","middleName":"","lastName":"Guo","suffix":""},{"id":390075859,"identity":"8e4e5e95-f12a-45f3-82a8-8c186394852c","order_by":5,"name":"Xinran Liu","email":"","orcid":"","institution":"School of Life Sciences, Westlake University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xinran","middleName":"","lastName":"Liu","suffix":""},{"id":390075860,"identity":"b874c55f-b1ae-4826-9d3b-d2bc2476b16f","order_by":6,"name":"Wen Yang","email":"","orcid":"","institution":"School of Life Sciences, Westlake University/Westlake Laboratory of Life Sciences and Biomedicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wen","middleName":"","lastName":"Yang","suffix":""}],"badges":[],"createdAt":"2024-11-22 02:20:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5500973/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5500973/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":75153486,"identity":"99bc9d98-2bd7-4d86-9053-3c893eb186af","added_by":"auto","created_at":"2025-01-31 09:44:46","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3143977,"visible":true,"origin":"","legend":"Article File","description":"","filename":"dNdSFunManuscript22Nov2024.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5500973/v1_covered_9c59ba71-c1f7-4411-af61-3a277deb6ad2.pdf"},{"id":71470683,"identity":"1d9b38a1-9d0d-451f-8b34-6a79164cdaee","added_by":"auto","created_at":"2024-12-16 04:01:46","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":7930761,"visible":true,"origin":"","legend":"Supplementary Figures","description":"","filename":"dNdSFunSuppFigures22Nov2024.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5500973/v1/e39ded8c38460778798bd140.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Characterizing selection signatures in coding and noncoding regions of 14,886 cancer genomes","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"","lastPublishedDoi":"10.21203/rs.3.rs-5500973/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5500973/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Clonal selection drives cancer development, but quantifying selection on noncoding somatic mutations remains largely unexplored. Here, we introduce dNdS-Fun, an extension of the dN/dS framework to quantify selection of both coding and noncoding somatic mutations, thereby enhancing the discovery of driver genes. Applying dNdS-Fun to whole-genome sequencing data from 14,886 cancer patients across 31 cancer types, we identified 196 genes under positive selection across multiple cancer types or datasets. Of these, 83 were previously unrecognized as drivers, and 56 were identified solely through noncoding mutations. Additionally, we observed widespread negative selection throughout the genome, particularly enriched in essential or cancer-dependent genes. Twenty genes exhibited an overall signature of negative selection but showed positive selection in noncoding elements, indicating both their conserved functions and adaptive regulatory roles in tumorigenesis. Our study reveals pervasive selection signatures of non-coding mutations, providing important insights for future research on their roles in cancer progression.","manuscriptTitle":"Characterizing selection signatures in coding and noncoding regions of 14,886 cancer genomes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-16 04:01:41","doi":"10.21203/rs.3.rs-5500973/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":"95050e59-9e42-42ac-8c5f-578e01e74e1a","owner":[],"postedDate":"December 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":41581367,"name":"Health sciences/Diseases/Cancer/Cancer therapy/Targeted therapies"},{"id":41581368,"name":"Biological sciences/Cancer/Cancer prevention"}],"tags":[],"updatedAt":"2025-01-31T09:36:35+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-16 04:01:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5500973","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5500973","identity":"rs-5500973","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}