GenBlosum: On Determining Whether Cancer Mutations Are Functional or Random

GenBlosum: On Determining Whether Cancer Mutations Are Functional or Random | 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 GenBlosum: On Determining Whether Cancer Mutations Are Functional or Random Alejandro Leyva, Muhammad Khalid Khan Niazi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8348224/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 Genetic mutations have proven to be the epicenters of cancer and disease progression. Traditional WXS sequencing and BLOSUM scoring can be used to infer the evolutionary conservation of amino acid substitutions, though these approaches are not informed by evolutionary variants or probable base pair sequence changes. Within gene mutation analysis, most tools focus on the probability of amino acid changes, evolutionary conservation, or codon switching; however, no method is available that can integrate all levels of probability to compare onto a distributionally neutral model. We took the TCGA BRCA cohort and analyzed all mutation sequences for TP53 and PIK3CA, and developed a model that uses BLOSUM scoring and statistical analysis of base pair changes to generate the statistical significance of genetic mutations within the cohort. The mutational distribution was compared against a stochastic neutral model to determine the significance of all mutations in the cohort. Within the TCGA BRCA cohort, the model showed that TP53 and PIK3CA mutations were significant , and that TP53 was significantly more mutated than observationally neutral patterns relative to a codon-aware stochastic neutral model. Bioinformatics somatic mutation codon-aware model BLOSUM neutral evolution cancer genomics TP53 PIK3CA Monte Carlo simulation Full Text Additional Declarations The authors declare no competing interests. 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. 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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-8348224","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":559556718,"identity":"a4899967-e048-4b77-9852-24db6cf6235f","order_by":0,"name":"Alejandro Leyva","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYBACPghlI8cPYTAT1sIGodKMJRtI1HI4ccMBorWw95hJ/GBgTtx8vP2ZBEOFdWIDQS08Z8wkexjYjLedOWMmwXAmnQgtEjnGBjwMPLLbbuSwSTC2HSZCi/wbY8M/DBKMm2ekP5Ng/EeMFgkew8c8DAaKGyQSzCQYG4jRwpNW+FjGIMFY4swZY4uEY+nGBLXwsx/ecPBNxX85/vb2hzc+1FjLEtTCwMBhwMBgAGUnEFYOAuwPiFM3CkbBKBgFIxcAAMoTNt34I1FJAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0009-0002-0731-9383","institution":"Ohio State University","correspondingAuthor":true,"prefix":"","firstName":"Alejandro","middleName":"","lastName":"Leyva","suffix":""},{"id":559556719,"identity":"08786d8b-b8cc-4243-a155-5e621b2abe3e","order_by":1,"name":"Muhammad Khalid Khan Niazi","email":"","orcid":"https://orcid.org/0000-0002-1278-7512","institution":"Ohio State University","correspondingAuthor":false,"prefix":"","firstName":"Muhammad","middleName":"Khalid Khan","lastName":"Niazi","suffix":""}],"badges":[],"createdAt":"2025-12-12 18:12:28","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-8348224/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8348224/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":98432114,"identity":"c8c85849-a5b5-4692-9978-17b945e52a8f","added_by":"auto","created_at":"2025-12-17 16:49:01","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1351284,"visible":true,"origin":"","legend":"","description":"","filename":"GeneBlossums11.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8348224/v1_covered_f5489e9c-6ad0-4aa8-bdc2-0ff728136083.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eGenBlosum: On Determining Whether Cancer Mutations Are Functional or Random\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"The Ohio State University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"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":"somatic mutation, codon-aware model, BLOSUM, neutral evolution, cancer genomics, TP53, PIK3CA, Monte Carlo simulation","lastPublishedDoi":"10.21203/rs.3.rs-8348224/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8348224/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGenetic mutations have proven to be the epicenters of cancer and disease progression. 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