Bayesian Analysis of the Rate of Spontaneous Malignant Mesothelioma Among BAP1 Mutant Mice in the Absence of Asbestos Exposure

Bayesian Analysis of the Rate of Spontaneous Malignant Mesothelioma Among BAP1 Mutant Mice in the Absence of Asbestos Exposure | 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 Bayesian Analysis of the Rate of Spontaneous Malignant Mesothelioma Among BAP1 Mutant Mice in the Absence of Asbestos Exposure Dahlia M. Nielsen, Mei Hsu, Michael Zapata, Giovanni Ciavarra, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4987023/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Jan, 2025 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Cancers of the mesothelium, such as malignant mesothelioma (MM), historically have been attributed solely to exposure to asbestos. Recent large scale genetic and genomic functional studies now show that approximately 20% of all human mesotheliomas are causally linked to highly penetrant inherited (germline) pathogenic mutations in numerous cancer related genes. The rarity of these mutations in humans makes it difficult to perform statistically conclusive genetic studies to understand their biological effects. This has created a disconnect between functional and epidemiological studies. However, since the molecular pathogenesis of MM in mice accurately recapitulates that of human disease, this disconnect between functional and epidemiological studies can be overcome by using inbred mouse strains that harbor mutation(s) in genes involved in the disease. Most mouse studies have focused on the effect of asbestos exposure, leaving the effects of genetic mutations in the absence of exposure understudied. Here, using existing peer-reviewed studies, we investigate the rate of spontaneous MM among mice with and without germline genetic mutations, in the absence of asbestos exposure. We leveraged these published data to generate a historical control dataset (HCD) to allow us to improve statistical power and account for genetic heterogeneity between studies. Our Bayesian analyses indicate that the odds of spontaneous MM among germline BAP1 mutant mice is substantially larger than that of wildtype mice. These results support the existing biological study findings that mesotheliomas can arise in the presence of pathogenic germline mutations, independently of asbestos exposure. Biological sciences/Cancer/Mesothelioma Biological sciences/Genetics/Cancer genomics Mesothelioma Asbestos BAP1 Mouse Studies Historical Control Data Bayesian Statistics Figures Figure 1 Full Text Additional Declarations Competing interest reported. DMN declares no competing interests. MH, MZ and LvZ are employees of ArrayXpress Inc., which is a genomics company that provides research and scientific expert witness consultation in civil tort cases, among other services. LvZ serves as an expert witness in personal injury litigation. GC is an employee of Lumanity Clinical & Regulatory, which is a consultative company providing research and expert services in legal matters. Supplementary Files SAScodeallSUPPLEMENTAL.pdf Cite Share Download PDF Status: Published Journal Publication published 02 Jan, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Accepted 19 Dec, 2024 Reviews received at journal 05 Nov, 2024 Reviewers agreed at journal 24 Oct, 2024 Reviews received at journal 18 Sep, 2024 Reviewers agreed at journal 10 Sep, 2024 Reviewers agreed at journal 09 Sep, 2024 Reviewers invited by journal 09 Sep, 2024 Editor assigned by journal 09 Sep, 2024 Editor invited by journal 09 Sep, 2024 Submission checks completed at journal 04 Sep, 2024 First submitted to journal 27 Aug, 2024 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-4987023","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":356427173,"identity":"76a4da5a-adc6-4ba5-9b89-4082cf4ca3b7","order_by":0,"name":"Dahlia M. Nielsen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAUlEQVRIie3OMWvCQBTA8XccnMtp1vNbXBGEojRf5Y6ALkEKBSfnm9Jmtd+i3Tq+EmiXNFkDLkqWDh3SRXSw9NKpFBJ0E3r/6XG8H+8AXK5zDDlBBeO/z6yVgCUT4EBPIQDJCaT3+oa4XuS+38mT988nmHlxKqGaJ42kn84UqpeVjnjALu9TuBFFKMkyayYSQ4mKrRSHgA26BvSD4JJ2TQvJPyz5ynzulWxwqImXSnpoI/YbqA2SSAS0JDWBUFLSQvqFvaLvAh0V5ZDcGqGXxeT6OcqmjaSXhxeb3fbK78S6rPZmrOM4eVzv5qNG8jsmAMTPhEft22h17KbL5XL9r74BYy1chQPxOu8AAAAASUVORK5CYII=","orcid":"","institution":"North Carolina State University","correspondingAuthor":true,"prefix":"","firstName":"Dahlia","middleName":"M.","lastName":"Nielsen","suffix":""},{"id":356427175,"identity":"97a755ec-ac3b-4d5d-a6ca-71f7ed21ca5f","order_by":1,"name":"Mei Hsu","email":"","orcid":"","institution":"ArrayXpress, Inc","correspondingAuthor":false,"prefix":"","firstName":"Mei","middleName":"","lastName":"Hsu","suffix":""},{"id":356427177,"identity":"8698e276-40f2-4365-99bd-bbdbb2e3074e","order_by":2,"name":"Michael Zapata","email":"","orcid":"","institution":"ArrayXpress, Inc","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Zapata","suffix":""},{"id":356427178,"identity":"d9c2c8b1-4ce9-480a-ab4d-021e89943d24","order_by":3,"name":"Giovanni Ciavarra","email":"","orcid":"","institution":"Lumanity","correspondingAuthor":false,"prefix":"","firstName":"Giovanni","middleName":"","lastName":"Ciavarra","suffix":""},{"id":356427179,"identity":"fc6a026b-c885-4d31-b045-1a0f0419c0d1","order_by":4,"name":"Leonel Zyl","email":"","orcid":"","institution":"ArrayXpress, Inc","correspondingAuthor":false,"prefix":"","firstName":"Leonel","middleName":"","lastName":"Zyl","suffix":""}],"badges":[],"createdAt":"2024-08-27 22:52:48","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4987023/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4987023/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-84069-w","type":"published","date":"2025-01-02T15:57:41+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":66035987,"identity":"b577046a-f2b8-45ef-a7be-710f6a4f0966","added_by":"auto","created_at":"2024-10-07 04:47:43","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":77788,"visible":true,"origin":"","legend":"\u003cp\u003ePosterior probability distributions of the parameters P\u003csub\u003ew\u003c/sub\u003e and P\u003csub\u003em\u003c/sub\u003e (probability of an MM occurrence among wildtype and mutant mice, respectively). The distribution of P\u003csub\u003ew\u003c/sub\u003e is much narrower than that of P\u003csub\u003em\u003c/sub\u003e, reflecting the larger sample size contributed by the down-weighted HCD along with the base data. The 95% credible intervals of these distributions do not overlap.\u003c/p\u003e","description":"","filename":"BAP1MMFigure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4987023/v1/0b56912b128f2b033dc90fdd.jpg"},{"id":73094410,"identity":"76a33f9c-8cf2-40c6-bf32-64aa3878bddf","added_by":"auto","created_at":"2025-01-06 16:23:43","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":479058,"visible":true,"origin":"","legend":"","description":"","filename":"BAP1MMFINAL.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4987023/v1_covered_adb135a5-f2ad-4f54-a571-2342bb7a490c.pdf"},{"id":66035988,"identity":"f85fa84f-6ba7-41c5-a6a7-c51be4d063ca","added_by":"auto","created_at":"2024-10-07 04:47:43","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":96195,"visible":true,"origin":"","legend":"","description":"","filename":"SAScodeallSUPPLEMENTAL.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4987023/v1/b21ceeb234dca0e24bdf4c04.pdf"}],"financialInterests":"Competing interest reported. DMN declares no competing interests. MH, MZ and LvZ are employees of ArrayXpress Inc., which is a genomics company that provides research and scientific expert witness consultation in civil tort cases, among other services. LvZ serves as an expert witness in personal injury litigation. GC is an employee of Lumanity Clinical \u0026 Regulatory, which is a consultative company providing research and expert services in legal matters.","formattedTitle":"Bayesian Analysis of the Rate of Spontaneous Malignant Mesothelioma Among BAP1 Mutant Mice in the Absence of Asbestos Exposure","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"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":"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":"Mesothelioma, Asbestos, BAP1, Mouse Studies, Historical Control Data, Bayesian Statistics","lastPublishedDoi":"10.21203/rs.3.rs-4987023/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4987023/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Cancers of the mesothelium, such as malignant mesothelioma (MM), historically have been attributed solely to exposure to asbestos. Recent large scale genetic and genomic functional studies now show that approximately 20% of all human mesotheliomas are causally linked to highly penetrant inherited (germline) pathogenic mutations in numerous cancer related genes. The rarity of these mutations in humans makes it difficult to perform statistically conclusive genetic studies to understand their biological effects. This has created a disconnect between functional and epidemiological studies. However, since the molecular pathogenesis of MM in mice accurately recapitulates that of human disease, this disconnect between functional and epidemiological studies can be overcome by using inbred mouse strains that harbor mutation(s) in genes involved in the disease. Most mouse studies have focused on the effect of asbestos exposure, leaving the effects of genetic mutations in the absence of exposure understudied. Here, using existing peer-reviewed studies, we investigate the rate of spontaneous MM among mice with and without germline genetic mutations, in the absence of asbestos exposure. We leveraged these published data to generate a historical control dataset (HCD) to allow us to improve statistical power and account for genetic heterogeneity between studies. Our Bayesian analyses indicate that the odds of spontaneous MM among germline BAP1 mutant mice is substantially larger than that of wildtype mice. These results support the existing biological study findings that mesotheliomas can arise in the presence of pathogenic germline mutations, independently of asbestos exposure.","manuscriptTitle":"Bayesian Analysis of the Rate of Spontaneous Malignant Mesothelioma Among BAP1 Mutant Mice in the Absence of Asbestos Exposure","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-07 04:47:39","doi":"10.21203/rs.3.rs-4987023/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2024-12-19T08:24:49+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-05T14:36:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"9752091394065020738370292840035745550","date":"2024-10-24T19:26:00+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-18T10:11:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"77478775525227184831166103934393937980","date":"2024-09-10T09:52:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"222641111358196609394138180066515701469","date":"2024-09-09T16:41:36+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-09T15:43:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-09T15:38:25+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-09-09T04:48:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-09-04T10:43:12+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-08-27T22:51:27+00:00","index":"","fulltext":""}],"status":"published","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}}],"origin":"","ownerIdentity":"9942f258-fc2e-46d9-a324-7a69a3da6312","owner":[],"postedDate":"October 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":37904217,"name":"Biological sciences/Cancer/Mesothelioma"},{"id":37904218,"name":"Biological sciences/Genetics/Cancer genomics"}],"tags":[],"updatedAt":"2025-01-06T16:21:51+00:00","versionOfRecord":{"articleIdentity":"rs-4987023","link":"https://doi.org/10.1038/s41598-024-84069-w","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-01-02 15:57:41","publishedOnDateReadable":"January 2nd, 2025"},"versionCreatedAt":"2024-10-07 04:47:39","video":"","vorDoi":"10.1038/s41598-024-84069-w","vorDoiUrl":"https://doi.org/10.1038/s41598-024-84069-w","workflowStages":[]},"version":"v1","identity":"rs-4987023","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4987023","identity":"rs-4987023","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}