Genes associated with genetic and rare lung diseases and the risk of lung cancer

Genes associated with genetic and rare lung diseases and the risk of lung cancer | 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 Genes associated with genetic and rare lung diseases and the risk of lung cancer Albert Rosenberger, Heike Bickeböller, David C Christiani, Neil E. Caporaso, and 30 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7029929/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Apr, 2026 Read the published version in BMC Cancer → Version 1 posted 10 You are reading this latest preprint version Abstract Background We investigated whether markers, genes or terms of the Human Phenotype Ontology associated with genetic or rare diseases (GARDs) that affect airway or lung function are associated with lung cancer. Methods Genes of interest were extracted from GARD , OMIM , ORPHANET and Monarch Initiative. Individual SNP, gene level and gene-set analyses were performed for 52,207 SNPs, 1,677 genes or for 620 terms of the Human Phenotype Ontology . The analysis included 14,068 lung cancer cases and 12,390 cancer-free control subjects of European descent from the International Lung Cancer Consortium ILCCO. Results The marker rs56113850 (OR = 0.893, 95%CI: 0.862–0.924) was associated with lung cancer (p = 1.2x10 − 10 ). This marker is located in CYP2A6 as well as in an enhancer region of LTBP4 , which is associated with cutis laxa. A suggestive significant association was observed for two markers associated with the DMD gene, which is linked to Duchenne muscular dystrophy. The gene sets "Abnormal circulating adrenocorticotropin concentration" and "Central nervous system neoplasm" were found to be significantly enriched with GARD genes, and can therefore be considered to be associated with lung cancer. Conclusions Genes associated with genetic and rare lung diseases do not generally appear to carry risk factors for lung cancer. However, genes associated with the hypothalamic-pituitary-adrenal axis show some, but rather weak or complex, associations with lung cancer. Tests at the gene level provide extremely inhomogeneous results, even when applied to the same data. lung cancer genomic marker rare disease GARD gene-set analysis gene-based test adrenocorticotropic hormone Hypothalamic-Pituitary-Adrenal axis OMIM Orphanet CYP2A6 DMD LTBP4 Full Text Additional Declarations No competing interests reported. Supplementary Files GARDgenesandLCSupportinginformationV1.8ohneKorrekturen.pdf Cite Share Download PDF Status: Published Journal Publication published 01 Apr, 2026 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Revision requested 13 Feb, 2026 Reviews received at journal 21 Aug, 2025 Reviewers agreed at journal 21 Aug, 2025 Reviews received at journal 14 Aug, 2025 Reviewers agreed at journal 06 Aug, 2025 Reviewers invited by journal 06 Aug, 2025 Editor invited by journal 07 Jul, 2025 Editor assigned by journal 04 Jul, 2025 Submission checks completed at journal 04 Jul, 2025 First submitted to journal 02 Jul, 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-7029929","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":497789606,"identity":"c5f863ce-0f61-4cf1-b6a3-ccf684521cd6","order_by":0,"name":"Albert Rosenberger","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAw0lEQVRIiWNgGAWjYPCCA3JAwoCBgY0ELcaka0lsIFoL/+zDhz983HEnfX5E8uYXDGU2hLVInEtLk5x55lnuxhtpZRYM59KIsOYMjxkzb9vh3I2zc8wMGNsOE9Yhf4bH+PPftsPphhAt/wlrMTjDYyANNDxBXjrH+AFj2wHCWgzPsKVJ9rY9M9wg/6yMIeFcMmEtcmeYD3/42XZHXr7n8OYPH8rsCGtBuPAAA5tEAgkagOHQwMD8gSQdo2AUjIJRMGIAAPo0PnqQiBshAAAAAElFTkSuQmCC","orcid":"","institution":"University Medical Center, GeorgAugust‐University Göttingen","correspondingAuthor":true,"prefix":"","firstName":"Albert","middleName":"","lastName":"Rosenberger","suffix":""},{"id":497789607,"identity":"6a38f440-82d5-4adc-af29-9ccbd8e690da","order_by":1,"name":"Heike Bickeböller","email":"","orcid":"","institution":"University Medical Center, GeorgAugust‐University Göttingen","correspondingAuthor":false,"prefix":"","firstName":"Heike","middleName":"","lastName":"Bickeböller","suffix":""},{"id":497789608,"identity":"dc8fd3a2-8090-4f91-9cbb-d375e782d781","order_by":2,"name":"David C Christiani","email":"","orcid":"","institution":"Harvard T.H. 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Individual SNP, gene level and gene-set analyses were performed for 52,207 SNPs, 1,677 genes or for 620 terms of the \u003cem\u003eHuman Phenotype Ontology\u003c/em\u003e. The analysis included 14,068 lung cancer cases and 12,390 cancer-free control subjects of European descent from the International Lung Cancer Consortium ILCCO.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe marker rs56113850 (OR\u0026thinsp;=\u0026thinsp;0.893, 95%CI: 0.862\u0026ndash;0.924) was associated with lung cancer (p\u0026thinsp;=\u0026thinsp;1.2x10\u003csup\u003e\u0026minus;\u0026thinsp;10\u003c/sup\u003e). This marker is located in CYP2A6 as well as in an enhancer region of \u003cem\u003eLTBP4\u003c/em\u003e, which is associated with cutis laxa. A suggestive significant association was observed for two markers associated with the \u003cem\u003eDMD\u003c/em\u003e gene, which is linked to Duchenne muscular dystrophy. The gene sets \"Abnormal circulating adrenocorticotropin concentration\" and \"Central nervous system neoplasm\" were found to be significantly enriched with GARD genes, and can therefore be considered to be associated with lung cancer.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eGenes associated with genetic and rare lung diseases do not generally appear to carry risk factors for lung cancer. However, genes associated with the hypothalamic-pituitary-adrenal axis show some, but rather weak or complex, associations with lung cancer. Tests at the gene level provide extremely inhomogeneous results, even when applied to the same data.\u003c/p\u003e","manuscriptTitle":"Genes associated with genetic and rare lung diseases and the risk of lung cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-11 07:54:55","doi":"10.21203/rs.3.rs-7029929/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-13T10:22:13+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-21T16:12:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"80868399688687034610977928002191553424","date":"2025-08-21T12:21:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-14T14:34:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"235981272267355251031938245697459281123","date":"2025-08-06T07:37:59+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-06T07:17:57+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-07-07T20:45:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-04T04:09:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-04T04:09:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-07-02T13:35:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ac755d0c-f604-433b-9420-21bbc9761690","owner":[],"postedDate":"August 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-07T16:03:14+00:00","versionOfRecord":{"articleIdentity":"rs-7029929","link":"https://doi.org/10.1186/s12885-026-15934-2","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2026-04-01 15:58:30","publishedOnDateReadable":"April 1st, 2026"},"versionCreatedAt":"2025-08-11 07:54:55","video":"","vorDoi":"10.1186/s12885-026-15934-2","vorDoiUrl":"https://doi.org/10.1186/s12885-026-15934-2","workflowStages":[]},"version":"v1","identity":"rs-7029929","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7029929","identity":"rs-7029929","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}