A high-penetrance intergenic variant at 9p21 confers melanoma susceptibility

A high-penetrance intergenic variant at 9p21 confers melanoma susceptibility | 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 Biological Sciences - Article A high-penetrance intergenic variant at 9p21 confers melanoma susceptibility Maria Teresa Landi, Linh Bui-Raborn, Lorenza Pastorino, Donato Calista, and 52 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9636010/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 Approximately 10% of cutaneous malignant melanoma cases are familial. Variants in CDKN2A account for up to 40% of melanoma-prone families, with an additional ~10% explained by other genes. Many CDKN2A mutation-negative families show linkage to chromosome-band 9p21, which harbors CDKN2A, suggesting non-coding variants may contribute to familial risk. Here, whole-genome sequencing revealed a novel 100 kb deletion mapping to 9p21 in a gene-desert region, 205 kb from CDKN2A, cosegregating in a four-case family from Genoa, Italy. The deletion overlaps melanocyte enhancers that interact with the promoters of CDKN2A p16 and p14 transcripts and is predicted to reduce p16 expression. Using a nearby rare exonic variant in MTAP (rs755147810) on the deletion haplotype, we searched for deletion carriers in WES data from high-risk melanoma patients and controls and identified 22 cases and a single control carrying rs755147810 and the deletion. The association with melanoma in case-control analysis was highly significant (3,319 cases and 5,680 controls; P=1.27x10-6; OR=27.50). We observe loss-of-heterozygosity of the wild-type allele in a carrier’s tumor sample. The founder haplotype with the most recent common ancestor dates approximately 26 generations, broadly overlapping the period when Italy was struck by devastating outbreaks of plague that decimated the population creating a genetic bottleneck. Our results provide evidence of a high-penetrance intergenic variant conferring melanoma susceptibility, with potential for genetic screening of high-risk individuals. Biological sciences/Cancer/Skin cancer/Melanoma Biological sciences/Cancer/Cancer genomics Biological sciences/Genetics/Cancer genetics cutaneous melanoma family study genetic susceptibility deletion structural variant founder mutation CDKN2A Full Text Additional Declarations Yes there is potential Competing Interest. K.P. received support for attending meetings and/or travel from Abbvie, Sanofi; participation on Advisory Board Meeting (outside of the submitted work) for Abbvie, Almirall, Beiersdorf, BMS, Galderma, Leo Pharma, Lilly, Novartis, Sun-Pharma, MSD, Philogen, Pierre Fabre, Regeneron, Sanofi. R.I.H. received consulting fees for Almirall, stock options and advisor from Evereden, investigator (pending) for Lumo Imaging, speaking fees for MJH Life Sciences, Med Learning Group and Prime Education, research grants from Veriskin and Vita Imaging, advisor for ZuraBio. L.W. received consulting fees from Chronicle Medical Software. The remaining authors declare no competing interests. Supplementary Files SupplementaryNoteFINAL.pdf Supplementary Note SupplementaryTables8FINAL630PM.xlsx Supplementary Tables SupplementaryFiguressubmissionv8FINAL.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-9636010","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":636120460,"identity":"ba1eb93c-ecd4-429d-bbee-ad1d12d6ecd9","order_by":0,"name":"Maria Teresa 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R.I.H. received consulting fees for Almirall, stock options and advisor from Evereden, investigator (pending) for Lumo Imaging, speaking fees for MJH Life Sciences, Med Learning Group and Prime Education, research grants from Veriskin and Vita Imaging, advisor for ZuraBio. L.W. received consulting fees from Chronicle Medical Software. The remaining authors declare no competing interests.","formattedTitle":"A high-penetrance intergenic variant at 9p21 confers melanoma susceptibility","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":"cutaneous melanoma, family study, genetic susceptibility, deletion, structural variant, founder mutation, CDKN2A","lastPublishedDoi":"10.21203/rs.3.rs-9636010/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9636010/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Approximately 10% of cutaneous malignant melanoma cases are familial. Variants in CDKN2A account for up to 40% of melanoma-prone families, with an additional ~10% explained by other genes. Many CDKN2A mutation-negative families show linkage to chromosome-band 9p21, which harbors CDKN2A, suggesting non-coding variants may contribute to familial risk. Here, whole-genome sequencing revealed a novel 100 kb deletion mapping to 9p21 in a gene-desert region, 205 kb from CDKN2A, cosegregating in a four-case family from Genoa, Italy. The deletion overlaps melanocyte enhancers that interact with the promoters of CDKN2A p16 and p14 transcripts and is predicted to reduce p16 expression. Using a nearby rare exonic variant in MTAP (rs755147810) on the deletion haplotype, we searched for deletion carriers in WES data from high-risk melanoma patients and controls and identified 22 cases and a single control carrying rs755147810 and the deletion. The association with melanoma in case-control analysis was highly significant (3,319 cases and 5,680 controls; P=1.27x10-6; OR=27.50). We observe loss-of-heterozygosity of the wild-type allele in a carrier’s tumor sample. The founder haplotype with the most recent common ancestor dates approximately 26 generations, broadly overlapping the period when Italy was struck by devastating outbreaks of plague that decimated the population creating a genetic bottleneck. Our results provide evidence of a high-penetrance intergenic variant conferring melanoma susceptibility, with potential for genetic screening of high-risk individuals.","manuscriptTitle":"A high-penetrance intergenic variant at 9p21 confers melanoma susceptibility","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-12 16:29:32","doi":"10.21203/rs.3.rs-9636010/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":"ceb196fa-ac45-4585-abfb-d4e65c8be7b7","owner":[],"postedDate":"May 12th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Reject before peer review","date":"2026-05-13T11:09:56+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-05-07T10:35:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"Nature","date":"2026-05-07T02:13:04+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":67704075,"name":"Biological sciences/Cancer/Skin cancer/Melanoma"},{"id":67704076,"name":"Biological sciences/Cancer/Cancer genomics"},{"id":67704077,"name":"Biological sciences/Genetics/Cancer genetics"}],"tags":[],"updatedAt":"2026-05-13T11:23:13+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-12 16:29:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9636010","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9636010","identity":"rs-9636010","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}