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dc.contributor.authorDavies, Helenen
dc.contributor.authorHodgson, Kirstyen
dc.contributor.authorSchwalbe, Edwarden
dc.contributor.authorCoxhead, Jonathanen
dc.contributor.authorSinclair, Naomien
dc.contributor.authorZou, Xueqingen
dc.contributor.authorCockell, Simonen
dc.contributor.authorHusain, Akhtaren
dc.contributor.authorNik-Zainal Abidin, Serenaen
dc.contributor.authorRajan, Neilen
dc.date.accessioned2019-11-10T00:30:35Z
dc.date.available2019-11-10T00:30:35Z
dc.date.issued2019-10-17en
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/298781
dc.description.abstractPatients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes. Here, we comprehensively profile the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families and discover recurrent mutations in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic, methylation and transcriptomic profiling in selected tumors suggest that isoform-specific DNMT3A2 mutations are associated with dysregulated methylation. Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumors. These findings contribute to existing paradigms of cutaneous tumorigenesis and metastasis.
dc.description.sponsorshipN.R.’s work was supported by a Wellcome Trust funded Intermediate Clinical Fellowship-WT097163MA. N.R.’s research is also supported by the Newcastle NIHR Biomedical Research Center (BRC) and the Newcastle MRC/EPSRC Molecular Pathology Node. K.H. is supported by a Ph.D. studentship from the British Skin Foundation. H.R.D. is funded by a CRUK Grand Challenge Award (C60100/A25274) and S.N.-Z. is funded by a CRUK Advanced Clinician Scientist Award (C60100/A23916). S.N.-Z.’s research is also funded by a Wellcome-Beit Award, Wellcome Strategic Award (101126/Z/13/Z), CRUK Grand Challenge Award (C60100/A25274), and Josef Steiner Award 2019.
dc.format.mediumElectronicen
dc.languageengen
dc.publisherSpringer Nature
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectHumansen
dc.subjectSkin Neoplasmsen
dc.subjectNeoplastic Syndromes, Hereditaryen
dc.subjectProto-Oncogene Proteinsen
dc.subjectRepressor Proteinsen
dc.subjectRetrospective Studiesen
dc.subjectGene Expression Profilingen
dc.subjectPedigreeen
dc.subjectDNA Mutational Analysisen
dc.subjectDNA Methylationen
dc.subjectEpigenesis, Geneticen
dc.subjectMutationen
dc.subjectFemaleen
dc.subjectMaleen
dc.subjectWhole Exome Sequencingen
dc.subjectDeubiquitinating Enzyme CYLDen
dc.subjectDNA (Cytosine-5-)-Methyltransferasesen
dc.titleEpigenetic modifiers DNMT3A and BCOR are recurrently mutated in CYLD cutaneous syndrome.en
dc.typeArticle
prism.issueIdentifier1en
prism.publicationDate2019en
prism.publicationNameNature communicationsen
prism.startingPage4717
prism.volume10en
dc.identifier.doi10.17863/CAM.45836
dcterms.dateAccepted2019-09-23en
rioxxterms.versionofrecord10.1038/s41467-019-12746-wen
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-10-17en
dc.contributor.orcidSchwalbe, Edward [0000-0002-1190-9469]
dc.contributor.orcidZou, Xueqing [0000-0003-1143-1028]
dc.contributor.orcidNik-Zainal, Nik [0000-0001-5054-1727]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (23916)
pubs.funder-project-idWellcome Trust (101126/Z/13/Z)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International