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dc.contributor.authorPolubothu, S
dc.contributor.authorZecchin, D
dc.contributor.authorAl-Olabi, L
dc.contributor.authorLionarons, DA
dc.contributor.authorHarland, M
dc.contributor.authorHorswell, S
dc.contributor.authorThomas, AC
dc.contributor.authorHunt, L
dc.contributor.authorWlodarchak, N
dc.contributor.authorAguilera, P
dc.contributor.authorBrand, S
dc.contributor.authorBryant, D
dc.contributor.authorCarrera, C
dc.contributor.authorChen, H
dc.contributor.authorElgar, G
dc.contributor.authorHarwood, CA
dc.contributor.authorHowell, M
dc.contributor.authorLarue, L
dc.contributor.authorLoughlin, S
dc.contributor.authorMacDonald, J
dc.contributor.authorMalvehy, J
dc.contributor.authorBarberan, SM
dc.contributor.authorda Silva, VM
dc.contributor.authorMolina, M
dc.contributor.authorMorrogh, D
dc.contributor.authorMoulding, D
dc.contributor.authorNsengimana, J
dc.contributor.authorPittman, A
dc.contributor.authorPuig-Butillé, J-A
dc.contributor.authorParmar, K
dc.contributor.authorSebire, NJ
dc.contributor.authorScherer, S
dc.contributor.authorStadnik, P
dc.contributor.authorStanier, P
dc.contributor.authorTell, G
dc.contributor.authorWaelchli, R
dc.contributor.authorZarrei, M
dc.contributor.authorPuig, S
dc.contributor.authorBataille, V
dc.contributor.authorXing, Y
dc.contributor.authorHealy, E
dc.contributor.authorMoore, GE
dc.contributor.authorDi, W-L
dc.contributor.authorNewton-Bishop, J
dc.contributor.authorDownward, J
dc.contributor.authorKinsler, VA
dc.date.accessioned2021-07-01T15:39:12Z
dc.date.available2021-07-01T15:39:12Z
dc.date.issued2021-06-18
dc.identifier.citationGenetics in medicine : official journal of the American College of Medical Genetics, 2021
dc.identifier.issn1098-3600
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4660
dc.identifier.eissn1530-0366
dc.identifier.doi10.1038/s41436-021-01204-y
dc.description.abstractPurpose Much of the heredity of melanoma remains unexplained. We sought predisposing germline copy-number variants using a rare disease approach.Methods Whole-genome copy-number findings in patients with melanoma predisposition syndrome congenital melanocytic nevus were extrapolated to a sporadic melanoma cohort. Functional effects of duplications in PPP2R3B were investigated using immunohistochemistry, transcriptomics, and stable inducible cellular models, themselves characterized using RNAseq, quantitative real-time polymerase chain reaction (qRT-PCR), reverse phase protein arrays, immunoblotting, RNA interference, immunocytochemistry, proliferation, and migration assays.Results We identify here a previously unreported genetic susceptibility to melanoma and melanocytic nevi, familial duplications of gene PPP2R3B. This encodes PR70, a regulatory unit of critical phosphatase PP2A. Duplications increase expression of PR70 in human nevus, and increased expression in melanoma tissue correlates with survival via a nonimmunological mechanism. PPP2R3B overexpression induces pigment cell switching toward proliferation and away from migration. Importantly, this is independent of the known microphthalmia-associated transcription factor (MITF)-controlled switch, instead driven by C21orf91. Finally, C21orf91 is demonstrated to be downstream of MITF as well as PR70.Conclusion This work confirms the power of a rare disease approach, identifying a previously unreported copy-number change predisposing to melanocytic neoplasia, and discovers C21orf91 as a potentially targetable hub in the control of phenotype switching.
dc.formatPrint-Electronic
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleInherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype.
dc.typeJournal Article
dcterms.dateAccepted2021-04-27
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41436-021-01204-y
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2021-06-18
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfGenetics in medicine : official journal of the American College of Medical Genetics
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Lung Cancer Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Lung Cancer Group
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Lung Cancer Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Lung Cancer Group
pubs.publication-statusPublished
pubs.embargo.termsNo embargo
icr.researchteamLung Cancer Group
icr.researchteamLung Cancer Groupen_US
dc.contributor.icrauthorDownward, Julian David Harryen


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