dc.contributor.author | Polubothu, S | |
dc.contributor.author | Zecchin, D | |
dc.contributor.author | Al-Olabi, L | |
dc.contributor.author | Lionarons, DA | |
dc.contributor.author | Harland, M | |
dc.contributor.author | Horswell, S | |
dc.contributor.author | Thomas, AC | |
dc.contributor.author | Hunt, L | |
dc.contributor.author | Wlodarchak, N | |
dc.contributor.author | Aguilera, P | |
dc.contributor.author | Brand, S | |
dc.contributor.author | Bryant, D | |
dc.contributor.author | Carrera, C | |
dc.contributor.author | Chen, H | |
dc.contributor.author | Elgar, G | |
dc.contributor.author | Harwood, CA | |
dc.contributor.author | Howell, M | |
dc.contributor.author | Larue, L | |
dc.contributor.author | Loughlin, S | |
dc.contributor.author | MacDonald, J | |
dc.contributor.author | Malvehy, J | |
dc.contributor.author | Barberan, SM | |
dc.contributor.author | da Silva, VM | |
dc.contributor.author | Molina, M | |
dc.contributor.author | Morrogh, D | |
dc.contributor.author | Moulding, D | |
dc.contributor.author | Nsengimana, J | |
dc.contributor.author | Pittman, A | |
dc.contributor.author | Puig-Butillé, J-A | |
dc.contributor.author | Parmar, K | |
dc.contributor.author | Sebire, NJ | |
dc.contributor.author | Scherer, S | |
dc.contributor.author | Stadnik, P | |
dc.contributor.author | Stanier, P | |
dc.contributor.author | Tell, G | |
dc.contributor.author | Waelchli, R | |
dc.contributor.author | Zarrei, M | |
dc.contributor.author | Puig, S | |
dc.contributor.author | Bataille, V | |
dc.contributor.author | Xing, Y | |
dc.contributor.author | Healy, E | |
dc.contributor.author | Moore, GE | |
dc.contributor.author | Di, W-L | |
dc.contributor.author | Newton-Bishop, J | |
dc.contributor.author | Downward, J | |
dc.contributor.author | Kinsler, VA | |
dc.date.accessioned | 2021-07-01T15:39:12Z | |
dc.date.available | 2021-07-01T15:39:12Z | |
dc.date.issued | 2021-06-18 | |
dc.identifier.citation | Genetics in medicine : official journal of the American College of Medical Genetics, 2021 | |
dc.identifier.issn | 1098-3600 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4660 | |
dc.identifier.eissn | 1530-0366 | |
dc.identifier.doi | 10.1038/s41436-021-01204-y | |
dc.description.abstract | Purpose 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.format | Print-Electronic | |
dc.language | eng | |
dc.language.iso | eng | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.title | Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-04-27 | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1038/s41436-021-01204-y | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2021-06-18 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Genetics in medicine : official journal of the American College of Medical Genetics | |
pubs.notes | No 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-status | Published | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Lung Cancer Group | |
icr.researchteam | Lung Cancer Group | en_US |
dc.contributor.icrauthor | Downward, Julian David Harry | |