Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype.
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Date
2021-06-18ICR Author
Author
Polubothu, S
Zecchin, D
Al-Olabi, L
Lionarons, DA
Harland, M
Horswell, S
Thomas, AC
Hunt, L
Wlodarchak, N
Aguilera, P
Brand, S
Bryant, D
Carrera, C
Chen, H
Elgar, G
Harwood, CA
Howell, M
Larue, L
Loughlin, S
MacDonald, J
Malvehy, J
Barberan, SM
da Silva, VM
Molina, M
Morrogh, D
Moulding, D
Nsengimana, J
Pittman, A
Puig-Butillé, J-A
Parmar, K
Sebire, NJ
Scherer, S
Stadnik, P
Stanier, P
Tell, G
Waelchli, R
Zarrei, M
Puig, S
Bataille, V
Xing, Y
Healy, E
Moore, GE
Di, W-L
Newton-Bishop, J
Downward, J
Kinsler, VA
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Research team
Lung Cancer Group
Lung Cancer Group
Language
eng
Date accepted
2021-04-27
License start date
2021-06-18
Citation
Genetics in medicine : official journal of the American College of Medical Genetics, 2021