The Francis Crick Institute
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Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype.

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journal contribution
posted on 2021-09-30, 12:34 authored by Satyamaanasa Polubothu, Davide Zecchin, Lara Al-Olabi, Daniël A Lionarons, Mark Harland, Stuart Horswell, Anna C Thomas, Lilian Hunt, Nathan Wlodarchak, Paula Aguilera, Sarah Brand, Dale Bryant, Cristina Carrera, Hui Chen, Greg Elgar, Catherine A Harwood, Michael Howell, Lionel Larue, Sam Loughlin, Jeff MacDonald, Josep Malvehy, Sara Martin Barberan, Vanessa Martins da Silva, Miriam Molina, Deborah Morrogh, Dale Moulding, Jérémie Nsengimana, Alan Pittman, Joan-Anton Puig-Butillé, Kiran Parmar, Neil J Sebire, Stephen Scherer, Paulina Stadnik, Philip Stanier, Gemma Tell, Regula Waelchli, Mehdi Zarrei, Susana Puig, Véronique Bataille, Yongna Xing, Eugene Healy, Gudrun E Moore, Wei-Li Di, Julia Newton-Bishop, Julian Downward, Veronica A Kinsler
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.


Crick (Grant ID: 10008, Grant title: STP High Throughput Screening) Crick (Grant ID: 10002, Grant title: STP Bioinformatics & Biostatistics) Crick (Grant ID: 10070, Grant title: Downward FC001070) Crick (Grant ID: 10001, Grant title: STP Advanced Sequencing)