Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype
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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 Kinsler Toggle all authors (46)
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.
Journal details
Journal Genetics in Medicine
Volume 23
Issue number 9
Pages 1636-1647
Available online
Publication date
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Publisher website (DOI) 10.1038/s41436-021-01204-y
Europe PubMed Central 34145395
Pubmed 34145395