Accueil >
Publications >
Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype

Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype

1 sept. 2021Genetics in Medicine

Auteurs

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

Résumé

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.

Membres

LIONEL LARUE

Directeur de recherche Inserm