Inherited duplications of PPP2R3B promote naevi and melanoma via a novel C21orf91-driven proliferative phenotype

Veronica A Kinsler, et al.

Jun 27, 2019

Received Date: 28th May 19

Satyamaanasa Polubothu, Lara Al-Olabi, Daniël A Lionarons, Mark Harland, Anna C Thomas, Stuart Horswell, Lilian Hunt, Nathan Wlodarchak, Paula Aguilera, Sarah Brand, Dale Bryant, Philip Beales, Cristina Carrera, Hui Chen, Greg Elgar, Catherine A Harwood, Michael Howell, Dagan Jenkins, 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, Juan-Anton Puig-Butillé, Kiran Parmar, Neil J Sebire, Stephen Scherer, Paulina Stadnik, Philip Stanier, Gemma Tell, Regula Waelchli, Mehdi Zarrei, Davide Zecchin, Susana Puig, Véronique Bataille, Yongna Xing, Eugene Healy, Gudrun E Moore, Wei-Li Di, Julia Newton-Bishop, Julian Downward, Veronica A Kinsler 

The majority of the heredity of melanoma remains unexplained, however inherited copy number changes have not yet been systematically studied.  The genetic environment is highly relevant to treatment stratification, and new gene discovery is therefore desirable.  Using an unbiased whole genome screening approach for copy number we identify here a novel melanoma predisposing factor, familial duplications of gene PPP2R3B, encoding a regulatory unit of critical phosphatase PP2A. Significant correlation between expression of PPP2R3B in tumour tissue and survival in a large melanoma cohort was confirmed, and associated with a non-immunological expression profile. Mechanistically, construction and extensive characterization of a stable, inducible cellular model for PPP2R3B overexpression revealed induction of pigment cell switching towards proliferation and away from migration.   Importantly, this was independent of the known microphthalmia-associated transcription factor (MITF)-controlled pigment cell phenotype switch, and was instead driven by uncharacterised gene C21orf91.  Bioinformatic studies point to C21orf91 as a novel target of MITF, and therefore a potential hub in the control of phenotype switching in melanoma. This study identifies novel germline copy number variants in PPP2R3B predisposing to melanocytic neoplasia, and uncovers a new potential therapeutic target C21orf91 in the control of pigment cell proliferation.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

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