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 C21orf91as 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.

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