Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype.
Creators: name: Polubothu, Satyamaanasa
name: Zecchin, Davide
name: Al-Olabi, Lara
name: Lionarons, Daniël A
name: Harland, Mark
name: Horswell, Stuart
name: Thomas, Anna C
name: Hunt, Lilian
name: Wlodarchak, Nathan
name: Aguilera, Paula
name: Brand, Sarah
name: Bryant, Dale
name: Carrera, Cristina
name: Chen, Hui
name: Elgar, Greg
name: Harwood, Catherine A
name: Howell, Michael
name: Larue, Lionel
name: Loughlin, Sam
name: MacDonald, Jeff
name: Malvehy, Josep
name: Barberan, Sara Martin
name: da Silva, Vanessa Martins
name: Molina, Miriam
name: Morrogh, Deborah
name: Moulding, Dale
name: Nsengimana, Jérémie
name: Pittman, Alan
name: Puig-Butillé, Joan-Anton
name: Parmar, Kiran
name: Sebire, Neil J
name: Scherer, Stephen
name: Stadnik, Paulina
name: Stanier, Philip
name: Tell, Gemma
name: Waelchli, Regula
name: Zarrei, Mehdi
name: Puig, Susana
name: Bataille, Véronique
name: Xing, Yongna
name: Healy, Eugene
name: Moore, Gudrun E
name: Di, Wei-Li
name: Newton-Bishop, Julia
name: Downward, Julian
name: Kinsler, Veronica A
Publisher: name: The Francis Crick Institute
Year: 2021
Subjects: classificationCode: Model organisms
subject: Model organisms
classificationCode: Tumour Biology
subject: Tumour Biology
classificationCode: Signalling & Oncogenes
subject: Signalling &amp; Oncogenes
classificationCode: Gene Expression
subject: Gene Expression
classificationCode: Genetics & Genomics
subject: Genetics &amp; Genomics
classificationCode: Developmental Biology
subject: Developmental Biology
classificationCode: Genome Integrity & Repair
subject: Genome Integrity &amp; Repair
classificationCode: Chemical Biology & High Throughput
subject: Chemical Biology &amp; High Throughput
classificationCode: Computational & Systems Biology
subject: Computational &amp; Systems Biology

description: 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.