Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype
| Autor: | Daniël A. Lionarons, Davide Zecchin, Jeffrey R. MacDonald, Wei-Li Di, Hui Chen, Miriam Molina, Stuart Horswell, Gemma Tell, Véronique Bataille, Dale Bryant, Julia Newton-Bishop, Philip Stanier, Gudrun E. Moore, Kiran Parmar, Josep Malvehy, Catherine A. Harwood, Satyamaanasa Polubothu, Cristina Carrera, Jérémie Nsengimana, Veronica A. Kinsler, Julian Downward, Nathan Wlodarchak, Alan Pittman, Susana Puig, Yongna Xing, Neil J. Sebire, Anna C. Thomas, Mark Harland, L. Al-Olabi, Mehdi Zarrei, Michael Howell, Sarah Brand, Paulina Stadnik, Stephen W. Scherer, Lilian Hunt, Eugene Healy, Dale Moulding, Paula Aguilera, J.A. Puig-Butillé, Deborah Morrogh, Vanessa Martins da Silva, Sam Loughlin, Regula Waelchli, Sara Martin Barberan, Greg Elgar, Lionel Larue |
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| Přispěvatelé: | Oncology, CCA - Cancer biology and immunology, CCA - Cancer Treatment and Quality of Life |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Model organisms Skin Neoplasms Gene Expression Biology Germline Article 030207 dermatology & venereal diseases 03 medical and health sciences Signalling & Oncogenes 0302 clinical medicine Congenital melanocytic nevus medicine Genetic predisposition Nevus Humans Gene Melanoma Genetics (clinical) Computational & Systems Biology Chemical Biology & High Throughput Genome Integrity & Repair Tumour Biology Microphthalmia-associated transcription factor medicine.disease Phenotype Immunohistochemistry 030104 developmental biology Cancer research Genetics & Genomics Developmental Biology |
| Zdroj: | Genetics in medicine, 23(9), 1636-1647. Lippincott Williams and Wilkins Genetics in Medicine |
| ISSN: | 1098-3600 |
| Popis: | Purpose\ud Much of the heredity of melanoma remains unexplained. We sought predisposing germline copy-number variants using a rare disease approach.\ud \ud Methods\ud 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.\ud \ud Results\ud 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.\ud \ud Conclusion\ud 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. |
| Databáze: | OpenAIRE |
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