TY - JOUR
T1 - Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype
AU - Polubothu, Satyamaanasa
AU - Zecchin, Davide
AU - Al-Olabi, Lara
AU - Lionarons, Daniël A
AU - Harland, Mark
AU - Horswell, Stuart
AU - Thomas, Anna C
AU - Hunt, Lilian
AU - Wlodarchak, Nathan
AU - Aguilera, Paula
AU - Brand, Sarah
AU - Bryant, Dale
AU - Carrera, Cristina
AU - Chen, Hui
AU - Elgar, Greg
AU - Harwood, Catherine A
AU - Howell, Michael
AU - Larue, Lionel
AU - Loughlin, Sam
AU - MacDonald, Jeff
AU - Malvehy, Josep
AU - Barberan, Sara Martin
AU - da Silva, Vanessa Martins
AU - Molina, Miriam
AU - Morrogh, Deborah
AU - Moulding, Dale
AU - Nsengimana, Jérémie
AU - Pittman, Alan
AU - Puig-Butillé, Joan-Anton
AU - Parmar, Kiran
AU - Sebire, Neil J
AU - Scherer, Stephen
AU - Stadnik, Paulina
AU - Stanier, Philip
AU - Tell, Gemma
AU - Waelchli, Regula
AU - Zarrei, Mehdi
AU - Puig, Susana
AU - Bataille, Véronique
AU - Xing, Yongna
AU - Healy, Eugene
AU - Moore, Gudrun E
AU - Di, Wei-Li
AU - Newton-Bishop, Julia
AU - Downward, Julian
AU - Kinsler, Veronica A
N1 - Funding Information: We gratefully acknowledge the participation of all patients. V.A.K., A.C.T. and the work presented in this study were funded by the Wellcome Trust (grant WT104076MA). S.P. was funded by Caring Matters Now Charity and by the Newlife Foundation (grant 15-16/10). The work was supported by the Great Ormond Street Hospital Children’s Charity (GOSHCC) Livingstone Skin Research Centre, and by the UK National Institute for Health Research through the Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust, and the UCL GOS Institute of Child Health. Publisher Copyright: © 2021, The Author(s).
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85108210444&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41436-021-01204-y
DO - https://doi.org/10.1038/s41436-021-01204-y
M3 - Article
C2 - 34145395
SN - 1098-3600
VL - 23
SP - 1636
EP - 1647
JO - Genetics in medicine
JF - Genetics in medicine
IS - 9
ER -