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Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype

Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype
Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype

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.

1098-3600
1636-1647
Polubothu, Satyamaanasa
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Lionarons, Daniël A
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Harland, Mark
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Bataille, Véronique
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Xing, Yongna
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Healy, Eugene
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Moore, Gudrun E
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Di, Wei-Li
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Newton-Bishop, Julia
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Downward, Julian
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Kinsler, Veronica A
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Polubothu, Satyamaanasa
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Zecchin, Davide
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Al-Olabi, Lara
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Lionarons, Daniël A
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Horswell, Stuart
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Thomas, Anna C
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Hunt, Lilian
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Wlodarchak, Nathan
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Aguilera, Paula
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Brand, Sarah
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Bryant, Dale
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Carrera, Cristina
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Chen, Hui
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Elgar, Greg
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Harwood, Catherine A
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Howell, Michael
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Malvehy, Josep
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Barberan, Sara Martin
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Morrogh, Deborah
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Moulding, Dale
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Nsengimana, Jérémie
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Pittman, Alan
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Puig-Butillé, Joan-Anton
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Parmar, Kiran
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Sebire, Neil J
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Scherer, Stephen
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Stadnik, Paulina
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Stanier, Philip
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Tell, Gemma
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Waelchli, Regula
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Zarrei, Mehdi
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Puig, Susana
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Xing, Yongna
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Healy, Eugene
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Moore, Gudrun E
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Di, Wei-Li
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Newton-Bishop, Julia
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Downward, Julian
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Kinsler, Veronica A
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Polubothu, Satyamaanasa, Zecchin, Davide, Al-Olabi, Lara, Lionarons, Daniël A, Harland, Mark, Horswell, Stuart, Thomas, Anna C, Hunt, Lilian, Wlodarchak, Nathan, Aguilera, Paula, Brand, Sarah, Bryant, Dale, Carrera, Cristina, Chen, Hui, Elgar, Greg, Harwood, Catherine A, Howell, Michael, Larue, Lionel, Loughlin, Sam, MacDonald, Jeff, Malvehy, Josep, Barberan, Sara Martin, Martins da Silva, Vanessa, Molina, Miriam, Morrogh, Deborah, Moulding, Dale, Nsengimana, Jérémie, Pittman, Alan, Puig-Butillé, Joan-Anton, Parmar, Kiran, Sebire, Neil J, Scherer, Stephen, Stadnik, Paulina, Stanier, Philip, Tell, Gemma, Waelchli, Regula, Zarrei, Mehdi, Puig, Susana, Bataille, Véronique, Xing, Yongna, Healy, Eugene, Moore, Gudrun E, Di, Wei-Li, Newton-Bishop, Julia, Downward, Julian and Kinsler, Veronica A (2021) Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype. Genetics in Medicine, 23 (9), 1636-1647. (doi:10.1038/s41436-021-01204-y).

Record type: Article

Abstract

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.

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Inherited_duplications_of_PPP2R3B_predispose_to_naevi_and_melanoma_via_a_C21orf91_driven_proliferative_phenotype - Accepted Manuscript
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Accepted/In Press date: 27 April 2021
Published date: September 2021
Additional Information: © 2021. The Author(s).
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Identifiers

Local EPrints ID: 451756
URI: http://eprints.soton.ac.uk/id/eprint/451756
DOI: doi:10.1038/s41436-021-01204-y
ISSN: 1098-3600
PURE UUID: ba3083cd-097f-4769-a98e-9f242ad78d2b

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Date deposited: 25 Oct 2021 16:34
Last modified: 17 Mar 2024 06:32

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Contributors

Author: Satyamaanasa Polubothu
Author: Davide Zecchin
Author: Lara Al-Olabi
Author: Daniël A Lionarons
Author: Mark Harland
Author: Stuart Horswell
Author: Anna C Thomas
Author: Lilian Hunt
Author: Nathan Wlodarchak
Author: Paula Aguilera
Author: Sarah Brand
Author: Dale Bryant
Author: Cristina Carrera
Author: Hui Chen
Author: Greg Elgar
Author: Catherine A Harwood
Author: Michael Howell
Author: Lionel Larue
Author: Sam Loughlin
Author: Jeff MacDonald
Author: Josep Malvehy
Author: Sara Martin Barberan
Author: Vanessa Martins da Silva
Author: Miriam Molina
Author: Deborah Morrogh
Author: Dale Moulding
Author: Jérémie Nsengimana
Author: Alan Pittman
Author: Joan-Anton Puig-Butillé
Author: Kiran Parmar
Author: Neil J Sebire
Author: Stephen Scherer
Author: Paulina Stadnik
Author: Philip Stanier
Author: Gemma Tell
Author: Regula Waelchli
Author: Mehdi Zarrei
Author: Susana Puig
Author: Véronique Bataille
Author: Yongna Xing
Author: Eugene Healy
Author: Gudrun E Moore
Author: Wei-Li Di
Author: Julia Newton-Bishop
Author: Julian Downward
Author: Veronica A Kinsler

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