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

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

doi:10.1038/s41436-021-01204-y

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

Satyamaanasa Polubothu
, Davide Zecchin
, Lara Al-Olabi
, Daniël A Lionarons
, Mark Harland
, Stuart Horswell
, Anna C Thomas
, Lilian Hunt
, Nathan Wlodarchak
, Paula Aguilera
, Sarah Brand
, Dale Bryant
, Cristina Carrera
, Hui Chen
, Greg Elgar
, Catherine A Harwood
, Michael Howell
, Lionel Larue
, Sam Loughlin
, Jeff MacDonald

Josep Malvehy, Sara Martin Barberan, Vanessa Martins da Silva, Miriam Molina, Deborah Morrogh, Dale Moulding, Jérémie Nsengimana, Alan Pittman, Joan-Anton Puig-Butillé, Kiran Parmar, Neil J Sebire, Stephen Scherer, Paulina Stadnik, Philip Stanier, Gemma Tell, Regula Waelchli, Mehdi Zarrei, Susana Puig, Véronique Bataille, Yongna Xing, Eugene Healy, Gudrun E Moore, Wei-Li Di, Julia Newton-Bishop, Julian Downward, Veronica A Kinsler

The Francis Crick Institute
UCL GOS Institute of Child Health
St James’s University Hospital
University of Wisconsin-Madison
Unit of Medical and Molecular Genetics, University Hospital Sant Joan de Deu Barcelona, 08950, Barcelona, Spain.
Blizzard Institute
Developmental Genetics of Melanocytes
Great Ormond Street Hospital for Children NHS Foundation Trust
The Hospital for Sick Children
St. George's University of London
MRC Social Genetic and Developmental Psychiatry Centre, King's College London, London, United Kingdom; Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
Great Ormond Street Hospital for Children, London, WC1N 3JH, UK.
University Hospital Southampton NHS Foundation Trust

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1636-1647
Number of pages	12
Journal	Genetics in medicine
Volume	23
Issue number	9
DOIs	https://doi.org/10.1038/s41436-021-01204-y
Publication status	Published - Sept 2021

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SDG 3 Good Health and Well-being

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10.1038/s41436-021-01204-y

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Polubothu, S., Zecchin, D., Al-Olabi, L., Lionarons, D. A., Harland, M., Horswell, S., Thomas, A. C., Hunt, L., Wlodarchak, N., Aguilera, P., Brand, S., Bryant, D., Carrera, C., Chen, H., Elgar, G., Harwood, C. A., Howell, M., Larue, L., Loughlin, S., ... Kinsler, V. A. (2021). Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype. Genetics in medicine, 23(9), 1636-1647. https://doi.org/10.1038/s41436-021-01204-y

@article{75382c70476d416dbee7d740f4cd1cb9,

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

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.",

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

note = "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{\textquoteright}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: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = sep,

doi = "10.1038/s41436-021-01204-y",

language = "English",

volume = "23",

pages = "1636--1647",

journal = "Genetics in medicine",

issn = "1098-3600",

publisher = "Lippincott Williams and Wilkins",

number = "9",

}

Polubothu, S, Zecchin, D, Al-Olabi, L, Lionarons, DA, Harland, M, Horswell, S, Thomas, AC, Hunt, L, Wlodarchak, N, Aguilera, P, Brand, S, Bryant, D, Carrera, C, Chen, H, Elgar, G, Harwood, CA, Howell, M, Larue, L, Loughlin, S, MacDonald, J, Malvehy, J, Barberan, SM, da Silva, VM, Molina, M, Morrogh, D, Moulding, D, Nsengimana, J, Pittman, A, Puig-Butillé, J-A, Parmar, K, Sebire, NJ, Scherer, S, Stadnik, P, Stanier, P, Tell, G, Waelchli, R, Zarrei, M, Puig, S, Bataille, V, Xing, Y, Healy, E, Moore, GE, Di, W-L, Newton-Bishop, J, Downward, J & Kinsler, VA 2021, 'Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype', Genetics in medicine, vol. 23, no. 9, pp. 1636-1647. https://doi.org/10.1038/s41436-021-01204-y

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 - https://www.scopus.com/pages/publications/85108210444

U2 - 10.1038/s41436-021-01204-y

DO - 10.1038/s41436-021-01204-y

M3 - Article

SN - 1098-3600

VL - 23

SP - 1636

EP - 1647

JO - Genetics in medicine

JF - Genetics in medicine

IS - 9

ER -

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

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