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

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Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype
Genetics in Medicine ( IF 8.8 ) Pub Date : 2021-06-18 , DOI: 10.1038/s41436-021-01204-y
Satyamaanasa Polubothu _{1,

2,

3} , Davide Zecchin _{1,

2} , Lara Al-Olabi ₂ , Daniël A Lionarons ₄ , Mark Harland ₅ , Stuart Horswell ₆ , Anna C Thomas ₂ , Lilian Hunt ₇ , Nathan Wlodarchak ₈ , Paula Aguilera ₉ , Sarah Brand ₂ , Dale Bryant _{1,

2} , Cristina Carrera ₉ , Hui Chen ₈ , Greg Elgar ₇ , Catherine A Harwood ₁₀ , Michael Howell ₁₁ , Lionel Larue ₁₂ , Sam Loughlin ₁₃ , Jeff MacDonald ₁₄ , Josep Malvehy ₉ , Sara Martin Barberan _{1,

2} , Vanessa Martins da Silva _{2,

9} , Miriam Molina ₄ , Deborah Morrogh ₁₃ , Dale Moulding ₂ , Jérémie Nsengimana ₅ , Alan Pittman ₁₅ , Joan-Anton Puig-Butillé ₉ , Kiran Parmar ₁₆ , Neil J Sebire ₁₇ , Stephen Scherer ₁₄ , Paulina Stadnik ₂ , Philip Stanier ₂ , Gemma Tell ₈ , Regula Waelchli ₃ , Mehdi Zarrei ₁₄ , Susana Puig ₉ , Véronique Bataille ₁₅ , Yongna Xing ₈ , Eugene Healy ₁₈ , Gudrun E Moore ₂ , Wei-Li Di ₁₉ , Julia Newton-Bishop ₅ , Julian Downward ₄ , Veronica A Kinsler _{1,

2,

3}

Affiliation

Mosaicism and Precision Medicine Laboratory, Francis Crick Institute, London, UK.
Genetics and Genomic Medicine, UCL GOS Institute of Child Health, London, UK.
Paediatric Dermatology, Great Ormond Street Hospital for Children, London, UK.
Oncogene Biology Laboratory, Francis Crick Institute, London, UK.
Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, Cancer Research UK Clinical Centre at Leeds, St James's University Hospital, Leeds, UK.
Bioinformatics and Biostatistics, Francis Crick Institute, London, UK.
Advanced Sequencing Facility, Francis Crick Institute, London, UK.
McArdle Laboratory, Department of Oncology, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA.
Department of Dermatology, Hospital Clínic de Barcelona (Melanoma Unit), University of Barcelona, IDIBAPS, Barcelona & CIBERER, Barcelona, Spain.
Centre for Cell Biology and Cutaneous Research, Blizzard Institute, Barts, London, UK.
High Throughput Screening Facility, Francis Crick Institute, London, UK.
Centre de Recherche, Developmental Genetics of Melanocytes, Institut Curie, Orsay, France.
North East Thames Regional Genetics Laboratory Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
Bioinformatics, St George's University of London, London, UK.
Department of Twin Research and Genetic Epidemiology, King's College London, South Wing Block D, London, UK.
Department of Histopathology, Great Ormond Street Hospital for Children, London, UK.
Department of Dermatology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
Infection, Immunity and Inflammation Programme, Immunobiology Section, UCL GOS Institute of Child Health, London, UK.

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.

中文翻译：

PPP2R3B 的遗传性重复通过 C21orf91 驱动的增殖表型易患痣和黑色素瘤

目的

黑色素瘤的大部分遗传因素仍然无法解释。我们使用罕见疾病方法寻找易感种系拷贝数变异。

方法

将患有黑色素瘤易感综合征先天性黑色素细胞痣患者的全基因组拷贝数结果外推到散发性黑色素瘤队列。使用免疫组织化学、转录组学和稳定的诱导细胞模型研究了PPP2R3B中重复的功能影响，这些模型本身使用 RNAseq、定量实时聚合酶链反应 (qRT-PCR)、反相蛋白阵列、免疫印迹、RNA 干扰、免疫细胞化学、增殖进行表征和迁移测定。

结果

我们在此发现了一种先前未报道的对黑色素瘤和黑色素细胞痣的遗传易感性，即基因PPP2R3B的家族性重复。它编码 PR70，关键磷酸酶 PP2A 的调节单位。重复增加了人痣中 PR70 的表达，而黑色素瘤组织中表达的增加通过非免疫机制与生存相关。PPP2R3B过度表达诱导色素细胞转向增殖和远离迁移。重要的是，这与已知的小眼球相关转录因子 (MITF) 控制的开关无关，而是由C21orf91驱动。最后，C21orf91 被证明是 MITF 以及 PR70 的下游。