Evidence map›Paper›PMID 34145395›Full record

ArticleGenetics in medicine : official journal of the American College of Medical Genetics2021

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 and 36 more

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In one paragraph

Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
0.5field-weighted citation impact, top 38% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed, 7 citations in OpenAlex.

  1. Article
  2. Targeting PP2A in cancer: an underrated option.Journal of experimental & clinical cancer research : CR · 2025
    Review
  3. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

46 authors at 14 institutions in 5 countries.

Satyamaanasa PolubothuMosaicism and Precision Medicine Laboratory, Francis Crick Institute, London, UK.ORCID 0000-0001-7195-5670
Davide ZecchinMosaicism and Precision Medicine Laboratory, Francis Crick Institute, London, UK.
Lara Al-OlabiGenetics and Genomic Medicine, UCL GOS Institute of Child Health, London, UK.
Daniël A LionaronsOncogene Biology Laboratory, Francis Crick Institute, London, UK.
Mark HarlandSection of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, Cancer Research UK Clinical Centre at Leeds, St James's University Hospital, Leeds, UK.
Stuart HorswellBioinformatics and Biostatistics, Francis Crick Institute, London, UK.
Anna C ThomasGenetics and Genomic Medicine, UCL GOS Institute of Child Health, London, UK.
Lilian HuntAdvanced Sequencing Facility, Francis Crick Institute, London, UK.
Nathan WlodarchakMcArdle Laboratory, Department of Oncology, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA.
Paula AguileraDepartment of Dermatology, Hospital Clínic de Barcelona (Melanoma Unit), University of Barcelona, IDIBAPS, Barcelona & CIBERER, Barcelona, Spain.
Sarah BrandGenetics and Genomic Medicine, UCL GOS Institute of Child Health, London, UK.
Dale BryantMosaicism and Precision Medicine Laboratory, Francis Crick Institute, London, UK.
Cristina CarreraDepartment of Dermatology, Hospital Clínic de Barcelona (Melanoma Unit), University of Barcelona, IDIBAPS, Barcelona & CIBERER, Barcelona, Spain.
Hui ChenMcArdle Laboratory, Department of Oncology, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA.
Greg ElgarAdvanced Sequencing Facility, Francis Crick Institute, London, UK.
Catherine A HarwoodCentre for Cell Biology and Cutaneous Research, Blizzard Institute, Barts, London, UK.
Michael HowellHigh Throughput Screening Facility, Francis Crick Institute, London, UK.
Lionel LarueCentre de Recherche, Developmental Genetics of Melanocytes, Institut Curie, Orsay, France.
Sam LoughlinNorth East Thames Regional Genetics Laboratory Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Jeff MacDonaldThe Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
Josep MalvehyDepartment of Dermatology, Hospital Clínic de Barcelona (Melanoma Unit), University of Barcelona, IDIBAPS, Barcelona & CIBERER, Barcelona, Spain.
Sara Martin BarberanMosaicism and Precision Medicine Laboratory, Francis Crick Institute, London, UK.
Vanessa Martins da SilvaGenetics and Genomic Medicine, UCL GOS Institute of Child Health, London, UK.
Miriam MolinaOncogene Biology Laboratory, Francis Crick Institute, London, UK.
Deborah MorroghNorth East Thames Regional Genetics Laboratory Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Dale MouldingGenetics and Genomic Medicine, UCL GOS Institute of Child Health, London, UK.
Jérémie NsengimanaSection of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, Cancer Research UK Clinical Centre at Leeds, St James's University Hospital, Leeds, UK.
Alan PittmanBioinformatics, St George's University of London, London, UK.
Joan-Anton Puig-ButilléDepartment of Dermatology, Hospital Clínic de Barcelona (Melanoma Unit), University of Barcelona, IDIBAPS, Barcelona & CIBERER, Barcelona, Spain.
Kiran ParmarDepartment of Twin Research and Genetic Epidemiology, King's College London, South Wing Block D, London, UK.
Neil J SebireDepartment of Histopathology, Great Ormond Street Hospital for Children, London, UK.
Stephen SchererThe Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
Paulina StadnikGenetics and Genomic Medicine, UCL GOS Institute of Child Health, London, UK.
Philip StanierGenetics and Genomic Medicine, UCL GOS Institute of Child Health, London, UK.
Gemma TellMcArdle Laboratory, Department of Oncology, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA.
Regula WaelchliPaediatric Dermatology, Great Ormond Street Hospital for Children, London, UK.
Mehdi ZarreiThe Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
Susana PuigDepartment of Dermatology, Hospital Clínic de Barcelona (Melanoma Unit), University of Barcelona, IDIBAPS, Barcelona & CIBERER, Barcelona, Spain.
Véronique BatailleBioinformatics, St George's University of London, London, UK.
Yongna XingMcArdle Laboratory, Department of Oncology, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA.
Eugene HealyDepartment of Dermatology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
Gudrun E MooreGenetics and Genomic Medicine, UCL GOS Institute of Child Health, London, UK.
Wei-Li DiInfection, Immunity and Inflammation Programme, Immunobiology Section, UCL GOS Institute of Child Health, London, UK.
Julia Newton-BishopSection of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, Cancer Research UK Clinical Centre at Leeds, St James's University Hospital, Leeds, UK.
Julian DownwardOncogene Biology Laboratory, Francis Crick Institute, London, UK.
Veronica A KinslerMosaicism and Precision Medicine Laboratory, Francis Crick Institute, London, UK. veronica.kinsler@crick.ac.uk.ORCID 0000-0001-6256-327X
The Francis Crick Institute · GBUniversity College London · GBCentro de Investigación Biomédica en Red · ESGreat Ormond Street Hospital · GBUniversity of Wisconsin–Madison · USCancer Research UK · GBHospital for Sick Children · CAGreat Ormond Street Hospital for Children NHS Foundation Trust · GBSt George's, University of London · GBInstitut Curie · FRInstitute of Infection and Immunity · CAKing's College London · GBQueen Mary University of London · GBUniversity Hospital Southampton NHS Foundation Trust · GB

Funding

Training in Cancer Biology Training GrantT32CA009135 · NCI · UNIVERSITY OF WISCONSIN-MADISON · PI SUGDEN, WILLIAM M. · 1985 to 2024
$10.4M
Structural and Cellular Choreography for Decommissioning and Recycling of PP2A HoloenzymesR01GM137090 · NIGMS · UNIVERSITY OF WISCONSIN-MADISON · PI XING, YONGNA · 2021 to 2024
$1.3M
NCI NIH HHS T32 CA009135NIGMS NIH HHS R01 GM137090Wellcome Trust
6 · The paper itself

Abstract

purposeMuch of the heredity of melanoma remains unexplained. We sought predisposing germline copy-number variants using a rare disease approach.

methodsWhole-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.

resultsWe 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.

conclusionThis 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.

Indexed as

MelanomaNevusSkin NeoplasmsHumansImmunohistochemistryPhenotype

Identifiers

PMID34145395
PMCPMC8460442
OpenAlexW3166955828

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.