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Massively parallel reporter assays of melanoma risk variants identify MX2 as a gene promoting melanoma

  1. Author:
    Choi, Jiyeon [ORCID]
    Zhang, Tongwu [ORCID]
    Vu, Andrew
    Ablain, Julien [ORCID]
    Makowski, Matthew M
    Colli, Leandro M
    Xu, Mai
    Hennessey, Rebecca C
    Yin, Jinhu
    Rothschild, Harriet
    Gräwe, Cathrin
    Kovacs, Michael A
    Funderburk, Karen M
    Brossard, Myriam [ORCID]
    Taylor, John [ORCID]
    Pasaniuc, Bogdan
    Chari,Raj
    Chanock, Stephen J [ORCID]
    Hoggart, Clive J
    Demenais, Florence [ORCID]
    Barrett, Jennifer H [ORCID]
    Law, Matthew H [ORCID]
    Iles, Mark M [ORCID]
    Yu, Kai
    Vermeulen, Michiel [ORCID]
    Zon, Leonard I [ORCID]
    Brown, Kevin M [ORCID]

  2. Author Address

    Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA., Stem Cell Program and Division of Hematology/Oncology, Boston Children 39;s Hospital and Dana-Farber Cancer Institute, Boston, MA, 02115, USA., Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 XZ, Nijmegen, The Netherlands., Universit 233; de Paris, UMRS-1124, Institut National de la Sant 233; et de la Recherche M 233;dicale (INSERM), F-75006, Paris, France., Leeds Institute for Data Analytics, School of Medicine, University of Leeds, Leeds, LS2 9JT, UK., Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90024, USA., Genome Modification Core, Frederick National Lab for Cancer Research, National Cancer Institute, Frederick, MD, 21701, USA., Department of Medicine, Imperial College London, London, SW7 2BU, UK., Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia., Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA. kevin.brown3@nih.gov.,
    1. Year: 2020
    2. Date: Jun 01
    3. Epub Date: 2020 06 01
  2. Journal: Nature communications
    1. 11
    2. 1
    3. Pages: 2718
  4. Type of Article: Article
  5. Article Number: 2718
  6. ISSN: 2041-1723
  1. Abstract:

    Genome-wide association studies (GWAS) have identified ~20 melanoma susceptibility loci, most of which are not functionally characterized. Here we report an approach integrating massively-parallel reporter assays (MPRA) with cell-type-specific epigenome and expression quantitative trait loci (eQTL) to identify susceptibility genes/variants from multiple GWAS loci. From 832 high-LD variants, we identify 39 candidate functional variants from 14 loci displaying allelic transcriptional activity, a subset of which corroborates four colocalizing melanocyte cis-eQTL genes. Among these, we further characterize the locus encompassing the HIV-1 restriction gene, MX2 (Chr21q22.3), and validate a functional intronic variant, rs398206. rs398206 mediates the binding of the transcription factor, YY1, to increase MX2 levels, consistent with the cis-eQTL of MX2 in primary human melanocytes. Melanocyte-specific expression of human MX2 in a zebrafish model demonstrates accelerated melanoma formation in a BRAFV600E background. Our integrative approach streamlines GWAS follow-up studies and highlights a pleiotropic function of MX2 in melanoma susceptibility.

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External Sources

  1. View Full Text
  2. DOI: 10.1038/s41467-020-16590-1
  3. PMID: 32483191
  4. View record in Web of Science®
  5. WOS: 000542983000010
  6. PII : 10.1038/s41467-020-16590-1

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  1. Fiscal Year: FY2019-2020
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