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

Author

Listed:
  • Jiyeon Choi

    (National Cancer Institute)

  • Tongwu Zhang

    (National Cancer Institute)

  • Andrew Vu

    (National Cancer Institute)

  • Julien Ablain

    (Boston Children’s Hospital and Dana-Farber Cancer Institute)

  • Matthew M. Makowski

    (Radboud University Nijmegen)

  • Leandro M. Colli

    (National Cancer Institute)

  • Mai Xu

    (National Cancer Institute)

  • Rebecca C. Hennessey

    (National Cancer Institute)

  • Jinhu Yin

    (National Cancer Institute)

  • Harriet Rothschild

    (Boston Children’s Hospital and Dana-Farber Cancer Institute)

  • Cathrin Gräwe

    (Radboud University Nijmegen)

  • Michael A. Kovacs

    (National Cancer Institute)

  • Karen M. Funderburk

    (National Cancer Institute)

  • Myriam Brossard

    (Université de Paris, UMRS-1124, Institut National de la Santé et de la Recherche Médicale (INSERM))

  • John Taylor

    (University of Leeds)

  • Bogdan Pasaniuc

    (University of California, Los Angeles)

  • Raj Chari

    (Frederick National Lab for Cancer Research, National Cancer Institute)

  • Stephen J. Chanock

    (National Cancer Institute)

  • Clive J. Hoggart

    (Imperial College London)

  • Florence Demenais

    (Université de Paris, UMRS-1124, Institut National de la Santé et de la Recherche Médicale (INSERM))

  • Jennifer H. Barrett

    (University of Leeds)

  • Matthew H. Law

    (Statistical Genetics, QIMR Berghofer Medical Research Institute)

  • Mark M. Iles

    (University of Leeds)

  • Kai Yu

    (National Cancer Institute)

  • Michiel Vermeulen

    (Radboud University Nijmegen)

  • Leonard I. Zon

    (Boston Children’s Hospital and Dana-Farber Cancer Institute)

  • Kevin M. Brown

    (National Cancer Institute)

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.

Suggested Citation

  • Jiyeon Choi & Tongwu Zhang & Andrew Vu & Julien Ablain & Matthew M. Makowski & Leandro M. Colli & Mai Xu & Rebecca C. Hennessey & Jinhu Yin & Harriet Rothschild & Cathrin Gräwe & Michael A. Kovacs & K, 2020. "Massively parallel reporter assays of melanoma risk variants identify MX2 as a gene promoting melanoma," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16590-1
    DOI: 10.1038/s41467-020-16590-1
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    Cited by:

    1. Kashi Raj Bhattarai & Robert J. Mobley & Kelly R. Barnett & Daniel C. Ferguson & Baranda S. Hansen & Jonathan D. Diedrich & Brennan P. Bergeron & Satoshi Yoshimura & Wenjian Yang & Kristine R. Crews &, 2024. "Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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