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

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, Karen M. Funderburk, Myriam Brossard, John Taylor, Bogdan Pasaniuc, Raj Chari, Stephen J. Chanock, Clive J. Hoggart, Florence Demenais, Jennifer H. Barrett, Matthew H. Law, Mark M. Iles, Kai Yu, Michiel Vermeulen, Leonard I. Zon and Kevin M. Brown ()
Additional contact information
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

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16590-1

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