Journal Article

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

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

2020

Overview

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 BRAF V600E background. Our integrative approach streamlines GWAS follow-up studies and highlights a pleiotropic function of MX2 in melanoma susceptibility. There are more than 20 known melanoma susceptibility genes. Here, using a massively parallel reporter assay, the authors identify risk-associated variants that alter gene transcription, and demonstrate that expression of one such gene, MX2 , leads to the promotion of melanoma in a zebrafish model.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/89 / 45/15 / 45/23 / 45/43 / 45/47 / 49/39 / 631/208/205/2138 / 631/208/68 / 631/67/1813/1634 / 631/67/68 / 82/58 / Animals / Assaying / Biochemistry, Molecular Biology / Cancer / Cell Line, Tumor / Danio rerio / Disease Models, Animal / Gene expression / Gene Expression Regulation / Gene mapping / Genes / Genes, Reporter - genetics / Genetic Predisposition to Disease - genetics / Genome-wide association studies / Genome-Wide Association Study - methods / Genomes / Genomics / HEK293 Cells / HIV / Human immunodeficiency virus / Humanities and Social Sciences / Humans / Life Sciences / Melanocytes / Melanocytes - metabolism / Melanoma / Melanoma - genetics / Melanoma - pathology / multidisciplinary / Mutation / Myxovirus Resistance Proteins - genetics / Polymorphism, Single Nucleotide / Proto-Oncogene Proteins B-raf - genetics / Proto-Oncogene Proteins B-raf - metabolism / Quantitative trait loci / Quantitative Trait Loci - genetics / Science / Science (multidisciplinary) / YY1 protein / Zebrafish / Zebrafish - genetics / Zebrafish - metabolism