Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.
Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
Nat Commun. 2020 Jun 1;11(1):2718. doi: 10.1038/s41467-020-16590-1.
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 background. Our integrative approach streamlines GWAS follow-up studies and highlights a pleiotropic function of MX2 in melanoma susceptibility.
全基因组关联研究（GWAS）已经确定了约 20 个黑色素瘤易感性位点，其中大多数尚未进行功能表征。在这里，我们报告了一种整合大规模平行报告分析（MPRA）与细胞类型特异性表观基因组和表达数量性状基因座（eQTL）的方法，以从多个 GWAS 位点中识别易感基因/变体。从 832 个高 LD 变体中，我们从 14 个显示等位转录活性的位点中鉴定出 39 个候选功能变体，其中一部分证实了四个共定位黑素细胞顺式 eQTL 基因。在这些基因中，我们进一步表征了包含 HIV-1 限制基因 MX2（Chr21q22.3）的基因座，并验证了一个功能性内含子变体 rs398206。rs398206 介导转录因子 YY1 的结合，增加 MX2 水平，与原发性人黑素细胞中 MX2 的顺式 eQTL 一致。在斑马鱼模型中，人类 MX2 的黑素细胞特异性表达表明在 BRAF 背景下加速了黑色素瘤的形成。我们的综合方法简化了 GWAS 后续研究，并强调了 MX2 在黑色素瘤易感性中的多效性功能。
