A Comprehensive cis-eQTL Analysis Revealed Target Genes in Breast Cancer Susceptibility Loci Identified in Genome-wide Association Studies
A Comprehensive cis-eQTL Analysis Revealed Target Genes in Breast Cancer Susceptibility Loci Identified in Genome-wide Association Studies
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全面的 cis-eQTL 分析揭示了全基因组关联研究中确定的乳腺癌易感性位点的靶基因
DOI：
10.1016/j.ajhg.2018.03.016
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发表时间：
2018-05-03
影响因子：
9.8
通讯作者：
Zheng, Wei
中科院分区：
文献类型：
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作者：
Guo, Xingyi;Lin, Weiqiang;Zheng, Wei
全基因组关联研究(GWAS)已经确定了150多个共同的乳腺癌风险基因位点。然而，目标基因和潜在的机制在很大程度上仍然不清楚。我们使用来自乳腺癌分子分类国际联合会(METABRIC)、癌症基因组图谱(TCGA)和基因类型-组织表达(GTEx)项目的正常或肿瘤乳腺转录组数据进行顺式表达数量性状基因座(cis-eQTL)分析。在结合MetTABRIC和TCGA的荟萃分析结果和本杰米尼-霍奇伯格(BH)调整的p<；0.05的GTEx结果后，我们确定了51个铅变体的101个基因。在雌激素受体阳性(ER+)和雌激素受体阴性(ER-)细胞系中使用荧光素酶报告基因分析，我们发现潜在的功能性单核苷酸多态(SNPs)的替代等位基因rs11552449(DCLREIB)、rs7257932(SSBP4)、rs3747479(MRPS30)、rs2236007(PAX9)和rs73134739(ATG10)与参考等位基因相比，可以显著改变其靶基因的启动子活性。此外，我们在乳腺癌细胞系中进行了体外实验，我们的结果表明，DCLREIB、MRPS30和ATG10通过某些细胞行为的破坏在乳腺肿瘤的发生中发挥了重要作用。我们的发现揭示了与遗传易感性风险基因相关的潜在靶基因，并为更好地理解乳腺癌的发病机制提供了潜在的机制。
Genome-wide association studies (GWASs) have identified more than 150 common genetic loci for breast cancer risk. However, the target genes and underlying mechanisms remain largely unknown. We conducted a cis-expression quantitative trait loci (cis-eQTL) analysis using normal or tumor breast transcriptome data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), The Cancer Genome Atlas (TCGA), and the Genotype-Tissue Expression (GTEx) project. We identified a total of 101 genes for 51 lead variants after combing the results of a meta-analysis of METABRIC and TCGA, and the results from GTEx at a Benjamini-Hochberg (BH)-adjusted p < 0.05. Using luciferase reporter assays in both estrogen-receptor positive (ER+) and negative (ER-) cell lines, we showed that alternative alleles of potential functional single-nucleotide polymorphisms (SNPs), rs11552449 (DCLREIB), rs7257932 (SSBP4), rs3747479 (MRPS30), rs2236007 (PAX9), and rs73134739 (ATG10), could significantly change promoter activities of their target genes compared to reference alleles. Furthermore, we performed in vitro assays in breast cancer cell lines, and our results indicated that DCLREIB, MRPS30, and ATG10 played a vital role in breast tumorigenesis via certain disruption of cell behaviors. Our findings revealed potential target genes for associations of genetic susceptibility risk loci and provided underlying mechanisms for a better understanding of the pathogenesis of breast cancer.