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首页> 外文期刊>PLoS Genetics >DNA methylation and cis-regulation of gene expression by prostate cancer risk SNPs
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DNA methylation and cis-regulation of gene expression by prostate cancer risk SNPs

机译：DNA甲基化和<斜斜体> CIS - 前列腺癌风险SNPS的基因表达

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Genome-wide association studies have identified more than 100 SNPs that increase the risk of prostate cancer (PrCa). We identify and compare expression quantitative trait loci (eQTLs) and CpG methylation quantitative trait loci (meQTLs) among 147 established PrCa risk SNPs in primary prostate tumors (n = 355 from a Seattle-based study and n = 495 from The Cancer Genome Atlas, TCGA) and tumor-adjacent, histologically benign samples (n = 471 from a Mayo Clinic study). The role of DNA methylation in eQTL regulation of gene expression was investigated by data triangulation using several causal inference approaches, including a proposed adaptation of the Causal Inference Test ( CIT ) for causal direction. Comparing eQTLs between tumors and benign samples, we show that 98 of the 147 risk SNPs were identified as eQTLs in the tumor-adjacent benign samples, and almost all 34 eQTL identified in tumor sets were also eQTLs in the benign samples. Three lines of results support the causal role of DNA methylation. First, nearly 100 of the 147 risk SNPs were identified as meQTLs in one tumor set, and almost all eQTLs in tumors were meQTLs. Second, the loss of eQTLs in tumors relative to benign samples was associated with altered DNA methylation. Third, among risk SNPs identified as both eQTLs and meQTLs, mediation analyses suggest that over two-thirds have evidence of a causal role for DNA methylation, mostly mediating genetic influence on gene expression. In summary, we provide a comprehensive catalog of eQTLs, meQTLs and putative cancer genes for known PrCa risk SNPs. We observe that a substantial portion of germline eQTL regulatory mechanisms are maintained in the tumor development, despite somatic alterations in tumor genome. Finally, our mediation analyses illuminate the likely intermediary role of CpG methylation in eQTL regulation of gene expression.
机译：基因组 - 宽协会研究鉴定了100多个SNP，从而增加了前列腺癌的风险（PRCA）。我们识别和比较在原发性前列腺肿瘤中的147个已建立的PRCA风险SNP中的表达定量性状基因座（EQTLS）和CpG甲基化定量性状基因座（MEQTLS）（N = 355来自西雅图的研究，N = 495来自癌症基因组地图集， TCGA）和肿瘤相邻的组织学上良性样品（来自Mayo诊所研究的N = 471）。 DNA甲基化在基因表达的EQTL调节中的作用通过数据三角测量使用若干因果推理方法来研究，包括建议适应因果方向的因果推理测试（CIT）。比较肿瘤与良性样品之间的EQTLS，我们表明，147个风险SNP中的98个被鉴定为肿瘤相邻良性样品中的EQTL，并且在肿瘤套件中鉴定的几乎所有34个EQTL也是良性样本中的EQTL。三行结果支持DNA甲基化的因果作用。首先，147个风险SNP中的近100个被鉴定为一个肿瘤集中的MEQTL，并且几乎所有肿瘤的EQTL都是MEQTLS。其次，相对于良性样品的肿瘤中的EQTLS的损失与改变的DNA甲基化有关。第三，在被确定为eqtls和meqtls的风险SNP中，中介分析表明，超过三分之二具有DNA甲基化的因果作用的证据，大多介导对基因表达的遗传影响。总之，我们为已知的PRCA风险SNP提供了eqtls，meqtls和推定癌症基因的全面目录。我们观察到，尽管肿瘤基因组体细胞改变，但是在肿瘤发育中，大部分种系EQTL调节机制保持在肿瘤发育中。最后，我们的中介分析照亮了CpG甲基化在基因表达的EQTL调节中的可能中介作用。

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