A genome-wide survey over the ChIP-on-chip identified androgen receptor-binding genomic regions identifies a novel prostate cancer susceptibility locus at 12q13.13.
A genome-wide survey over the ChIP-on-chip identified androgen receptor-binding genomic regions identifies a novel prostate cancer susceptibility locus at 12q13.13.
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DOI：
10.1158/1055-9965.epi-11-0523
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Xu J
中科院分区：
文献类型：
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作者：
Feng J;Sun J;Kim ST;Lu Y;Wang Z;Zhang Z;Gronberg H;Isaacs WB;Zheng SL;Xu J
GWAS鉴定的前列腺癌（PCa）风险相关SNP的分子机制在很大程度上仍然无法解释。最近的一项发现表明，PCa风险SNP在含有雄激素受体（AR）结合位点的基因组区域中富集，这表明AR信号传导的改变是一种潜在的重要机制。为了通过利用这些知识探索新的关联，我们利用先前对芯片上芯片中含有的SNP进行的荟萃分析，使用来自约翰霍普金斯医院（JHH）和癌症易感性遗传标记（CGEMS）研究的GWAS数据鉴定AR结合基因组区域，随后评估了来自瑞典前列腺癌（CAPS）研究的第三个人群中的最高关联。一个SNP（rs 4919743：G>A）位于12q13.13处的KRT 8基因座，其编码角蛋白（K8），长期用作前列腺上皮恶性肿瘤标志物，并与几种癌症类型的肿瘤发生有关，被鉴定为与PCa风险相关。在所有三个研究人群中，PCa病例的次要“A”等位基因频率始终高于对照组，合并优势比为1.22（95% CI：1.13-1.32），总体P值为4.50 × 10−7（Bonferroni校正P = 0.006）。我们已经确定了一个新的遗传位点，与前列腺癌的风险。这项研究表明，在促进新的疾病相关的遗传位点的搜索的生物学知识的巨大潜力。这一发现值得在其他研究中进一步复制。
The molecular mechanisms for the GWAS-identified prostate cancer (PCa) risk-associated SNPs remain largely unexplained. One recent finding that the PCa risk SNPs are enriched in genomic regions containing androgen receptor (AR) binding sites has suggested altered AR signaling as a potentially important mechanism. To explore novel associations by leveraging this knowledge, we utilized a meta-analysis previously performed over SNPs harbored in ChIP-on-chip identified AR binding genomic regions using the GWAS data from the Johns Hopkins Hospital (JHH) and the Cancer Genetic Markers of Susceptibility (CGEMS) study, and subsequently evaluated the top associations in a third population from the CAncer of the Prostate in Sweden (CAPS) study. One SNP (rs4919743: G>A), located at the KRT8 locus at 12q13.13 which encodes a keratin protein (K8) long used as a prostate epithelial malignancy marker and implicated in the tumorigenesis of several cancer types, was identified to be associated with PCa risk. The frequency of its minor “A” allele was consistently higher in PCa cases than in controls in all three study populations, with a combined odds ratio of 1.22 (95% CI: 1.13–1.32) and an overall P-value of 4.50 × 10−7 (Bonferroni-corrected P = 0.006). We have identified a novel genetic locus that is associated with PCa risk. This study illustrated the great potential of prior biological knowledge in facilitating the search for novel disease-associated genetic loci. This finding warrants further replication in other studies.