Functional characterization of the 12p12.1 renal cancer-susceptibility locus implicates BHLHE41.
Functional characterization of the 12p12.1 renal cancer-susceptibility locus implicates BHLHE41.
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DOI：
10.1038/ncomms12098
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发表时间：
2016-07-07
影响因子：
16.6
通讯作者：
Chanock SJ
中科院分区：
文献类型：
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作者：
Bigot P;Colli LM;Machiela MJ;Jessop L;Myers TA;Carrouget J;Wagner S;Roberson D;Eymerit C;Henrion D;Chanock SJ
全基因组关联研究已经确定了多个肾细胞癌（RCC）易感基因座。在这里，我们使用区域插补和12p12.1位点的生物信息学分析，以确定单核苷酸多态性（SNP）rs7132434作为一个潜在的功能变异。荧光素酶测定证明等位基因特异性调节活性，并与来自电迁移率变动测定的数据一起，表明AP-1转录因子结合在rs7132434处的等位基因特异性差异。在对癌症基因组图谱数据的分析中，与rs7132434高度相关的SNP显示BHLHE 41表达的等位基因特异性差异（趋势P值=6.3 × 10−7）。过表达BHLHE 41的细胞产生更大的小鼠异种移植肿瘤，而RNA-seq分析显示，组成性增加的BHLHE 41诱导IL-11的表达。我们得出结论，RCC风险等位基因在12p12.1映射到rs7132434，在一个增强子，上调BHLHE 41的表达，这反过来又诱导IL-11，IL-6细胞因子家族的成员中的功能变体。 肾细胞癌的常见易感单倍型位于染色体12p12.1。在这里，作者表明变异rs7132434改变了AP-1转录因子的结合，这增加了BHLHE 41在肾细胞中的表达。
Genome-wide association studies have identified multiple renal cell carcinoma (RCC) susceptibility loci. Here, we use regional imputation and bioinformatics analysis of the 12p12.1 locus to identify the single-nucleotide polymorphism (SNP) rs7132434 as a potential functional variant. Luciferase assays demonstrate allele-specific regulatory activity and, together with data from electromobility shift assays, suggest allele-specific differences at rs7132434 for AP-1 transcription factor binding. In an analysis of The Cancer Genome Atlas data, SNPs highly correlated with rs7132434 show allele-specific differences in BHLHE41 expression (trend P value=6.3 × 10−7). Cells overexpressing BHLHE41 produce larger mouse xenograft tumours, while RNA-seq analysis reveals that constitutively increased BHLHE41 induces expression of IL-11. We conclude that the RCC risk allele at 12p12.1 maps to rs7132434, a functional variant in an enhancer that upregulates BHLHE41 expression which, in turn, induces IL-11, a member of the IL-6 cytokine family. A common susceptibility haplotype for renal cell carcinoma is located on chromosome 12p12.1. Here, the authors show that the variant rs7132434 alters binding of the AP-1 transcription factor, which increases the expression of BHLHE41 in renal cells.