Identification and characterization of functional risk variants for colorectal cancer mapping to chromosome 11q23.1
Identification and characterization of functional risk variants for colorectal cancer mapping to chromosome 11q23.1
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DOI：
10.1093/hmg/ddt584
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发表时间：
2014-04-15
影响因子：
3.5
通讯作者：
Casey, Graham
中科院分区：
文献类型：
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作者：
Biancolella, Michela;Fortini, Barbara K.;Casey, Graham
全基因组结直肠癌相关研究已经确定了一些与中等风险相关的常见变异，包括染色体11q23.1上的rs3802842。有几个基因映射到这个区域，但rs3802842没有映射到任何已知的转录或调控序列。因此，我们推测rs3802842不是功能性单核苷酸多态(SNP)，而是与功能性SNP连锁不平衡(S)。我们在SW480和HCT-116 CRC细胞中进行了组蛋白修饰的CHIP-SEQ，并将通过ENCODE获得的CHIP-SEQ和DNase I超敏数据整合到包含11q23.1上的rs3802842的137 kb基因组区域中。我们用定位于基因C11orf92和C11orf93的双向启动子区域的rs3802842在LD中鉴定了SNP rs10891246。在对风险等位基因进行突变后，启动子表现出较低水平的报告基因表达。第二个SNP rs7130173与rs3802842一起在LD中被定位到一个候选的增强子区域，该区域在HCT-116和SW480 CRC细胞中都显示出很强的单向活性。与普通等位基因相比，rs7130173的风险等位基因的增强子活性降低，电迁移率漂移分析显示核蛋白结合亲和力降低，提示差异转录因子(TF)结合。SNPs rs10891246和rs7130173位于同一单倍型，对邻近基因的表达数量性状基因座(EQTL)分析表明C11orf53、C11orf92和C11orf93是候选目标基因。这些结果表明rs10891246和rs7130173是定位于11q23.1的功能性SNPs，C11orf53、C11orf92和C11orf93是新的候选靶基因。
Genome-wide association studies of colorectal cancer (CRC) have identified a number of common variants associated with modest risk, including rs3802842 at chromosome 11q23.1. Several genes map to this region but rs3802842 does not map to any known transcribed or regulatory sequences. We reasoned, therefore, that rs3802842 is not the functional single-nucleotide polymorphism (SNP), but is in linkage disequilibrium (LD) with a functional SNP(s). We performed ChIP-seq for histone modifications in SW480 and HCT-116 CRC cells, and incorporated ChIP-seq and DNase I hypersensitivity data available through ENCODE within a 137-kb genomic region containing rs3802842 on 11q23.1. We identified SNP rs10891246 in LD with rs3802842 that mapped within a bidirectional promoter region of genes C11orf92 and C11orf93. Following mutagenesis to the risk allele, the promoter demonstrated lower levels of reporter gene expression. A second SNP rs7130173 was identified in LD with rs3802842 that mapped to a candidate enhancer region, which showed strong unidirectional activity in both HCT-116 and SW480 CRC cells. The risk allele of rs7130173 demonstrated reduced enhancer activity compared with the common allele, and reduced nuclear protein binding affinity in electromobility shift assays compared with the common allele suggesting differential transcription factor (TF) binding. SNPs rs10891246 and rs7130173 are on the same haplotype, and expression quantitative trait loci (eQTL) analyses of neighboring genes implicate C11orf53, C11orf92 and C11orf93 as candidate target genes. These data imply that rs10891246 and rs7130173 are functional SNPs mapping to 11q23.1 and that C11orf53, C11orf92 and C11orf93 represent novel candidate target genes involved in CRC etiology.