cis-Expression QTL analysis of established colorectal cancer risk variants in colon tumors and adjacent normal tissue.
cis-Expression QTL analysis of established colorectal cancer risk variants in colon tumors and adjacent normal tissue.
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DOI：
10.1371/journal.pone.0030477
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Le Marchand L
中科院分区：
文献类型：
--
作者：
Loo LW;Cheng I;Tiirikainen M;Lum-Jones A;Seifried A;Dunklee LM;Church JM;Gryfe R;Weisenberger DJ;Haile RW;Gallinger S;Duggan DJ;Thibodeau SN;Casey G;Le Marchand L
全基因组关联研究（GWAS）已确定了19种与结直肠癌相关的风险变异。由于这些风险变异大多位于基因编码区之外，我们进行了顺式表达数量性状位点（cis - eQTL）分析，以研究对邻近基因表达可能具有的调控功能。40例微卫星稳定且CpG岛甲基化表型阴性的结直肠肿瘤以及配对的相邻正常结肠组织被用于全基因组单核苷酸多态性（SNP）和基因表达谱分析。我们发现3种风险变异（分别使用近乎完美的代理rs706771、rs11623717和rs2059252的rs10795668、rs4444235和rs9929218）与附近基因（上下游<2Mb）的表达水平显著相关（错误发现率q值≤0.05）。我们观察到在10p14的rs10795668的结直肠癌低风险等位基因（A）与ATP5C1表达增加（q = 0.024）之间存在关联，以及在14q22.2的rs4444235的结直肠癌高风险等位基因（C）与DLGAP5表达增加（q = 0.041）之间存在关联，这两种情况均在肿瘤样本中。在16q22.1的rs9929218的结直肠癌低风险等位基因（A）与相邻正常结肠组织样本中NOL3（q = 0.017）和DDX28（q = 0.046）的表达显著降低相关。在这4个基因中，DLGAP5和NOL3先前已被报道在结肠癌发生中起作用，ATP5C1和DDX28分别是参与细胞代谢和分裂的线粒体蛋白。GWAS研究结果、先前的功能研究以及此处描述的cis - eQTL分析相结合，表明结直肠癌GWAS所确定的3个风险位点具有调节邻近基因表达的假定功能活性。
Genome-wide association studies (GWAS) have identified 19 risk variants associated with colorectal cancer. As most of these risk variants reside outside the coding regions of genes, we conducted cis-expression quantitative trait loci (cis-eQTL) analyses to investigate possible regulatory functions on the expression of neighboring genes. Forty microsatellite stable and CpG island methylator phenotype-negative colorectal tumors and paired adjacent normal colon tissues were used for genome-wide SNP and gene expression profiling. We found that three risk variants (rs10795668, rs4444235 and rs9929218, using near perfect proxies rs706771, rs11623717 and rs2059252, respectively) were significantly associated (FDR q-value ≤0.05) with expression levels of nearby genes (<2 Mb up- or down-stream). We observed an association between the low colorectal cancer risk allele (A) for rs10795668 at 10p14 and increased expression of ATP5C1 (q = 0.024) and between the colorectal cancer high risk allele (C) for rs4444235 at 14q22.2 and increased expression of DLGAP5 (q = 0.041), both in tumor samples. The colorectal cancer low risk allele (A) for rs9929218 at 16q22.1 was associated with a significant decrease in expression of both NOL3 (q = 0.017) and DDX28 (q = 0.046) in the adjacent normal colon tissue samples. Of the four genes, DLGAP5 and NOL3 have been previously reported to play a role in colon carcinogenesis and ATP5C1 and DDX28 are mitochondrial proteins involved in cellular metabolism and division, respectively. The combination of GWAS findings, prior functional studies, and the cis-eQTL analyses described here suggest putative functional activities for three of the colorectal cancer GWAS identified risk loci as regulating the expression of neighboring genes.
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