Systematic search for enhancer elements and somatic allelic imbalance at seven low-penetrance colorectal cancer predisposition loci.
Systematic search for enhancer elements and somatic allelic imbalance at seven low-penetrance colorectal cancer predisposition loci.
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DOI：
10.1186/1471-2350-12-23
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发表时间：
2011-02-14
影响因子：
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通讯作者：
Aaltonen LA
中科院分区：
文献类型：
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作者：
Niittymäki I;Tuupanen S;Li Y;Järvinen H;Mecklin JP;Tomlinson IP;Houlston RS;Karhu A;Aaltonen LA
在全基因组关联研究中，10个染色体位点的常见单核苷酸多态性（SNP）已被证明是结直肠癌（CRC）的易感基因。到目前为止，仅提出了三个位点与遗传变异相关的CRC易感性的合理生物学机制，每个位点都指向通过远端调控元件影响基因表达的变异。在本研究中，我们的目的是深入了解7个低多态性CRC基因座的分子基础，标记为15q13的rs4779584，10p14的rs10795668，11q23的rs3802842，14q22的rs4444235，16q22的rs9929218，19q13的rs10411210，和20p12的rs961253。通过分析杂合子患者肿瘤和相应正常组织样本中的等位基因失衡，研究了可能的危险等位基因的体细胞获得或保护等位基因的丢失。从计算机模拟预测的位于CRC相关连接不平衡区域内的增强子元件中搜索功能变体。在7个基因座中的任何一个都没有观察到靶向SNP的等位基因不平衡。总共，在与最初的7个标记SNP相同的基于人群的病例对照系列中，对预测会破坏潜在转录因子结合序列的12个SNP进行了基因分型。没有显示与CRC相关。等位基因不平衡分析的结果表明，7个CRC风险变异体在肿瘤进展中不是体细胞选择的。生物信息学方法无法在七个基因座中的任何一个上精确定位致癌变异。虽然有可能许多CRC易感基因座通过靶向转录因子结合位点参与基因表达的控制，但也应考虑其他可能性，如调节RNA。
Common single-nucleotide polymorphisms (SNPs) in ten chromosomal loci have been shown to predispose to colorectal cancer (CRC) in genome-wide association studies. A plausible biological mechanism of CRC susceptibility associated with genetic variation has so far only been proposed for three loci, each pointing to variants that affect gene expression through distant regulatory elements. In this study, we aimed to gain insight into the molecular basis of seven low-penetrance CRC loci tagged by rs4779584 at 15q13, rs10795668 at 10p14, rs3802842 at 11q23, rs4444235 at 14q22, rs9929218 at 16q22, rs10411210 at 19q13, and rs961253 at 20p12. Possible somatic gain of the risk allele or loss of the protective allele was studied by analyzing allelic imbalance in tumour and corresponding normal tissue samples of heterozygous patients. Functional variants were searched from in silico predicted enhancer elements locating inside the CRC-associating linkage-disequilibrium regions. No allelic imbalance targeting the SNPs was observed at any of the seven loci. Altogether, 12 SNPs that were predicted to disrupt potential transcription factor binding sequences were genotyped in the same population-based case-control series as the seven tagging SNPs originally. None showed association with CRC. The results of the allelic imbalance analysis suggest that the seven CRC risk variants are not somatically selected for in the neoplastic progression. The bioinformatic approach was unable to pinpoint cancer-causing variants at any of the seven loci. While it is possible that many of the predisposition loci for CRC are involved in control of gene expression by targeting transcription factor binding sites, also other possibilities, such as regulatory RNAs, should be considered.