Pittman Alan M, Naranjo Silvia, Webb Emily, Broderick Peter, Lips Esther H, van Wezel Tom, Morreau Hans, Sullivan Kate, Fielding Sarah, Twiss Philip, Vijayakrishnan Jayaram, Casares Fernando, Qureshi Mobshra, Gómez-Skarmeta José Luis, Houlston Richard S
Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
Genome Res. 2009 Jun;19(6):987-93. doi: 10.1101/gr.092668.109. Epub 2009 Apr 24.
Recent genome-wide scans for colorectal cancer (CRC) have revealed the SMAD7 (mothers against decapentaplegic homolog 7) gene as a locus associated with a modest, but highly significant increase in CRC risk. To identify the causal basis of the association between 18q21 variation and CRC, we resequenced the 17-kb region of linkage disequilibrium and evaluated all variants in 2532 CRC cases and 2607 controls. A novel C to G single nucleotide polymorphism (SNP) at 44,703,563 bp was maximally associated with CRC risk (P = 5.98 x 10(-7); > or =1.5-fold more likely to be causal than other variants). Using transgenic assays in Xenopus laevis as a functional model, we demonstrate that the G risk allele leads to reduced reporter gene expression in the colorectum (P = 5.4 x 10(-3)). Electrophoretic mobility shift assays provided evidence for the role of Novel 1 in transcription factor binding. We propose that the novel SNP we have identified is the functional change leading to CRC predisposition through differential SMAD7 expression and, hence, aberrant TGF-beta signaling.
近期针对结直肠癌（CRC）的全基因组扫描显示，SMAD7（抗十号染色体同源基因7）基因是一个与CRC风险适度但高度显著增加相关的基因座。为了确定18q21变异与CRC之间关联的因果基础，我们对17 kb的连锁不平衡区域进行了重测序，并评估了2532例CRC病例和2607例对照中的所有变异。在44,703,563 bp处发现的一个新的C到G单核苷酸多态性（SNP）与CRC风险的关联最为显著（P = 5.98 x 10(-7)；比其他变异导致因果关系的可能性高1.5倍或更多）。利用非洲爪蟾的转基因分析作为功能模型，我们证明G风险等位基因导致结肠中报告基因表达降低（P = 5.4 x 10(-3)）。电泳迁移率变动分析为Novel 1在转录因子结合中的作用提供了证据。我们提出，我们鉴定出的新SNP是通过差异SMAD7表达导致CRC易感性的功能变化，从而导致异常的TGF-β信号传导。
