Section of Cancer Genetics, Institute of Cancer Research, Surrey, UK.
Oncogene. 2012 Aug 16;31(33):3777-84. doi: 10.1038/onc.2011.564. Epub 2011 Dec 12.
Common genetic variation at human 14q22.2 tagged by rs4444235 is significantly associated with colorectal cancer (CRC) risk. Re-sequencing was used to comprehensively annotate the 17kb region of strong linkage disequilibrium encompassing rs4444235. Through bioinformatic analyses using H3K4Me1, H3K4Me3, and DNase-I hypersensitivity chromatin signatures and evolutionary conservation we identified seven candidate disease-causing single-nucleotide polymorphisms mapping to six regions within the 17-kb region predicted to have regulatory potential. Reporter gene studies of these regions demonstrated that the element to which rs4444235 maps acts as an allele-specific transcriptional enhancer. Allele-specific expression studies in CRC cell lines heterozygous for rs4444235 showed significantly increased expression of bone morphogenetic protein-4 (BMP4) associated with the risk allele (P<0.001). These data provide evidence for a functional basis for the non-coding risk variant rs4444235 at 14q22.2 and emphasizes the importance of genetic variation in the BMP pathway genes as determinants of CRC risk.
位于人类 14q22.2 上的 rs4444235 标记的常见遗传变异与结直肠癌（CRC）风险显著相关。重新测序用于全面注释包含 rs4444235 的强连锁不平衡的 17kb 区域。通过使用 H3K4Me1、H3K4Me3 和 DNase-I 超敏染色质特征以及进化保守性的生物信息学分析，我们鉴定出了七个候选疾病单核苷酸多态性，这些单核苷酸多态性映射到 17kb 区域内的六个区域，这些区域被预测具有调节潜能。对这些区域的报告基因研究表明，rs4444235 所映射的元件作为一个等位基因特异性转录增强子发挥作用。CRC 细胞系中杂合子 rs4444235 的等位基因特异性表达研究表明，与风险等位基因相关的骨形态发生蛋白 4（BMP4）表达显著增加（P<0.001）。这些数据为 14q22.2 上的非编码风险变异 rs4444235 提供了功能基础的证据，并强调了 BMP 通路基因中的遗传变异作为 CRC 风险决定因素的重要性。
