School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
Am J Hum Genet. 2013 Apr 4;92(4):489-503. doi: 10.1016/j.ajhg.2013.01.002. Epub 2013 Mar 27.
Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.
对来自 41 项病例对照研究的 89,050 名欧洲受试者中的 4,405 个变异进行分析，在 11q13 处鉴定出了三个与雌激素受体阳性肿瘤独立相关的信号。最强的信号映射到一个转录增强子元件，其中最佳候选致病变异 rs554219 的 G 等位基因增加了乳腺癌的风险，降低了报告基因检测中 ELK4 转录因子的结合和荧光素酶活性，并且可能与肿瘤中 cyclin D1 蛋白水平降低有关。另一个候选变异 rs78540526 位于同一增强子元件中。风险关联信号 2 rs75915166 在沉默元件内创建了一个 GATA3 结合位点。染色质构象研究表明，这些增强子和沉默元件相互作用，并且与它们的可能靶基因 CCND1 相互作用。
