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Abstract：
A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).
摘要：
遗传和功能方法的组合已经在2q35确定了三个独立的乳腺癌风险基因座。最近的精细比例图分析，以完善这些关联，导致1（信号1），5（信号2），和42个(信号3)可信的因果变异在这些基因座。我们使用公开可用的硅DNA酶I和ChIP-seq数据以及体外报告基因和CRISPR测定来注释信号2和3。我们鉴定了在两个信号处增强来自IGFBP5启动子的细胞类型特异性转录的推定调控元件(在信号2处推定调控元件的表达增加30至40倍,在信号3处推定调控元件的表达增加2至3倍)。我们进一步确定了信号2的五个可信因果变异之一，1.4kb缺失(esv3594306)，作为可能的因果变异;该变异的缺失等位基因与IGFBP5表达平均额外增加1.3倍(MCF-7)和2.2倍(T-47D)相关。我们提出了一个模型，其中esv3594306的缺失等位基因并置两个转录因子结合区（由雌激素受体αChIP-seq峰注释）以生成单个扩展的调节元件。这种调节元件增加肿瘤抑制基因IGFBP5的细胞类型特异性表达，因此，降低雌激素受体阳性乳腺癌的风险(比值比=0.77,95%CI0.74-0.81,p=3.1×10-31).
