Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, AB, Canada.
Department of Oncology, University of Alberta, Edmonton, AB, Canada.
Int J Cancer. 2020 Mar 1;146(5):1219-1229. doi: 10.1002/ijc.32407. Epub 2019 May 27.
We previously identified a novel breast cancer susceptibility variant on chromosome 4q31.22 locus (rs1429142) conferring risk among women of European ancestry. Here, we report replication of findings, validation of the variant in diverse populations and fine-mapping of the associated locus in Caucasian population. The SNP rs1429142 (C/T, minor allele frequency 18%) showed association for the overall breast cancer risk in Stages 1-4 (n = 4,331 cases/4271 controls; p = 4.35 × 10 ; odds ratio, OR ,1.25), and an elevated risk among premenopausal women (n = 1,503 cases/4271 controls; p = 5.81 × 10 ; OR 1.40) in European populations. SNP rs1429142 was associated with premenopausal breast cancer risk in women of African (T/C; p-value 1.45 × 10 ; OR 1.2) but not from Chinese ancestry. Fine-mapping of the locus revealed several potential causal variants which are present within a single association signal, revealed from the conditional regression analysis. Functional annotation of the potential causal variants revealed three putative SNPs rs1366691, rs1429139 and rs7667633 with active enhancer functions inferred based on histone marks, DNase hypersensitive sites in breast cell line data. These putative variants were bound by transcription factors (C-FOS, STAT1/3 and POL2/3) with known roles in inflammatory pathways. Furthermore, Hi-C data revealed several short-range interactions in the fine-mapped locus harboring the putative variants. The fine mapped locus was predicted to be within a single topologically associated domain, potentially facilitating enhancer-promoter interactions possibly leading to the regulation of nearby genes.
我们之前在染色体 4q31.22 位置（rs1429142）发现了一个新的乳腺癌易感性变异，该变异增加了欧洲裔女性的乳腺癌患病风险。在此，我们报道了该发现的复制结果、在不同人群中对变异的验证结果，以及在高加索人群中对相关位点的精细映射结果。SNP rs1429142（C/T，次要等位基因频率 18%）与分期为 1-4 期的总体乳腺癌风险相关（n = 4331 例病例/4271 例对照；p = 4.35×10 ；优势比[OR]，1.25），且在欧洲人群中，在绝经前女性中风险升高（n = 1503 例病例/4271 例对照；p = 5.81×10 ；OR 1.40）。SNP rs1429142 与非洲裔女性的绝经前乳腺癌风险相关（T/C；p 值 1.45×10 ；OR 1.2），但与中国血统女性无关。该位点的精细映射显示，在条件回归分析揭示的单一关联信号内存在几个潜在的因果变异。潜在因果变异的功能注释显示，三个假定的 SNP rs1366691、rs1429139 和 rs7667633 具有基于组蛋白标记、乳腺细胞系数据中的 DNA 酶超敏位点推断出的活性增强子功能。这些假定的变体被转录因子（C-FOS、STAT1/3 和 POL2/3）结合，这些转录因子在炎症途径中具有已知作用。此外，Hi-C 数据显示，在包含假定变异体的精细映射区域中存在几个短程相互作用。精细映射的位点被预测为在单个拓扑相关结构域内，可能促进增强子-启动子相互作用，从而导致附近基因的调控。
