Cao Jingjing, Luo Chenglin, Yan Rui, Peng Rui, Wang Kaijuan, Wang Peng, Ye Hua, Song Chunhua
Department of Epidemiology and Statistics, College of Public health, Zhengzhou University, Zhengzhou, 450001, Henan Province, People's Republic of China.
Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, 79968, USA.
Med Oncol. 2016 Dec;33(12):135. doi: 10.1007/s12032-016-0849-2. Epub 2016 Nov 2.
BRCA1 and BRCA2 mutations confer an increased lifetime risk of breast cancer; however, the associations of microRNA (miRNA) binding site single nucleotide polymorphisms (SNPs) in 3' untranslated region (3'-UTR) of BRCA1 and BRCA2 with breast cancer (BC) risk were rarely reported. In this case-control study (498 BC patients and 498 matched controls), three SNPs (rs8176318, rs12516 and rs15869) were selected in the 3'-UTR of BRCA1 and BRCA2 genes, which were within miRNA-binding seed regions and might have potential function to regulate the expression of BRCA1/BRCA2. Unconditional logistic regression model was used to analyze the association between three SNPs and BC risk with adjustment of reproductive factors, and Student's t test was performed to assess relative expression of BRCA2 in human breast cancer cell lines. Multifactor dimensionality reduction method was applied to calculate gene-reproductive factors interactions. A novel finding showed that AC [odds ratio (OR) 1.524; 95% confidence interval (CI) 1.141-2.035] genotype of rs15869 in BRCA2 could increase the risk of BC and recombinant plasmid-pGenesil-1-miR-627 could negatively regulate the expression of BRCA2 in MCF-7 and MDA-MB-231 cells. Gene-reproductive factors interactions analysis revealed that rs15869 together with age at menarche and number of pregnancy could increase the risk of BC by 2.39-fold and TT genotype (OR 0.316; 95% CI 0.130-0.767) of rs8176318 had a significant association with progesterone receptor status in BC patients. Our findings suggest that the miRNA-binding SNPs in BRCA1/BRCA2 and their interaction with reproductive factors might contribute to BC risk, and miR-627 might down-regulate BRCA2 expression in MCF-7 and MDA-MB-231 cells.
BRCA1和BRCA2基因突变会增加患乳腺癌的终生风险；然而，BRCA1和BRCA2基因3'非翻译区（3'-UTR）中微小RNA（miRNA）结合位点单核苷酸多态性（SNP）与乳腺癌（BC）风险之间的关联鲜有报道。在这项病例对照研究（498例BC患者和498例匹配对照）中，在BRCA1和BRCA2基因的3'-UTR中选择了三个SNP（rs8176318、rs12516和rs15869），它们位于miRNA结合种子区域内，可能具有调节BRCA1/BRCA2表达的潜在功能。采用无条件逻辑回归模型分析三个SNP与BC风险之间的关联，并对生殖因素进行校正，同时进行Student's t检验以评估BRCA2在人乳腺癌细胞系中的相对表达。应用多因素降维方法计算基因-生殖因素相互作用。一项新发现表明，BRCA2中rs15869的AC基因型[比值比（OR）1.524；95%置信区间（CI）1.141 - 2.035]可增加BC风险，重组质粒-pGenesil-1-miR-627可在MCF-7和MDA-MB-231细胞中负向调节BRCA2的表达。基因-生殖因素相互作用分析显示，rs15869与初潮年龄和妊娠次数共同作用可使BC风险增加2.39倍，rs8176318的TT基因型（OR 0.316；95% CI 0.130 - 0.767）与BC患者的孕激素受体状态显著相关。我们的研究结果表明，BRCA1/BRCA2中miRNA结合SNP及其与生殖因素的相互作用可能导致BC风险增加，并且miR-627可能在MCF-7和MDA-MB-231细胞中下调BRCA2的表达。
