Wu Zhenzhen, Wang Peng, Song Chunhua, Wang Kaijuan, Yan Rui, Li Jingruo, Dai Liping
Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan, People's Republic of China.
Mol Genet Genomics. 2015 Jun;290(3):1141-53. doi: 10.1007/s00438-014-0983-5. Epub 2015 Jan 9.
MiRNA-binding-site single nucleotide polymorphisms (SNPs) in homologous recombination repair (HRR) pathway genes may change DNA repair capacity and affect susceptibility to cancer though complex gene-gene and gene-reproductive factors interactions. However, these SNPs associated with breast cancer (BC) are still unclear in Chinese women. Therefore, we conducted a case-control study to evaluate the genetic susceptibility of the five miRNA-binding-site SNPs in HRR pathway genes (MRE11A rs2155209, NBS1 rs2735383, RAD51 rs963917 and rs963918 and RAD52 rs7963551) in the development of BC. MRE11A rs2155209 and RAD52 rs7963551 were found to be associated with BC risk (ORadjusted: 1.87; 95 % CI: 1.23-2.86 and ORadjusted: 0.36; 95 % CI: 0.24-0.58). NBS1 rs2735383, RAD51 rs963917 and rs963918 were associated with BC risk after stratification according to reproductive factors. Haplotypes of Crs963917Ars963918 decreased the risk of BC (ORadjusted: 0.53; 95 % CI: 0.4-0.68), while the Trs963917Ars963918 and Trs963917Grs963918 haplotypes could increase the risk of BC (ORadjusted: 1.28; 95 % CI: 1.05-1.57 and ORadjusted: 1.31; 95 % CI: 1.09-1.62). Combined effect of risk alleles showed that the five SNPs were associated with increased BC risk in a dose-dependent manner (P trend = 0.003). The GC genotype of rs2735383, AG + GG genotype of rs963918 and AC + CC genotype of rs7963551 were associated with PR positivity of BC patients. These findings suggest that the miRNA-binding-site SNPs involved in HRR pathway genes may affect susceptibility of BC in Chinese women; moreover, the interactions of gene-gene and gene-reproductive factors play vital roles in the progression of BC. Further functional studies with larger sample are needed to support and validate these findings.
同源重组修复（HRR）通路基因中的微小RNA结合位点单核苷酸多态性（SNP）可能会改变DNA修复能力，并通过复杂的基因-基因和基因-生殖因素相互作用影响癌症易感性。然而，在中国女性中，这些与乳腺癌（BC）相关的SNP仍不清楚。因此，我们进行了一项病例对照研究，以评估HRR通路基因中5个微小RNA结合位点SNP（MRE11A rs2155209、NBS1 rs2735383、RAD51 rs963917和rs963918以及RAD52 rs7963551）在BC发生中的遗传易感性。发现MRE11A rs2155209和RAD52 rs7963551与BC风险相关（校正OR：1.87；95%CI：1.23 - 2.86和校正OR：0.36；95%CI：0.24 - 0.58）。根据生殖因素分层后，NBS1 rs2735383、RAD51 rs963917和rs963918与BC风险相关。单倍型Crs963917Ars963918降低了BC风险（校正OR：0.53；95%CI：0.4 - 0.68），而单倍型Trs963917Ars963918和Trs963917Grs963918则增加了BC风险（校正OR：1.28；95%CI：1.05 - 1.57和校正OR：1.31；95%CI：1.09 - 1.62）。风险等位基因的联合效应表明，这5个SNP与BC风险增加呈剂量依赖性相关（P趋势 = 0.003）。rs2735383的GC基因型、rs963918的AG + GG基因型和rs7963551的AC + CC基因型与BC患者的孕激素受体（PR）阳性相关。这些发现表明，参与HRR通路基因的微小RNA结合位点SNP可能会影响中国女性患BC的易感性；此外，基因-基因和基因-生殖因素的相互作用在BC的进展中起着至关重要的作用。需要进一步进行更大样本量的功能研究来支持和验证这些发现。
