Genetic variants of BLM interact with RAD51 to increase breast cancer susceptibility
Genetic variants of BLM interact with RAD51 to increase breast cancer susceptibility
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DOI：
10.1093/carcin/bgn233
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发表时间：
2009-01-01
期刊：
影响因子：
4.7
通讯作者：
Shen, Chen-Yang
中科院分区：
文献类型：
--
作者：
Ding, Shian-ling;Yu, Jyh-Cherng;Shen, Chen-Yang
家族性乳腺癌易感基因BRCA1和BRCA2在DNA双链断裂(DSB)修复的同源重组(HR)途径中的作用表明，HR和DNADSB修复机制在乳腺肿瘤的发生中具有重要的病因学意义。Bloom(BLM)解旋酶直接与RAD51重组酶相互作用，RAD51重组酶参与调节HR，因此研究这种相互作用是否与乳腺癌易感性有关是特别有意义的。这项基于单核苷酸多态性(SNP)的病例对照研究使用了933例乳腺癌患者和1539名健康对照的样本来检验这一假说。结果表明，BLM中的一个SNP(Rs2380165)和RAD51中的两个SNP(rs2412546和rs4417527)与乳腺癌风险相关。此外，基于RAD51中5个SNP组合的单倍型和双倍型分析表明，RAD51基因多态与乳腺癌风险之间存在很强的相关性(P<；0.05)。BLM和RAD51之间的交互作用在确定乳腺癌风险方面的支持来自于这一发现，即癌症风险与RAD51的高危基因型/单倍型对之间的关联在拥有BLM纯合子变异等位基因的女性中更强和更显著(P为交互作用<；0.05)。有趣的是，不仅位于BLM解旋酶结构域编码区的内含子SNP，而且位于RAD51相互作用结构域编码区的内含子SNP在决定乳腺癌易感性方面也显示出与RAD51多态的交互作用。我们的结果表明BLM和RAD51在乳腺癌的发生发展中起到了作用，并支持了这两个HR蛋白之间的功能相互作用在肿瘤发生中的意义。
The role of the familial breast cancer susceptibility genes, BRCA1 and BRCA2, in the homologous recombination (HR) pathway for DNA double-strand break (DSB) repair suggests that the mechanisms involved in HR and DNA DSB repair are of etiological importance during breast tumorigenesis. Bloom (BLM) helicase directly interacts with RAD51 recombinase, which is involved in regulating HR, and it is thus of particular interest to examine whether this interaction is associated with breast cancer susceptibility. This single-nucleotide polymorphism (SNP)-based case-control study was performed to examine this hypothesis using specimens from 933 patients with breast cancer and 1539 healthy controls. The results showed that one SNP (rs2380165) in BLM and two (rs2412546 and rs4417527) in RAD51 were associated with breast cancer risk. Furthermore, haplotype and diplotype analyses based on combinations of five SNPs in RAD51 revealed a strong association between RAD51 polymorphisms and breast cancer risk (P < 0.05). Support for the interaction between BLM and RAD51 in determining breast cancer risk came from the finding that the association between cancer risk and at-risk genotypes/haplotype pairs of RAD51 was stronger and more significant in women harboring homozygous variant alleles of BLM (P for interaction < 0.05). Interestingly, not only the intronic SNP located within the region encoding the helicase domain of BLM but also those within the RAD51-interaction domain-encoding region showed an interaction with RAD51 polymorphisms in determining breast cancer susceptibility. Our results suggest a contribution of BLM and RAD51 to breast cancer development and provide support for the tumorigenic significance of the functional interaction between these two HR proteins.