Ding Shian-Ling, Yu Jyh-Cherng, Chen Shou-Tung, Hsu Giu-Cheng, Kuo Shou-Jen, Lin Yu Hsin, Wu Pei-Ei, Shen Chen-Yang
Department of Nursing, Kang-Ning Junior College of Medical Care and Management, Taipei, Taiwan.
Carcinogenesis. 2009 Jan;30(1):43-9. doi: 10.1093/carcin/bgn233. Epub 2008 Oct 28.
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.
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DNA DSB修复所涉及的机制在乳腺肿瘤发生过程中具有病因学重要性。布鲁姆（BLM）解旋酶直接与参与调节HR的RAD51重组酶相互作用，因此，研究这种相互作用是否与乳腺癌易感性相关特别令人感兴趣。本基于单核苷酸多态性（SNP）的病例对照研究使用933例乳腺癌患者和1539例健康对照的样本对这一假设进行了检验。结果显示，BLM中的一个SNP（rs2380165）以及RAD51中的两个SNP（rs2412546和rs4417527）与乳腺癌风险相关。此外，基于RAD51中五个SNP组合的单倍型和双倍型分析显示，RAD51多态性与乳腺癌风险之间存在强关联（P < 0.05）。在携带BLM纯合变异等位基因的女性中，癌症风险与RAD51的风险基因型/单倍型对之间的关联更强且更显著，这一发现支持了BLM与RAD51在决定乳腺癌风险中的相互作用（相互作用P < 0.05）。有趣的是，不仅位于编码BLM解旋酶结构域区域内的内含子SNP，而且位于编码RAD51相互作用结构域区域内的SNP在决定乳腺癌易感性方面均与RAD51多态性存在相互作用。我们的结果表明BLM和RAD51对乳腺癌发展有影响，并为这两种HR蛋白之间功能相互作用的致瘤意义提供了支持。
