Cui Jian, Luo Jiangtao, Kim Yeong C, Snyder Carrie, Becirovic Dina, Downs Bradley, Lynch Henry, Wang San Ming
Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center , Omaha, NE , USA.
Department of Biostatistics, College of Public Health, University of Nebraska Medical Center , Omaha, NE , USA.
Front Oncol. 2016 Apr 13;6:92. doi: 10.3389/fonc.2016.00092. eCollection 2016.
Ku80 is a subunit of the Ku heterodimer that binds to DNA double-strand break ends as part of the non-homologous end joining (NHEJ) pathway. Ku80 is also involved in homologous recombination (HR) via its interaction with BRCA1. Ku80 is encoded by the XRCC5 gene that contains a variable number tandem repeat (VNTR) insertion in its promoter region. Different VNTR genotypes can alter XRCC5 expression and affect Ku80 production, thereby affecting NHEJ and HR pathways. VNTR polymorphism is associated with multiple types of sporadic cancer. In this study, we investigated its potential association with familial breast cancer at the germline level. Using PCR, PAGE, Sanger sequencing, and statistical analyses, we compared VNTR genotypes in the XRCC5 promoter between healthy individuals and three types of familial breast cancer cases: mutated BRCA1 (BRCA1 (+)), mutated BRCA2 (BRCA2 (+)), and wild-type BRCA1/BRCA2 (BRCAx). We observed significant differences of VNTR genotypes between control and BRCA1 (+) group (P < 0.0001) and BRCA2 (+) group (P = 0.0042) but not BRCAx group (P = 0.2185), and the differences were significant between control and cancer-affected BRCA1 (+) cases (P < 0.0001) and BRCA2 (+) cases (P = 0.0092) but not cancer-affected BRCAx cases (P = 0.4251). Further analysis indicated that 2R/2R (OR = 1.94, 95%CI = 1.26-2.95, P = 0.0096) and 2R/1R (OR = 1.58, 95%CI = 1.11-2.26, P = 0.0388) were associated with increased risk but 1R/1R (OR = 0.55, 95%CI = 0.35-0.84, P = 0.0196) and 1R/0R (OR = 0, 95%CI = 0-0.29, P = 0.0012) were associated with decreased risk in cancer-affected BRCA1 (+) group; 2R/1R (OR = 1.94, 95%CI = 1.14-3.32, P = 0.0242) was associated with increased risk in cancer-affected BRCA2 (+) group. No correlation was observed for the altered risk between cancer-affected or -unaffected carriers and between different age of cancer diagnosis in cancer-affected carriers. The frequently observed VNTR association with in BRCA1 (+) and BRCA2 (+) breast cancer group indicates that VNTR polymorphism in the XRCC5 promoter is associated with altered risk of breast cancer in BRCA1 (+) and BRCA2 (+) carriers.
Ku80是Ku异二聚体的一个亚基，作为非同源末端连接（NHEJ）途径的一部分与DNA双链断裂末端结合。Ku80还通过与BRCA1相互作用参与同源重组（HR）。Ku80由XRCC5基因编码，该基因在其启动子区域含有可变数量串联重复序列（VNTR）插入。不同的VNTR基因型可改变XRCC5表达并影响Ku80产生，从而影响NHEJ和HR途径。VNTR多态性与多种类型的散发性癌症相关。在本研究中，我们在种系水平上研究了其与家族性乳腺癌的潜在关联。通过聚合酶链反应（PCR）、聚丙烯酰胺凝胶电泳（PAGE）、桑格测序和统计分析，我们比较了健康个体与三种类型的家族性乳腺癌病例（突变型BRCA1（BRCA1(+)）、突变型BRCA2（BRCA2(+)）和野生型BRCA1/BRCA2（BRCAx））中XRCC5启动子的VNTR基因型。我们观察到对照组与BRCA1(+)组（P＜ 0.0001）和BRCA2(+)组（P = 0.0042）之间VNTR基因型存在显著差异，但与BRCAx组之间无显著差异（P = 0.2185），并且在对照组与患癌BRCA1(+)病例（P＜ 0.0001）和BRCA2(+)病例（P = 0.0092）之间差异显著，但与患癌BRCAx病例之间无显著差异（P = 0.4251）。进一步分析表明，在患癌BRCA1(+)组中，2R/2R（比值比（OR）= 1.94，95%置信区间（CI）= 1.26 - 2.95，P = 0.0096）和2R/1R（OR = 1.58，95%CI = 1.11 - 2.26，P = 0.0388）与风险增加相关，但1R/1R（OR = 0.55，95%CI = 0.35 - 0.84，P = 0.0196）和1R/0R（OR = 0，95%CI = 0 - 0.29，P = 0.0012）与风险降低相关；在患癌BRCA2(+)组中，2R/1R（OR = 1.94，95%CI = 1.14 - 3.32，P = 0.0242）与风险增加相关。在患癌或未患癌携带者之间以及患癌携带者中不同癌症诊断年龄之间未观察到风险改变的相关性。在BRCA1(+)和BRCA2(+)乳腺癌组中经常观察到的VNTR关联表明，XRCC5启动子中的VNTR多态性与BRCA1(+)和BRCA2(+)携带者患乳腺癌风险的改变相关。
