Differences of Variable Number Tandem Repeats in XRCC5 Promoter Are Associated with Increased or Decreased Risk of Breast Cancer in BRCA Gene Mutation Carriers.
Differences of Variable Number Tandem Repeats in XRCC5 Promoter Are Associated with Increased or Decreased Risk of Breast Cancer in BRCA Gene Mutation Carriers.
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DOI：
10.3389/fonc.2016.00092
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发表时间：
2016
影响因子：
4.7
通讯作者：
Wang SM
中科院分区：
文献类型：
--
作者：
Cui J;Luo J;Kim YC;Snyder C;Becirovic D;Downs B;Lynch H;Wang SM
Ku 80是Ku异源二聚体的亚基，其结合DNA双链断裂末端作为非同源末端连接（NHEJ）途径的一部分。Ku 80还通过与BRCA 1的相互作用参与同源重组（HR）。Ku 80由XRCC 5基因编码，该基因在其启动子区中含有可变数目串联重复序列（VNTR）插入。不同的VNTR基因型可以改变XRCC 5表达并影响Ku 80的产生，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。在这项研究中，我们在生殖细胞水平上调查了它与家族性乳腺癌的潜在关联。采用PCR、PAGE、桑格测序和统计分析，我们比较了健康个体和三种类型的家族性乳腺癌病例（突变型BRCA 1（BRCA 1+）、突变型BRCA 2（BRCA 2+）和野生型BRCA 1/BRCA 2（BRCA x））之间XRCC 5启动子的VNTR基因型。对照组与BRCA 1+组VNTR基因型差异有统计学意义BRCA 2+组与对照组比较，P < 0.0001（P = 0.0042），但BRCAx组无（P = 0.2185），BRCA 1+组与对照组比较差异有统计学意义（P < 0.0001）和BRCA 2+病例（P = 0.0092），但未发生癌症影响的BRCAx病例（P = 0.4251）。进一步分析表明，2 R/2 R（OR = 1.94，95%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1 R/1 R（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BRCA 1+组患癌风险降低相关; BRCA 2+组中2 R/1 R（OR = 1.94，95%CI = 1.14-3.32，P = 0.0242）与癌症风险增加相关。未观察到受癌症影响或未受癌症影响的携带者之间以及受癌症影响的携带者中不同癌症诊断年龄之间的风险改变的相关性。在BRCA 1+和BRCA 2+乳腺癌组中经常观察到的VNTR相关性表明，XRCC 5启动子中的VNTR多态性与BRCA 1+和BRCA 2+携带者乳腺癌风险的改变相关。
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.