Ling Hong, Li Shan, Wu Yang, Zheng Yi-Zi, Qiao Feng, Yao Ling, Cao Zhi-Gang, Ye Fu-Gui, Wu Jiong, Hu Xin, Wang Bin, Shao Zhi-Ming
Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Oncotarget. 2016 Mar 1;7(9):9759-72. doi: 10.18632/oncotarget.7112.
The tumor suppressor BRCA1 plays a pivotal role in maintaining genomic stability and tumor suppression. The BRCA1-A complex is required for recruitment of BRCA1 to DNA damage sites, DNA repair and cell cycle checkpoint control. Since germline mutations of BRCA1 often lead to breast tumors that are triple-negative breast cancer (TNBC) type, we aimed to investigate whether genetic deficiency in genes of the BRCA1-A complex is associated with risk to TNBC development.
We found that rs7250266 in the promoter region of NBA1 confers a decreased risk to TNBC development, but not to non-TNBC susceptibility. In addition, the haplotypes containing two polymorphisms rs7250266 and rs2278256 are associated with a lower chance of TNBC development specifically. Our studies also showed that the protective alleles of rs7250266 (C > G) and rs2278256 (T > C) down-regulate promoter activity of NBA1 in mammary epithelial cells.
We investigated associations between the BRCA1-A complex genes and TNBC developing risk in first case-control study of Chinese Han Women population including 414 patients with TNBC and 354 cancer-free controls. We detected 37 common variants in ABRAXAS, RAP80, BRE, BRCC36 and NBA1/MERIT40 genes encoding the BRCA1-A complex and evaluated their genetic susceptibility to the risk of TNBC. An additional cohort with 652 other types of breast cancer (non-TNBC) cases and 890 controls was used to investigate the associations between TNBC-specific SNPs genotype and non-TNBCs susceptibility.
Genetic variants in NBA1 may be an important genetic determinant of TNBC susceptibility. Further investigation and validation of these SNPs in larger cohorts may facilitate in predication and prevention of TNBC and in counseling individuals for risk of TNBC development.
肿瘤抑制因子BRCA1在维持基因组稳定性和抑制肿瘤方面发挥着关键作用。BRCA1-A复合物是将BRCA1募集到DNA损伤位点、进行DNA修复和细胞周期检查点控制所必需的。由于BRCA1的种系突变常导致三阴性乳腺癌（TNBC）类型的乳腺肿瘤，我们旨在研究BRCA1-A复合物基因的遗传缺陷是否与TNBC发生风险相关。
我们发现，NBA1启动子区域的rs7250266降低了TNBC发生风险，但与非TNBC易感性无关。此外，包含两个多态性rs7250266和rs2278256的单倍型与TNBC发生的可能性较低具体相关。我们的研究还表明，rs7250266（C>G）和rs2278256（T>C）的保护性等位基因下调了乳腺上皮细胞中NBA1的启动子活性。
在一项针对中国汉族女性人群的首例病例对照研究中，我们调查了BRCA1-A复合物基因与TNBC发生风险之间的关联，该研究包括414例TNBC患者和354例无癌对照。我们检测了编码BRCA1-A复合物的ABRAXAS、RAP80、BRE、BRCC36和NBA1/MERIT40基因中的37个常见变异，并评估了它们对TNBC风险的遗传易感性。另外一个包含652例其他类型乳腺癌（非TNBC）病例和890例对照的队列用于研究TNBC特异性单核苷酸多态性（SNP）基因型与非TNBC易感性之间的关联。
NBA1中的基因变异可能是TNBC易感性的重要遗传决定因素。在更大的队列中对这些SNP进行进一步研究和验证，可能有助于TNBC的预测和预防，以及为个体提供TNBC发生风险的咨询服务。
