Li Na, Zhou Ping, Zheng Jian, Deng Jieqiong, Wu Hongchun, Li Wei, Li Fang, Li Hongbin, Lu Jiachun, Zhou Yifeng, Zhang Chun
Department of Genetics, Medical College of Soochow University, Suzhou, China; Department of General Surgery, the Third Affiliated Hospital to Nantong University, Wuxi, China.
Department of General Surgery, the Third Affiliated Hospital to Nantong University, Wuxi, China.
PLoS One. 2014 May 30;9(5):e98251. doi: 10.1371/journal.pone.0098251. eCollection 2014.
Breast cancer, one of the most common malignancies diagnosed among women worldwide, is a complex polygenic disease in the etiology of which genetic factors play an important role. Thus far, a subset of breast cancer genetic susceptibility loci has been addressed among Asian woman through genome-wide association studies (GWASs). In this study, we identified numerous long, intergenic, noncoding RNAs (lincRNAs) enriched in these breast cancer risk-related loci and identified 16 single nucleotide polymorphisms (SNPs) located within the sequences of lincRNA exonic regions. We examined whether these 16 SNPs are associated with breast cancer risk in 2539 cancer patients and 2818 control subjects from eastern, southern, and northern Chinese populations. We found that the C allele of the rs12325489C>T polymorphism in the exonic regions of lincRNA-ENST00000515084 was associated with a significantly increased risk of breast cancer (adjusted odds ratio [OR] = 1.79; 95% confidence interval [CI] = 1.50-2.12), compared with the rs12325489TT genotype. Biochemical analysis demonstrated that the C to T base change at rs12325489C>T disrupts the binding site for miRNA-370, thereby influencing the transcriptional activity of lincRNA-ENST00000515084 in vitro and in vivo, and affecting cell proliferation and tumor growth. Our findings indicate that the rs12325489C>T polymorphism in the lincRNA-ENST00000515084 exon may be a genetic modifier in the development of breast cancer.
乳腺癌是全球女性中最常见的恶性肿瘤之一，是一种复杂的多基因疾病，其病因中遗传因素起着重要作用。迄今为止，通过全基因组关联研究（GWAS）已在亚洲女性中确定了一部分乳腺癌遗传易感性位点。在本研究中，我们鉴定了许多富集于这些乳腺癌风险相关位点的长链基因间非编码RNA（lincRNA），并确定了位于lincRNA外显子区域序列内的16个单核苷酸多态性（SNP）。我们在来自中国东部、南部和北部人群的2539例癌症患者和2818例对照受试者中检测了这16个SNP是否与乳腺癌风险相关。我们发现，与rs12325489 TT基因型相比，lincRNA-ENST00000515084外显子区域rs12325489C>T多态性的C等位基因与乳腺癌风险显著增加相关（调整后的优势比[OR]=1.79；95%置信区间[CI]=1.50-2.12）。生化分析表明，rs12325489C>T处的C到T碱基变化破坏了miRNA-370的结合位点，从而在体外和体内影响lincRNA-ENST00000515084的转录活性，并影响细胞增殖和肿瘤生长。我们的研究结果表明，lincRNA-ENST00000515084外显子中的rs12325489C>T多态性可能是乳腺癌发生发展中的一个遗传修饰因子。
