Jiang Yue, Du Fangzhi, Chen Fei, Qin Na, Jiang Zhu, Zhou Jin, Jiang Tao, Pu Zhening, Cheng Yue, Chen Jiaping, Dai Juncheng, Ma Hongxia, Jin Guangfu, Hu Zhibin, Yu Hao, Shen Hongbing
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
Mol Carcinog. 2017 Sep;56(9):2048-2057. doi: 10.1002/mc.22659. Epub 2017 May 2.
Long non-coding RNAs (lncRNAs) participate in the development of breast cancer. Genetic variants in lncRNAs may be involved in their abnormal expressions and associated with cancer risk. In the present study, we performed RNA sequencing on five paired breast cancer tumor and adjacent non-cancerous tissues to obtain differentially expressed lncRNAs. We systematically selected potential regulatory variants of these lncRNAs and investigated the associations between these variants and breast cancer susceptibility in 1486 breast cancer cases and 1519 cancer-free controls in a Chinese population. Eleven lncRNAs were significantly differentially expressed between breast cancer tumor and normal tissues (false discovery rate (FDR) ≤0.05 and fold-change ≥2), including two known lncRNAs HOTAIR and UCA1. We subsequently genotyped 20 variants located on these lncRNAs and identified two variants (rs11471161 in AC104135.3 and rs3751232 in RP11-1060J15.4) associated with breast cancer risk. Logistic regression analysis indicated that the variant allele of rs11471161 was significantly associated with a decreased breast cancer risk (additive model: OR = 0.84, 95%CI = 0.74-0.94, P = 0.004), while the variant allele of rs3751232 showed an increased risk of breast cancer (additive model: OR = 1.20, 95%CI = 1.02-1.40, P = 0.027). Further co-expression analysis indicated that AC104135.3 associated with ERBB2, which promotes the development and progression of breast cancer through overexpression. Together, these results suggest that genetic variants rs11471161 and rs3751232 in AC104135.3, and RP11-1060J15.4, respectively, may influence the susceptibility to breast cancer in the Chinese population. Further functional evaluations and larger studies are warranted to validate these findings.
长链非编码RNA（lncRNAs）参与乳腺癌的发展。lncRNAs中的基因变异可能涉及其异常表达，并与癌症风险相关。在本研究中，我们对五对乳腺癌肿瘤组织和相邻的非癌组织进行了RNA测序，以获得差异表达的lncRNAs。我们系统地选择了这些lncRNAs的潜在调控变异，并在中国人群中的1486例乳腺癌病例和1519例无癌对照中研究了这些变异与乳腺癌易感性之间的关联。在乳腺癌肿瘤组织和正常组织之间，有11种lncRNAs存在显著差异表达（错误发现率（FDR）≤0.05且变化倍数≥2），包括两种已知的lncRNAs，即HOTAIR和UCA1。随后，我们对位于这些lncRNAs上的20个变异进行了基因分型，并鉴定出两个与乳腺癌风险相关的变异（AC104135.3中的rs11471161和RP11-1060J15.4中的rs3751232）。逻辑回归分析表明，rs11471161的变异等位基因与降低的乳腺癌风险显著相关（相加模型：OR = 0.84，95%CI = 0.74 - 0.94，P = 0.004），而rs3751232的变异等位基因显示出增加的乳腺癌风险（相加模型：OR = 1.20，95%CI = 1.02 - 1.40，P = 0.027）。进一步的共表达分析表明，AC104135.3与ERBB2相关，ERBB2通过过表达促进乳腺癌的发展和进展。总之，这些结果表明，AC104135.3和RP11-1060J15.4中的基因变异rs11471161和rs3751232可能分别影响中国人群对乳腺癌的易感性。需要进一步的功能评估和更大规模的研究来验证这些发现。
