lncRNA遗传变异与乳腺癌的分子流行病学研究

Long ncRNAs are a class of transcripts longer than 200 nucleotides which lack open reading frames. They have been implicated as principal players in abundant biological process, such as transcriptional regulation and chromatin modification. In recent years, numerous special lncRNA were observed differently expressed in various diseases, especially cancer. However, the mechanisms by which these transcripts might affect breast tumor initiation and/or progression are currently unknown. We speculate that the genetic variant in lncRNAs may regulate the transcription activity and then influencing the development of cancer. In this study, we will conduct RNA-Seq to capture the transcripts of breast cancer tissues and para-tumorous tissues, obtaining the differently expressed lncRNAs. The potential functional genetic variants in these lncRNAs are selected through bioinformatics prediction and genotyped in a large sample set. In addition, functional studies are also carried out to explore the molecular biology mechanisms of the lncRNA related genetic variants in the development of breast cancer. The foundings of our study will enable us more thoroughly to comprehend the mechanisms of breast cancer, and have important vaule in its prevention and diagnosis.

长链非编码RNA（lncRNA）是一类长度大于200 bp的非编码RNA，可通过染色质修饰等机制参与多种重要生物学过程。近年来，研究发现lncRNA在肿瘤中存在明显的差异表达，其基因组上的遗传变异可调控其转录表达从而参与肿瘤的发生发展。迄今为止，lncRNA及其遗传变异在乳腺癌发生中的相关研究较少。本研究拟采用RNA-seq技术对乳腺癌组织及癌旁组织进行转录组测序，确定在癌和癌旁组织中差异表达的lncRNA，利用生物信息学分析筛选这些lncRNA上潜在的功能性遗传变异，在大样本病例-对照研究中分析其与乳腺癌易感性之间的关联，并通过分子生物学方法初步评价lncRNA相关遗传变异在乳腺癌发生中的功能机制，将为进一步阐明乳腺癌发生机制提供新思路，对乳腺癌的预防和诊治具有重要的指导价值。

长链非编码RNA（lncRNA）是一类长度大于200 bp的非编码RNA，可通过染色质修饰等机制参与多种重要生物学过程。近年来，研究发现lncRNA在肿瘤中存在明显的差异表达，其基因组上的遗传变异可调控其转录表达从而参与肿瘤的发生发展。迄今为止，lncRNA及其遗传变异在乳腺癌发生中的相关研究较少。本研究采用RNA-seq技术对5对乳腺癌组织及癌旁组织分别进行转录组测序，确定了11条在癌和癌旁组织中差异表达的lncRNA，利用RegulomeDB数据库筛选这些lncRNA上潜在的功能性遗传变异，最终在1486例经病理组织学确诊的乳腺癌新发病例和1519例性别年龄与之匹配的健康女性对照中分析了20个位点与乳腺癌易感性之间的关联。研究发现，在调整了年龄、初潮年龄、绝经状态之后，有两个位点在相加遗传模型中（AC104135.3 rs1147116，RP11-1060J15.4 rs3751232）与乳腺癌的发病风险存在统计学关联，分析显示rs1147116（TT>-）的改变降低了16%的乳腺癌患病风险(OR = 0.84, 95%CI = 0.74–0.94, P = 0.004)，而rs3751232（A>G）可以增加20%的乳腺癌患病风险(OR =1.20, 95%CI =1.02–1.40, P = 0.027)。进一步的生物信息学分析发现rs1147116和rs3751232能够影响转录因子的结合，且这两个位点所在的lncRNA与17,255个编码蛋白基因的共表达分析显示，AC104135.3与乳腺癌相关基因ERBB2存在显著共表达关系(Cor = 0.99, Pfdr = 0.0149)。本研究结构提示这两个遗传变异可能影响了中国人群乳腺癌的易感性，并初步阐明了影响乳腺癌发病风险的遗传变异及对应lncRNA的作用机制，为高危人群的筛检及乳腺癌的早期发现提供了理论和技术支持。