Department of Breast Surgical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
DNA Cell Biol. 2020 Jun;39(6):1051-1063. doi: 10.1089/dna.2020.5460. Epub 2020 Apr 30.
Triple-negative breast cancer (TNBC) is a high-risk subtype of breast cancer defined by negative expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Accumulating evidence indicates that alternative splicing (AS) events are correlated with the prognosis of cancer. RNA sequencing data and AS event data were manually curated from The Cancer Genome Atlas (TCGA) dataset and TCGA Splice Seq, respectively. Univariate and multivariate Cox regression analyses were applied to screen AS events associated with TNBC survival and to establish a prognostic model. A receiver operating characteristic (ROC) curve was used to evaluate the performance of the prognostic model. Differentially expressed gene analysis and functional enrichment analysis were harnessed to reveal the functional role of gene sets and to screen novel biomarkers. By integrated bioinformatics analysis of AS events and gene expression in TNBC, our study is the first to generate specific AS event profiles, prognostic AS event interaction networks, and splice factor-AS interaction networks for TNBC. Surprisingly, we found that the performance of the AS-based prognostic model was encouraging with a mean area under the ROC curve of 0.957 at 2-10 years. We also found that chemokine (C-C motif) ligand 16 (CCL16) expression was correlated with TNBC grade and could be a potential novel biomarker. In conclusion, this study provided a systematic analysis of prognostic AS event profiles and gene expression in TNBC. A novel prognostic model based on AS events may establish a foundation for future research investigating the diagnosis and treatment of TNBC.
三阴性乳腺癌（TNBC）是一种高风险的乳腺癌亚型，其定义为雌激素受体、孕激素受体和人表皮生长因子受体 2 的阴性表达。越来越多的证据表明，选择性剪接（AS）事件与癌症的预后相关。RNA 测序数据和 AS 事件数据分别从癌症基因组图谱（TCGA）数据集和 TCGA Splice Seq 中手动整理。分别应用单变量和多变量 Cox 回归分析筛选与 TNBC 生存相关的 AS 事件，并建立预后模型。使用接收者操作特征（ROC）曲线评估预后模型的性能。差异表达基因分析和功能富集分析用于揭示基因集的功能作用，并筛选新的生物标志物。通过对 TNBC 中 AS 事件和基因表达的综合生物信息学分析，我们的研究首次为 TNBC 生成了特定的 AS 事件谱、预后 AS 事件互作网络和剪接因子-AS 互作网络。令人惊讶的是，我们发现基于 AS 的预后模型的性能令人鼓舞，在 2-10 年内的 ROC 曲线下面积的平均值为 0.957。我们还发现趋化因子（C-C 基元）配体 16（CCL16）的表达与 TNBC 分级相关，可能是一种潜在的新型生物标志物。总之，本研究对 TNBC 中的预后 AS 事件谱和基因表达进行了系统分析。基于 AS 事件的新型预后模型可能为未来研究 TNBC 的诊断和治疗奠定基础。
