Wu Sijia, Wang Jiachen, Zhu Xinchao, Chyr Jacqueline, Zhou Xiaobo, Wu Xiaoming, Huang Liyu
School of Life Sciences and Technology, Xidian University, Xi'an, China.
Center for Computational Systems Medicine, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, United States.
Front Genet. 2021 Jan 14;11:604262. doi: 10.3389/fgene.2020.604262. eCollection 2020.
Triple-negative breast cancer (TNBC) is a type of breast cancer (BC) showing a high recurrence ratio and a low survival probability, which requires novel actionable molecular targets. The involvement of alternative splicing (AS) in TNBC promoted us to study the potential roles of AS events in the survival prognosis of TNBC patients.
A total of 150 TNBC patients from The Cancer Genome Atlas (TCGA) were involved in this work. To study the effects of AS in the recurrence-free survival (RFS) prognosis of TNBC, we performed the analyses as follows. First, univariate Cox regression model was applied to identify RFS-related AS events. Their host genes were analyzed by Metascape to discover the potential functions and involved pathways. Next, least absolute shrinkage and selection operator (LASSO) method was used to select the most informative RFS-related AS events to constitute an AS risk factor for RFS prognosis, which was evaluated by Kaplan-Meier (KM) and receiver operating characteristic (ROC) curves in all the data and also in different clinical subgroups. Furthermore, we analyzed the relationships between splicing factors (SFs) and these RFS-related AS events to seek the possibility that SFs regulated AS events to influence RFS. Then, we evaluated the potential of these RFS-related AS events in the overall survival (OS) prognosis from all the above aspects.
We identified a total of 546 RFS-related AS events, which were enriched in some splicing and TNBC-associated pathways. Among them, seven RFS-related events were integrated into a risk factor, exhibiting satisfactory RFS prognosis alone and even better performance when combined with clinical tumor-node-metastasis stages. Furthermore, the correlation analysis between SFs and the seven AS events revealed the hypotheses that SRPK3 might upregulate PCYT2_44231_AA to have an effect on RFS prognosis and that three other SFs may work together to downregulate FLAD1_7874_RI to influence RFS prognosis. In addition, the seven RFS-related AS events were validated to be promising in the OS prognosis of TNBC as well.
The abnormal AS events regulated by SFs may act as a kind of biomarker for the survival prognosis of TNBC.
三阴性乳腺癌（TNBC）是一种复发率高、生存率低的乳腺癌（BC）类型，需要新的可操作分子靶点。可变剪接（AS）在TNBC中的作用促使我们研究AS事件在TNBC患者生存预后中的潜在作用。
本研究纳入了来自癌症基因组图谱（TCGA）的150例TNBC患者。为了研究AS对TNBC无复发生存（RFS）预后的影响，我们进行了如下分析。首先，应用单变量Cox回归模型识别与RFS相关的AS事件。通过Metascape分析其宿主基因，以发现潜在功能和涉及的通路。接下来，使用最小绝对收缩和选择算子（LASSO）方法选择最具信息量的与RFS相关的AS事件，以构成RFS预后的AS风险因素，并通过Kaplan-Meier（KM）曲线和受试者工作特征（ROC）曲线在所有数据以及不同临床亚组中进行评估。此外，我们分析了剪接因子（SFs）与这些与RFS相关的AS事件之间的关系，以寻找SFs调节AS事件影响RFS的可能性。然后，我们从上述所有方面评估了这些与RFS相关的AS事件在总生存（OS）预后中的潜力。
我们共鉴定出546个与RFS相关的AS事件，这些事件在一些剪接和TNBC相关通路中富集。其中，7个与RFS相关的事件被整合为一个风险因素，单独显示出令人满意的RFS预后，与临床肿瘤-淋巴结-转移分期联合时表现更佳。此外，SFs与这7个AS事件之间的相关性分析揭示了以下假设：SRPK3可能上调PCYT2_44231_AA以影响RFS预后，另外3个SFs可能共同下调FLAD1_7874_RI以影响RFS预后。此外，这7个与RFS相关的AS事件在TNBC的OS预后中也被证实具有前景。
由SFs调节的异常AS事件可能作为TNBC生存预后的一种生物标志物。
