The Functional Impact of Alternative Splicing on the Survival Prognosis of Triple-Negative Breast Cancer

Frontiers in Genetics

Xiaobo Zhou¹  Sijia Wu¹  Jacqueline Chyr¹  Xiaoming Wu²  Jiachen Wang³  Xinchao Zhu³  Liyu Huang³ 

[1] Center for Computational Systems Medicine, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, United States;Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Sciences and Technology, Xi’an Jiaotong University, Xi’an, China;School of Life Sciences and Technology, Xidian University, Xi’an, China;

关键词: alternative splicing;    triple-negative breast cancer;    recurrence-free survival;    overall survival;    SRPK3;    ITGB3;   

DOI  :  10.3389/fgene.2020.604262

来源: DOAJ

【 摘 要 】

PurposeTriple-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.MethodsA 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.ResultsWe 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.ConclusionThe abnormal AS events regulated by SFs may act as a kind of biomarker for the survival prognosis of TNBC.

【 授权许可】

Unknown