Abstract
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.
Highlights
Alternative splicing (AS) contributes to transcriptional diversity and plasticity by selecting which transcript isoforms are produced in a specific cell at a given time (Park et al, 2018)
We identified a total of 546 recurrence-free survival (RFS)-related AS events, which were enriched in some splicing and triplenegative breast cancer (TNBC)-associated pathways
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
Summary
Alternative splicing (AS) contributes to transcriptional diversity and plasticity by selecting which transcript isoforms are produced in a specific cell at a given time (Park et al, 2018). About 95% of genes with multiple exons are alternatively spliced to give rise to different protein isoforms (Kim et al, 2018). Besides being a critical mechanism during cell development, cell differentiation, and regulation of cell-type-specific functions, aberrant AS is involved in multiple diseases, including triplenegative breast cancer (TNBC) (Chan et al, 2017; ClimenteGonzález et al, 2017). Triple-negative breast cancer (BC), a kind of BC that does not express the genes for estrogen receptor, progesterone receptor, and HER2/neu (Foulkes et al, 2010), is considered to be more aggressive, have a poorer prognosis, and show a higher recurrence ratio than other types of BCs (Zhu et al, 2016). The lack of targeted therapies, high recurrence ratio, and low survival probability have fostered a major effort to discover actionable molecular targets which could effectively differentiate between TNBC patients with better survival and others (Bianchini et al, 2016)
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