Abstract
ObjectiveAlternative splicing (AS) is the mechanism by which a few genes encode numerous proteins, and it redefines the concept of gene expression regulation. Recent studies showed that dysregulation of AS was an important cause of tumorigenesis and microenvironment formation. Therefore, we performed a systematic analysis to examine the role of AS in breast cancer (Breast Cancer, BrCa) progression.MethodsThe present study included 993 BrCa patients from The Cancer Genome Atlas (TCGA) database in the genome-wide analysis of AS events. We used differential and prognostic analyses and found differentially expressed alternative splicing (DEAS) events and independent prognostic factors related to patients’ overall survival (OS) and disease-free survival (DFS). We divided the patients into two groups based on these AS events and analyzed their clinical features, molecular subtyping and immune characteristics. We also constructed a splicing factor (SF) regulation network for key AS events and verified the existence of AS events in tissue samples using real-time quantitative PCR.ResultsA total of 678 AS events were identified as differentially expressed, of which 13 and 10 AS events were independent prognostic factors of patients’ OS and DFS, respectively. Unsupervised clustering analysis based on these prognostic factors indicated that the Cluster 1 group had a better prognosis and more immune cell infiltration. SFs were significantly related to the expression of AS events, and AA-RPS21 was significantly upregulated in tumors.ConclusionAlternative splicing expands the mechanism of breast cancer progression from a new perspective. Notably, alternative splicing may affect the patient’s prognosis by affecting the infiltration of immune cells. Our research provides important guidance for subsequent studies of AS in breast cancer.
Highlights
Breast cancer (BrCa) is the most common malignant tumor in women
A total of 993 patients who met the screening criteria were included in the study cohort, and the baseline characteristics of these patients are summarized in Supplementary Table 2
A total of 1,455,675 missing values were detected in the data integrity check, which accounted for approximately 4.1% of the total data volume
Summary
Breast cancer (BrCa) is the most common malignant tumor in women. There were approximately 2.1 million newly diagnosed BrCa cases worldwide in 2018, which accounts for approximately 25% of the total number of female malignancies and poses a serious threat to women’s health and a heavy burden to public health (Schneider et al, 2014; Bray et al, 2018). Researchers examined the mechanisms of the occurrence and development of BrCa from various aspects, such as gene expression disorders (Cruz et al, 2018), copy number variation (Long et al, 2018; Yang et al, 2019) and DNA methylation (Kresovich et al, 2019; Yari and Rahimi, 2019). These studies achieved promising results, they were primarily limited to the transcriptional level, and the post-transcriptional level, such as alternative splicing (AS), was neglected
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