Systemic Analysis of the Prognosis-Associated Alternative Polyadenylation Events in Breast Cancer

Abstract

Alternative polyadenylation (APA) is a post-translational modification that occurs during mRNA maturation in humans. Studies suggested that abnormal APA events are associated with the genesis and progression of malignant tumors. Here, we aimed to comprehensively evaluate the prognostic value of APA events involved in breast cancer (BC). Both APA events and clinical information for BC patients were downloaded from The Cancer Genome Atlas (TCGA) database to identify prognosis-related APA events in BC. A total of 462 APA events and 374 APA events were shown to be significantly related to overall survival (OS) and relapse-free survival (RFS), respectively, of BC patients. The TCGA set was randomly divided into a training and a test set. Key prognosis-related APA events were selected by LASSO regression to build prediction signatures for OS and RFS by multivariate Cox regression analysis in the training, test, and whole set. BC patients were stratified into high-risk and low-risk groups based on median risk scores. Kaplan-Meier survival analysis demonstrated that low-risk groups had better OS and RFS than high-risk groups in all three sets. The time-dependent receiver operating characteristic (ROC) curves showed that our signatures had a good predictive ability for survival and recurrence for BC patients in all three sets. The independent prognostic indicators-based nomogram model had excellent performance and considerable net benefit for predicting the OS and RFS in BC. A PPI network was constructed between key prognosis and core regulators associated with APA, consisting of 48 nodes and 244 edges. Functional enrichment analysis also revealed their association with RNA processing and RNA synthesis. Collectively, our data indicate that prognostic signatures based on APA events may be powerful prognostic predictors for OS and RFS in BC.

Construction of Two Alternative Polyadenylation Signatures to Predict the Prognosis of Sarcoma Patients

“…Current research mainly focused on the prognostic role of clinical data or gene level, overlooking the transcriptional level. As one of the important post-transcriptional regulatory mechanisms, APA events have shown a potentially robust predictive value for tumor patients (Venkat et al, 2020;Zhang et al, 2020b). Our study confirmed that APA events are valuable predictors for sarcoma patients, no matter whether in general patients or several subgroups.…”

“…Genes favoring distal PAS usage (long 3’ UTRs) have PDUI scores near 1, whereas genes favoring proximal PAS usage (short 3’ UTRs) have PDUI scores near 0 ( Venkat et al, 2020 ). To construct as credible a set of APA events as possible, only APA events that met the following criteria were included in this study: ( Von Mehren et al, 2018 ) percentage of samples with PDUI value ≥75%; ( Yang et al, 2019 ) average PDUI value ≥0.05 ( Li et al, 2019 ; Zhang et al, 2020b ). All data were downloaded from the public databases hence it was not required to obtain additional ethical approval for our study.…”

“…A robust prognostic signature is valuable for prognostic prediction, clinical management, and accurate clinical trial. Previous research indicated that APA events can serve as effective prognostic biomarkers for survival prediction and that the power of APA events exceeded clinical covariates ( Venkat et al, 2020 ; Zhang et al, 2020b ). Therefore, based on corresponding independent prognostic APA events, two prognostic signatures were established, including OS and PFS signatures.…”

A Review on the Carcinogenic Roles of DSCAM-AS1

“…In addition to serving as molecular sponge for miRNAs, DSCAM-AS1 can regulate carcinogenesis through modulation of alternative splicing and isoform regulation. Alternative polyadenylation events have been found to be correlated with development and progression of cancers ( Zhang et al, 2020c ). Moreover, 3′UTR shortening as another event associated with DSCAM-AS1 can repress expression of tumor-suppressor genes through disturbing competing endogenous RNA interaction ( Park et al, 2018 ).…”

Alternative polyadenylation: An enigma of transcript length variation in health and disease

“…Recent studies indicate potential application of APA in diagnosis, prognosis, and treatment of human diseases. APA signatures are now considered superior to many traditional clinical markers (Ji & Tian, 2009; Ogorodnikov et al, 2018; Xia et al, 2014; Y. Zhang et al, 2020). Several studies have indicated therapeutic advantage of APA that is targetable through CRISPR/Cas9 molecular editing system to alter or silence of aberrant PA‐sites (Niu et al, 2016; Xie et al, 2014).…”