1. Comprehensive analysis of alternative splicing across multiple transcriptomic cohorts reveals prognostic signatures in prostate cancer.
- Author
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Mou Z, Spencer J, McGrath JS, and Harries LW
- Subjects
- Male, Humans, Prognosis, Alternative Splicing genetics, Biomarkers, Tumor genetics, Membrane Proteins genetics, Neoplasm Proteins genetics, Transcriptome genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms diagnosis, Prostatic Neoplasms pathology
- Abstract
Background: Alternative splicing (AS) plays a crucial role in transcriptomic diversity and is a hallmark of cancer that profoundly influences the development and progression of prostate cancer (PCa), a prevalent and potentially life-limiting cancer among men. Accumulating evidence has highlighted the association between AS dysregulation and the onset and progression of PCa. However, a comprehensive and integrative analysis of AS profiles at the event level, utilising data from multiple high-throughput cohorts and evaluating the prognosis of PCa progression, remains lacking and calls for thorough exploration., Results: We identified a differentially expressed retained intron event in ZWINT across three distinct cohorts, encompassing an original array-based dataset profiled by us previously and two RNA sequencing (RNA-seq) datasets. Subsequent in-depth analyses of these RNA-seq datasets revealed 141 altered events, of which 21 demonstrated a significant association with patients' biochemical recurrence-free survival (BCRFS). We formulated an AS event-based prognostic signature, capturing six pivotal events in genes CYP4F12, NFATC4, PIGO, CYP3A5, ALS2CL, and FXYD3. This signature effectively differentiated high-risk patients diagnosed with PCa, who experienced shorter BCRFS, from their low-risk counterparts. Notably, the signature's predictive power surpassed traditional clinicopathological markers in forecasting 5-year BCRFS, demonstrating robust performance in both internal and external validation sets. Lastly, we constructed a novel nomogram that integrates patients' Gleason scores with pathological tumour stages, demonstrating improved prognostication of BCRFS., Conclusions: Prediction of clinical progression remains elusive in PCa. This research uncovers novel splicing events associated with BCRFS, augmenting existing prognostic tools, thus potentially refining clinical decision-making., (© 2023. The Author(s).)
- Published
- 2023
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