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. 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. 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.

中文翻译：

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对多个转录组队列的选择性剪接的综合分析揭示了前列腺癌的预后特征

选择性剪接 (AS) 在转录组多样性中发挥着至关重要的作用，是癌症的一个标志，它深刻影响前列腺癌 (PCa) 的发生和进展，前列腺癌是男性中普遍存在且可能限制生命的癌症。越来越多的证据强调了 AS 失调与 PCa 的发病和进展之间的关联。然而，仍然缺乏对事件水平上的 AS 概况进行全面综合的分析，利用多个高通量队列的数据并评估 PCa 进展的预后，需要进行彻底的探索。我们在三个不同的队列中发现了 ZWINT 中差异表达的保留内含子事件，包括我们之前分析的基于原始阵列的数据集和两个 RNA 测序 (RNA-seq) 数据集。随后对这些 RNA-seq 数据集的深入分析揭示了 141 个改变的事件，其中 21 个事件证明与患者的生化无复发生存期 (BCRFS) 显着相关。我们制定了基于 AS 事件的预后特征，捕获了基因 CYP4F12、NFATC4、PIGO、CYP3A5、ALS2CL 和 FXYD3 中的六个关键事件。这一特征有效地将诊断为 PCa 的高风险患者与低风险患者区分开来，这些患者的 BCRFS 较短。值得注意的是，该签名在预测 5 年 BCRFS 方面的预测能力超过了传统的临床病理学标记，在内部和外部验证集上都表现出了强大的性能。最后，我们构建了一个新颖的列线图，将患者的格里森评分与病理肿瘤分期相结合，证明 BCRFS 的预后得到改善。PCa 临床进展的预测仍然难以捉摸。这项研究揭示了与 BCRFS 相关的新颖剪接事件，增强了现有的预后工具，从而有可能改善临床决策。