Table_3_Genome-Wide Profiling Reveals the Landscape of Prognostic Alternative Splicing Signatures in Pancreatic Ductal Adenocarcinoma.docx

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive lethal malignancy. Identification of potential alternative splicing (AS) prognostic indicators and related splicing pathways for the prediction of PDAC outcomes is lacking but urgently needed. A combined strategy of prognostic assessment and computational biology was performed to investigate survival-related AS signatures and their correlation with splicing factors. The prognostic signatures of each type were conducted according to the top 10 prognosis-related AS events, which were filtered through univariate Cox regression analysis. A time-dependent receiver operating characteristic curve was constructed to access the predictive accuracy of prognostic signatures. The independent predictors were identified using multivariate Cox regression analysis. Potential regulation mechanisms between splicing factors and splicing events were investigated through regulatory networks and correlation analyses. A total of 915 overall survival (OS) and 480 recurrence-free survival (RFS)-related AS events were identified in 120 patients with PDAC. The independent prognostic signatures for each type displayed favorable accuracy for the prediction of OS and short-term RFS [area under the curves were >0.6] except for the Exclusive Exons type. The splicing regulatory networks showed potential interactions between splicing factors and AS parent genes. Moreover, a positive relationship was detected among each splicing factor and Percent Spliced In values of prognostic signatures. Our results provide a view of the landscape of prognosis-related AS events and reveal the potential correlation between splicing factors and prognostic signatures, which may represent novel outcome-predictor markers and opportunities for targeted therapy for PDAC.

胰腺导管腺癌（PDAC）是一种侵袭性致命的恶性肿瘤。对于识别潜在的替代剪接（AS）预后指标及其相关的剪接通路，以预测PDAC的预后，目前尚缺乏但迫切需要。本研究采用预后评估与计算生物学相结合的策略，以探讨与生存相关的AS特征及其与剪接因子的相关性。根据单因素Cox回归分析筛选出的前10个预后相关的AS事件，对每种类型的预后特征进行了分析。构建了时间依赖性的受试者工作特征曲线，以评估预后特征的预测准确性。通过多因素Cox回归分析确定了独立的预测因子。通过调控网络和相关性分析，研究了剪接因子与剪接事件之间的潜在调控机制。在120名PDAC患者中，共鉴定出915个总生存期（OS）和480个无病生存期（RFS）相关的AS事件。每种类型的独立预后特征在预测OS和短期RFS方面均显示出良好的准确性[曲线下面积均大于0.6]，除Exclusive Exons类型外。剪接调控网络显示了剪接因子与AS亲本基因之间的潜在相互作用。此外，在每种剪接因子与预后特征的百分比剪接值之间检测到正相关关系。我们的研究结果描绘了与预后相关的AS事件图谱，并揭示了剪接因子与预后特征之间的潜在相关性，这可能会代表新的预后预测标志物和PDAC靶向治疗的机遇。