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Profiles of alternative splicing in colorectal cancer and their clinical significance: A study based on large-scale sequencing data.
EBioMedicine ( IF 9.7 ) Pub Date : 2018-09-19 , DOI: 10.1016/j.ebiom.2018.09.021
Yongfu Xiong 1 , Ying Deng 2 , Kang Wang 3 , He Zhou 4 , Xiangru Zheng 4 , Liangyi Si 5 , Zhongxue Fu 1
EBioMedicine ( IF 9.7 ) Pub Date : 2018-09-19 , DOI: 10.1016/j.ebiom.2018.09.021
Yongfu Xiong 1 , Ying Deng 2 , Kang Wang 3 , He Zhou 4 , Xiangru Zheng 4 , Liangyi Si 5 , Zhongxue Fu 1
Affiliation
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BACKGROUND
Alternative splicing (AS), as a potent and pervasive mechanism of transcriptional regulatory, expands the genome's coding capacity and involves in the initiation and progression of cancer. Systematic analysis of alternative splicing in colorectal cancer (CRC) is lacking and greatly needed.
METHODS
RNA-Seq data and corresponding clinical information of CRC cohort were downloaded from the TCGA data portal. Then, a java application, known as SpliceSeq, was used to evaluate the RNA splicing patterns and calculate the Percent Spliced In (PSI) value. Differently expressed AS events (DEAS) were identified based on PSI value between paired CRC and adjacent tissues. DEAS and its splicing networks were further analyzed by bioinformatics methods. Kaplan-Meier, Cox proportional regression and unsupervised clustering analysis were used to evaluate the association between DEAS and patients' clinical features.
RESULTS
After strict filtering, a total of 34,334 AS events were identified, among which 421 AS events were found expressed differently. Parent genes of these DEAS play a important role in regulating CRC-related processes such as protein kinase activity (FDR<0.0001), PI3K-Akt signaling pathway (FDR = 0.0024) and p53 signaling pathway (FDR = 0.0143). 37 DEAS events were found to be associated with OS, and 68 DEAS events were found to be associated with DFS. Stratifying patients according to the PSI value of AT in CXCL12 and RI in CSTF3 formed significant Kaplan-Meier curves in both OS and DFS survival analysis. Unsupervised clustering analysis using DEAS revealed four clusters with distinct survival patterns, and associated with consensus molecular subtypes.
CONCLUSIONS
Large differences of AS events in CRC appear to exist, and these differences are likely to be important determinants of both prognosis and biological regulation. Our identified CRC-related AS events and uncovered splicing networks are valuable in deciphering the underlying mechanisms of AS in CRC, and provide clues of therapeutic targets to further validations.
中文翻译：
大肠癌中选择性剪接的概况及其临床意义：基于大规模测序数据的研究。
背景技术替代剪接（AS），作为转录调节的有效和普遍的机制，扩大了基因组的编码能力，并参与了癌症的发生和发展。缺乏对结直肠癌（CRC）选择性剪接的系统分析，因此非常需要。方法从TCGA数据门户网站下载RNA序列数据和CRC队列的相应临床信息。然后，使用一个名为SpliceSeq的Java应用程序来评估RNA剪接模式并计算“剪接百分比”（PSI）值。基于成对的CRC和邻近组织之间的PSI值，可以识别出差异表达的AS事件（DEAS）。通过生物信息学方法进一步分析了DEAS及其剪接网络。卡普兰·迈耶，使用Cox比例回归和无监督聚类分析来评估DEAS与患者临床特征之间的关联。结果经过严格过滤，共鉴定出34334个AS事件，其中421个AS事件表达不同。这些DEAS的亲本基因在调节CRC相关过程中起着重要作用，例如蛋白激酶活性（FDR <0.0001），PI3K-Akt信号通路（FDR = 0.0024）和p53信号通路（FDR = 0.0143）。发现37个DEAS事件与OS相关联，并且发现68个DEAS事件与DFS相关联。在OS和DFS生存分析中，根据CXCL12中AT的PSI值和CSTF3中RI的分层患者，形成了明显的Kaplan-Meier曲线。使用DEAS进行的无监督聚类分析显示了四个具有不同生存模式的聚类，并且与共有分子亚型相关。结论CRC中AS事件似乎存在很大差异，这些差异可能是预后和生物学调控的重要决定因素。我们发现的与CRC相关的AS事件和未发现的剪接网络对于破译CRC中AS的潜在机制非常有价值，并为进一步验证提供治疗靶标的线索。
更新日期：2018-09-19
中文翻译：
大肠癌中选择性剪接的概况及其临床意义：基于大规模测序数据的研究。
背景技术替代剪接（AS），作为转录调节的有效和普遍的机制，扩大了基因组的编码能力，并参与了癌症的发生和发展。缺乏对结直肠癌（CRC）选择性剪接的系统分析，因此非常需要。方法从TCGA数据门户网站下载RNA序列数据和CRC队列的相应临床信息。然后，使用一个名为SpliceSeq的Java应用程序来评估RNA剪接模式并计算“剪接百分比”（PSI）值。基于成对的CRC和邻近组织之间的PSI值，可以识别出差异表达的AS事件（DEAS）。通过生物信息学方法进一步分析了DEAS及其剪接网络。卡普兰·迈耶，使用Cox比例回归和无监督聚类分析来评估DEAS与患者临床特征之间的关联。结果经过严格过滤，共鉴定出34334个AS事件，其中421个AS事件表达不同。这些DEAS的亲本基因在调节CRC相关过程中起着重要作用，例如蛋白激酶活性（FDR <0.0001），PI3K-Akt信号通路（FDR = 0.0024）和p53信号通路（FDR = 0.0143）。发现37个DEAS事件与OS相关联，并且发现68个DEAS事件与DFS相关联。在OS和DFS生存分析中，根据CXCL12中AT的PSI值和CSTF3中RI的分层患者，形成了明显的Kaplan-Meier曲线。使用DEAS进行的无监督聚类分析显示了四个具有不同生存模式的聚类，并且与共有分子亚型相关。结论CRC中AS事件似乎存在很大差异，这些差异可能是预后和生物学调控的重要决定因素。我们发现的与CRC相关的AS事件和未发现的剪接网络对于破译CRC中AS的潜在机制非常有价值，并为进一步验证提供治疗靶标的线索。
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