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Genome-wide analysis reveals the association between alternative splicing and DNA methylation across human solid tumors.
BMC Medical Genomics ( IF 2.1 ) Pub Date : 2020-01-06 , DOI: 10.1186/s12920-019-0654-9
Xiaohui Sun 1 , Yiping Tian 2 , Jianming Wang 3 , Zeyuan Sun 4 , Yimin Zhu 1
Affiliation  

BACKGROUND Dysregulation of alternative splicing (AS) is a critical signature of cancer. However, the regulatory mechanisms of cancer-specific AS events, especially the impact of DNA methylation, are poorly understood. METHODS By using The Cancer Genome Atlas (TCGA) SpliceSeq and TCGA data for ten solid tumor types, association analysis was performed to characterize the potential link between cancer-specific AS and DNA methylation. Functional and pathway enrichment analyses were performed, and the protein-protein interaction (PPI) network was constructed with the String website. The prognostic analysis was carried out with multivariate Cox regressions models. RESULTS 15,818 AS events in 3955 annotated genes were identified across ten solid tumor types. The different DNA methylation patterns between tumor and normal tissues at the corresponding alternative spliced exon boundaries were shown, and 51.3% of CpG sites (CpGs) revealed hypomethylated in tumors. Notably, 607 CpGs were found to be highly correlated with 369 cancer-specific AS events after permutation tests. Among them, the hypomethylated CpGs account for 52.7%, and the number of down-regulated exons was 173. Furthermore, we found 38 AS events in 35 genes could serve as new molecular biomarkers to predict patient survival. CONCLUSIONS Our study described the relationship between DNA methylation and AS events across ten human solid tumor types and provided new insights into intragenic DNA methylation and exon usage during the AS process.

中文翻译:

全基因组分析揭示了跨人实体瘤的选择性剪接与DNA甲基化之间的关联。

背景技术选择性剪接(AS)的失调是癌症的关键特征。然而,对癌症特异性AS事件的调节机制,尤其是DNA甲基化的影响,了解甚少。方法利用癌症基因组图谱(TCGA)的SpliceSeq和TCGA数据对十种实体瘤类型进行关联分析,以表征癌症特异性AS与DNA甲基化之间的潜在联系。进行功能和途径富集分析,并使用String网站构建蛋白质-蛋白质相互作用(PPI)网络。用多变量Cox回归模型进行预后分析。结果在10种实体瘤类型中鉴定了3955个带注释的基因中的15818个AS事件。显示了在相应的替代剪接外显子边界处肿瘤与正常组织之间的不同DNA甲基化模式,并且51.3%的CpG位点(CpGs)在肿瘤中显示出低甲基化。值得注意的是,在置换测试后,发现607个CpG与369个癌症特异性AS事件高度相关。其中,低甲基化的CpGs占52.7%,下调外显子的数量为173。此外,我们发现35个基因中的38个AS事件可作为预测患者存活的新分子生物标记。结论我们的研究描述了10种人类实体肿瘤类型中DNA甲基化与AS事件之间的关系,并为AS过程中的基因内DNA甲基化和外显子使用提供了新的见解。3%的CpG位点(CpGs)在肿瘤中显示甲基化不足。值得注意的是,在置换测试后,发现607个CpG与369个癌症特异性AS事件高度相关。其中,低甲基化的CpGs占52.7%,下调外显子的数量为173。此外,我们发现35个基因中的38个AS事件可作为预测患者存活的新分子生物标记。结论我们的研究描述了10种人类实体肿瘤类型中DNA甲基化与AS事件之间的关系,并为AS过程中的基因内DNA甲基化和外显子使用提供了新的见解。3%的CpG位点(CpGs)在肿瘤中显示甲基化不足。值得注意的是,在置换测试后,发现607个CpG与369个癌症特异性AS事件高度相关。其中,低甲基化的CpGs占52.7%,下调外显子的数量为173。此外,我们发现35个基因中的38个AS事件可作为预测患者存活的新分子生物标记。结论我们的研究描述了10种人类实体肿瘤类型中DNA甲基化与AS事件之间的关系,并为AS过程中的基因内DNA甲基化和外显子使用提供了新的见解。我们发现35个基因中的38个AS事件可以作为预测患者生存的新分子生物标记。结论我们的研究描述了10种人类实体肿瘤类型中DNA甲基化与AS事件之间的关系,并为AS过程中的基因内DNA甲基化和外显子使用提供了新的见解。我们发现35个基因中的38个AS事件可以作为预测患者生存的新分子生物标记。结论我们的研究描述了10种人类实体肿瘤类型中DNA甲基化与AS事件之间的关系,并为AS过程中的基因内DNA甲基化和外显子使用提供了新的见解。
更新日期:2020-01-07
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