State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Signal Transduct Target Ther. 2022 Aug 22;7(1):270. doi: 10.1038/s41392-022-01098-5.
Alternative RNA splicing is one of the most important mechanisms of posttranscriptional gene regulation, which contributes to protein diversity in eukaryotes. It is well known that RNA splicing dysregulation is a critical mechanism in tumor pathogenesis and the rationale for the promising splice-switching therapeutics for cancer treatment. Although we have a comprehensive understanding of DNA mutations, abnormal gene expression profiles, epigenomics, and proteomics in lung adenocarcinoma (LUAD), little is known about its aberrant alternative splicing profiles. Here, based on the multi-omics data generated from over 1000 samples, we systematically studied the RNA splicing alterations in LUAD and revealed their biological and clinical implications. We identified 3688 aberrant alternative splicing events (AASEs) in LUAD, most of which were alternative promoter and exon skip. The specific regulatory roles of RNA binding proteins, somatic mutations, and DNA methylations on AASEs were comprehensively interrogated. We dissected the functional implications of AASEs and concluded that AASEs mainly affected biological processes related to tumor proliferation and metastasis. We also found that one subtype of LUAD with a particular AASEs pattern was immunogenic and had a better prognosis and response rate to immunotherapy. These findings revealed novel events related to tumorigenesis and tumor immune microenvironment and laid the foundation for the development of splice-switching therapies for LUAD.
选择性剪接是转录后基因调控最重要的机制之一，它为真核生物中的蛋白质多样性做出了贡献。众所周知，RNA 剪接失调是肿瘤发病机制中的一个关键机制，也是癌症治疗中颇具前景的剪接转换治疗的理论基础。尽管我们对肺腺癌（LUAD）中的 DNA 突变、异常基因表达谱、表观基因组学和蛋白质组学有了全面的了解，但对于其异常的选择性剪接谱却知之甚少。在这里，我们基于超过 1000 个样本的多组学数据，系统地研究了 LUAD 中的 RNA 剪接变化，并揭示了它们的生物学和临床意义。我们在 LUAD 中鉴定出 3688 个异常的选择性剪接事件（AASEs），其中大多数是选择性启动子和外显子跳跃。我们全面研究了 RNA 结合蛋白、体细胞突变和 DNA 甲基化对 AASEs 的特定调控作用。我们剖析了 AASEs 的功能意义，并得出结论，AASEs 主要影响与肿瘤增殖和转移相关的生物学过程。我们还发现，一种具有特定 AASEs 模式的 LUAD 亚型具有免疫原性，并且对免疫疗法有更好的预后和反应率。这些发现揭示了与肿瘤发生和肿瘤免疫微环境相关的新事件，并为 LUAD 的剪接转换治疗的发展奠定了基础。
