Comprehensive characterization of the alternative splicing landscape in head and neck squamous cell carcinoma reveals novel events associated with tumorigenesis and the immune microenvironment
Comprehensive characterization of the alternative splicing landscape in head and neck squamous cell carcinoma reveals novel events associated with tumorigenesis and the immune microenvironment
复制标题
头颈鳞状细胞癌中选择性剪接景观的综合表征揭示了与肿瘤发生和免疫微环境相关的新事件。
DOI：
10.7150/thno.36585
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Sun, Ying
中科院分区：
文献类型：
--
作者：
Li, Zhi-Xuan;Zheng, Zi-Qi;Sun, Ying
选择性剪接（AS）已成为肿瘤发生和微环境形成的关键事件。然而，对头颈部鳞状细胞癌（HNSC）中AS及其临床意义的综合分析是迫切需要的。研究方法：在464例HNSC患者的队列中，使用来自癌症基因组图谱（TCGA）计划的RNA-Seq数据进行AS事件的全基因组分析。在配对的HNSC和邻近的正常组织之间鉴定癌症相关的AS事件（CASE），并在功能富集分析中进行评价。使用生物信息学工具构建剪接网络和预后模型。对确定的CASE进行无监督聚类，并分析与临床、分子和免疫特征的关联。结果：我们在HNSC中共检测到32，309例AS事件，并确定了473例病例;其中91例在独立队列中得到验证（n = 15）。功能性蛋白质结构域经常改变，特别是通过影响癌症驱动因素的CASE，如PCSK 5。CASE亲本基因在与HNSC和肿瘤免疫微环境相关的通路中显著富集，如病毒致癌（FDR < 0.001）、人乳头瘤病毒感染（FDR < 0.001）、趋化因子（FDR < 0.001）和T细胞受体（FDR < 0.001）信号通路。富含免疫相关通路的CASE与免疫细胞浸润和细胞溶解活性密切相关。AS调控网络表明剪接因子（SF）表达与CASE之间存在显著相关性，并可能受SF甲基化调控。18例病例被确定为总生存期和无病生存期的独立预后因素。无监督聚类分析显示，AS为基础的集群和预后，分子特征和免疫功能之间的显着相关性。免疫原性特征和免疫亚群共同刻画了基于AS的聚类的免疫特征。结论：对HNSC中AS景观的这种全面的全基因组分析揭示了与致癌和免疫微环境相关的新AS事件，并对预后和治疗反应产生影响。
Alternative splicing (AS) has emerged as a key event in tumor development and microenvironment formation. However, comprehensive analysis of AS and its clinical significance in head and neck squamous cell carcinoma (HNSC) is urgently required. Methods: Genome-wide profiling of AS events using RNA-Seq data from The Cancer Genome Atlas (TCGA) program was performed in a cohort of 464 patients with HNSC. Cancer-associated AS events (CASEs) were identified between paired HNSC and adjacent normal tissues and evaluated in functional enrichment analysis. Splicing networks and prognostic models were constructed using bioinformatics tools. Unsupervised clustering of the CASEs identified was conducted and associations with clinical, molecular and immune features were analyzed. Results: We detected a total of 32,309 AS events and identified 473 CASEs in HNSC; among these, 91 were validated in an independent cohort (n = 15). Functional protein domains were frequently altered, especially by CASEs affecting cancer drivers, such as PCSK5. CASE parent genes were significantly enriched in pathways related to HNSC and the tumor immune microenvironment, such as the viral carcinogenesis (FDR < 0.001), Human Papillomavirus infection (FDR < 0.001), chemokine (FDR < 0.001) and T cell receptor (FDR < 0.001) signaling pathways. CASEs enriched in immune-related pathways were closely associated with immune cell infiltration and cytolytic activity. AS regulatory networks suggested a significant association between splicing factor (SF) expression and CASEs and might be regulated by SF methylation. Eighteen CASEs were identified as independent prognostic factors for overall and disease-free survival. Unsupervised clustering analysis revealed distinct correlations between AS-based clusters and prognosis, molecular characteristics and immune features. Immunogenic features and immune subgroups cooperatively depict the immune features of AS-based clusters. Conclusion: This comprehensive genome-wide analysis of the AS landscape in HNSC revealed novel AS events related to carcinogenesis and immune microenvironment, with implications for prognosis and therapeutic responses.