Pan-cancer analyses reveal regulation and clinical outcome association of the shelterin complex in cancer
Pan-cancer analyses reveal regulation and clinical outcome association of the shelterin complex in cancer
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DOI：
10.1093/bib/bbaa441
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发表时间：
2021-01-26
影响因子：
9.5
通讯作者：
Feng, Xuyang
中科院分区：
文献类型：
--
作者：
Luo, Zhenhua;Liu, Weijin;Feng, Xuyang
端粒的保护性复合体庇护蛋白在癌症中起着至关重要的作用。除了维持端粒完整性外，庇护蛋白还在各种生存途径中发挥作用。然而，癌症中庇护蛋白调控的详细机制仍然难以捉摸。在这里，我们使用来自癌症基因组图谱的多组学数据对33种癌症类型的9125个肿瘤样本进行了全面分析，并验证了中国胶质瘤基因组图谱和来自癌症细胞系百科全书的癌细胞系的一些发现。在基因组景观中，我们发现TRF1和POT1的扩增，TRF2-RAP1-TPP1的共扩增/缺失是主要的改变事件。基于庇护蛋白表达的聚类分析揭示了基因组不稳定程度不同的三种癌症集群。为了测量庇护蛋白在癌症中的整体活性，我们根据庇护蛋白的表达得出了一个庇护蛋白评分。通路分析显示，shelterin与E2F靶点呈正相关，与p53通路呈负相关。重要的是，庇护蛋白与肿瘤免疫有关，并预测对PD-1阻断免疫治疗的反应。深入的miRNA分析揭示了miRNA-庇护蛋白相互作用网络，p53调节的miRNA靶向多种庇护蛋白成分。我们还发现了大量调节庇护蛋白表达的lncrna。此外，我们发现shelterin的表达可用于预测24种癌症类型的患者生存。最后，通过挖掘连接地图数据库，我们发现了一些可能针对庇护蛋白的潜在药物。总之，本研究为进一步研究庇护蛋白的功能和治疗提供了广泛的分子特征，也代表了一种系统的方法来表征癌症中的关键蛋白复合物。
Shelterin, a protective complex at telomeres, plays essential roles in cancer. In addition to maintain telomere integrity, shelterin functions in various survival pathways. However, the detailed mechanisms of shelterin regulation in cancer remain elusive. Here, we perform a comprehensive analysis of shelterin in 9125 tumor samples across 33 cancer types using multi-omic data from The Cancer Genome Atlas, and validate some findings in Chinese Glioma Genome Atlas and cancer cell lines from Cancer Cell Line Encyclopedia. In the genomic landscape, we identify the amplification of TRF1 and POT1, co-amplification/deletion of TRF2-RAP1-TPP1 as the dominant alteration events. Clustering analysis based on shelterin expression reveals three cancer clusters with different degree of genome instability. To measure overall shelterin activity in cancer, we derive a shelterin score based on shelterin expression. Pathway analysis shows shelterin is positively correlated with E2F targets, while is negatively correlated with p53 pathway. Importantly, shelterin links to tumor immunity and predicts response to PD-1 blockade immune therapy. In-depth miRNA analysis reveals a miRNA-shelterin interaction network, with p53 regulated miRNAs targeting multiple shelterin components. We also identify a significant amount of lncRNAs regulating shelterin expression. In addition, we find shelterin expression could be used to predict patient survival in 24 cancer types. Finally, by mining the connective map database, we discover a number of potential drugs that might target shelterin. In summary, this study provides broad molecular signatures for further functional and therapeutic studies of shelterin, and also represents a systemic approach to characterize key protein complex in cancer.