Pan-Cancer Analyses Identify the CTC1-STN1-TEN1 Complex as a Protective Factor and Predictive Biomarker for Immune Checkpoint Blockade in Cancer.
Pan-Cancer Analyses Identify the CTC1-STN1-TEN1 Complex as a Protective Factor and Predictive Biomarker for Immune Checkpoint Blockade in Cancer.
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泛癌症分析确定 CTC1-STN1-TEN1 复合物作为癌症免疫检查点阻断的保护因子和预测生物标志物
DOI：
10.3389/fgene.2022.859617
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发表时间：
2022
影响因子：
3.7
通讯作者：
Feng X
中科院分区：
文献类型：
--
作者：
Wang L;Ma T;Liu W;Li H;Luo Z;Feng X
CTC 1-STN 1-TEN 1（CST）复合物在端粒复制和基因组稳定性中起着至关重要的作用。然而，癌症中CST调节的详细机制在很大程度上仍然未知。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CST进行了全面分析。在基因组景观中，我们确定CTC 1/STN 1缺失和突变以及TEN 1扩增为显性改变事件。CTC 1和STN 1在肿瘤中的表达较癌旁正常组织中的表达降低。基于CST表达的聚类分析揭示了三个癌症簇在生存、端粒酶活性、细胞增殖和基因组稳定性方面的差异。有趣的是，我们发现CTC 1和STN 1，而不是TEN 1，共表达，并与更好的生存相关。CTC 1-STN 1与CD 8 T细胞和B细胞正相关，并预测在癌症免疫治疗的外部数据集中对免疫检查点阻断的更好应答。通路分析显示MYC靶点与CTC 1-STN 1呈负相关。我们实验验证了CTC 1的敲除增加了c-MYC的mRNA水平。此外，CTC 1和STN 1被miRNA和lncRNA抑制。最后，通过挖掘连接图数据库，我们发现了一些潜在的药物，可能会对CST。总之，这项研究表明CTC 1-STN 1作为一种保护因子，并为CST在癌症中的进一步功能和治疗研究提供了广泛的分子特征。
The CTC1-STN1-TEN1 (CST) complex plays a crucial role in telomere replication and genome stability. However, the detailed mechanisms of CST regulation in cancer remain largely unknown. Here, we perform a comprehensive analysis of CST across 33 cancer types using multi-omic data from The Cancer Genome Atlas. In the genomic landscape, we identify CTC1/STN1 deletion and mutation and TEN1 amplification as the dominant alteration events. Expressions of CTC1 and STN1 are decreased in tumors compared to those in adjacent normal tissues. Clustering analysis based on CST expression reveals three cancer clusters displaying differences in survival, telomerase activity, cell proliferation, and genome stability. Interestingly, we find that CTC1 and STN1, but not TEN1, are co-expressed and associated with better survival. CTC1-STN1 is positively correlated with CD8 T cells and B cells and predicts a better response to immune checkpoint blockade in external datasets of cancer immunotherapy. Pathway analysis shows that MYC targets are negatively correlated with CTC1-STN1. We experimentally validated that knockout of CTC1 increased the mRNA level of c-MYC. Furthermore, CTC1 and STN1 are repressed by miRNAs and lncRNAs. Finally, by mining the connective map database, we discover a number of potential drugs that may target CST. In sum, this study illustrates CTC1-STN1 as a protective factor and provides broad molecular signatures for further functional and therapeutic studies of CST in cancer.