摘要

    自噬水平异常与多种癌症的发病机理有关，但是，其在肿瘤中的作用非常复杂，尚未得到明确的探讨。因此，我们旨在探讨自噬相关基因（ARGs）对肾肾透明细胞癌（KIRC）的预后价值。从癌症基因组图谱（TCGA）数据库获得的KIRC患者中鉴定出差异表达的ARG和转录因子（TF）。然后，进行了TFs和ARGs之间的网络，基因本体功能注释以及《京都议定书》的基因大全和基因组途径富集分析。接下来，我们进行了共识聚类，COX回归分析和Lasso回归分析，以鉴定预后的ARG。最后，建立了个体预后指标（PI，riskScore）。基于TCGA队列和ArrayExpress队列，还进行了生存分析，ROC曲线，独立预后分析和临床相关性分析以评估该PI。根据差异表达的ARGs，将KIRC患者成功分为两个群（P = 5.916e-04）。作为PI的AS，它是基于11个ARG构建的，并将OS方面的KIRC患者分为OS的高风险组和低风险组（对于TCGA队列，P = 4.885e-15，对于ArrayExpress队列，P = 6.366e-03 ）。 TCGA队列的ROC曲线的AUC达到0.747，ArrayExpress队列的ROC曲线的AUC达到0.779。而且，在单变量和多变量COX回归分析中，该PI被证明是有价值的独立预后因素（P <.001）。还进行了预后列线图，以可视化KIRC患者个体预测因子与生存率之间的关系。通过连通性图数据库，发现与ARGs相关的依替丁，头孢氨苄和甲代地高辛甲磺酸酯与KIRC呈负相关。这项研究为KIRC提供了有效的PI，并显示了TF和ARG之间的网络。根据差异表达的ARG，将KIRC患者成功地分为两个群。此外，还确定了与ARGs相关的小分子药物用于KIRC。

    Abnormal autophagic levels have been implicated in the pathogenesis of multiple cancers, however, its role in tumors is complex and has not yet been explored clearly. Hence, we aimed to explore the prognostic values of autophagy-related genes (ARGs) for kidney renal clear cell carcinoma (KIRC). Differentially expressed ARGs and transcription factors (TFs) were identified in KIRC patients obtaining from the The Cancer Genome Atlas (TCGA) database. Then, networks between TFs and ARGs, gene ontology functional annotations and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were conducted. Next, we performed consensus clustering, COX regression analysis and Lasso regression analysis to identify the prognostic ARGs. Finally, an individual prognostic index (PI, riskScore) was established. Based on TCGA cohort and ArrayExpress cohort, Survival analysis, ROC curve, independent prognostic analysis, and clinical correlation analysis were also performed to evaluate this PI. Based on differentially expressed ARGs, KIRC patients were successfully divided into two clusters (P = 5.916e-04). AS for PI, it was constructed based on 11 ARGs and significantly classified KIRC patients into high-risk group and low-risk group in terms of OS (P = 4.885e-15 for TCGA cohort, P = 6.366e-03 for ArrayExpress cohort). AUC of its ROC curve reached 0.747 for TCGA cohort and 0.779 for ArrayExpress cohort. What's more, this PI was proven to be a valuable independent prognostic factor in both univariate and multivariate COX regression analysis (P < .001). Prognostic nomograms were also performed to visualize the relationship between individual predictors and survival rates in patients with KIRC. By means of connectivity map database, emetine, cephaeline and co-dergocrine mesilate related to ARGs were found to be negatively correlated with KIRC. This study provided an effective PI for KIRC and also displayed networks between TFs and ARGs. KIRC patients were successfully divided into two clusters based on differentially expressed ARGs. Besides, small molecule drugs related to ARGs were also identified for KIRC.

    https://onlinelibrary.wiley.com/doi/full/10.1002/cam4.3367