Ma Yan, Zhang Xiaoyan, Yang Jiancheng, Jin Yanping, Xu Ying, Qiu Jianping
Department of Gynecology and Obstetrics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China.
Front Oncol. 2022 Mar 22;12:854615. doi: 10.3389/fonc.2022.854615. eCollection 2022.
Increasing evidence suggests that tumour necrosis factor (TNF) family genes play important roles in cervical cancer (CC). However, whether TNF family genes can be used as prognostic biomarkers of CC and the molecular mechanisms of TNF family genes remain unclear.
A total of 306 CC and 13 normal samples were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. We identified differentially expressed TNF family genes between CC and normal samples and subjected them to univariate Cox regression analysis for selecting prognostic TNF family genes. Least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analyses were performed to screen genes to establish a TNF family gene signature. Gene set enrichment analysis (GSEA) was performed to investigate the biological functions of the TNF family gene signature. Finally, methylation and copy number variation data of CC were used to analyse the potential molecular mechanisms of TNF family genes.
A total of 26 differentially expressed TNF family genes were identified between the CC and normal samples. Next, a TNF family gene signature, including CD27, EDA, TNF, TNFRSF12A, TNFRSF13C, and TNFRSF9 was constructed based on univariate Cox, LASSO, and multivariate Cox regression analyses. The TNF family gene signature was related to age, pathological stages M and N, and could predict patient survival independently of clinical factors. Moreover, KEGG enrichment analysis suggested that the TNF family gene signature was mainly involved in the TGF-β signaling pathway, and the TNF family gene signature could affect the immunotherapy response. Finally, we confirmed that the mRNA expressions of CD27, TNF, TNFRSF12A, TNFRSF13C, and TNFRSF9 were upregulated in CC, while that of EDA was downregulated. The mRNA expressions of CD27, EDA, TNF, TNFRSF12A, TNFRSF13C, and TNFRSF9 might be influenced by gene methylation and copy number variation.
Our study is the first to demonstrate that CD27, EDA, TNF, TNFRSF12A, TNFRSF13C, and TNFRSF9 might be used as prognostic biomarkers of CC and are associated with the immunotherapy response of CC.
越来越多的证据表明，肿瘤坏死因子（TNF）家族基因在宫颈癌（CC）中发挥重要作用。然而，TNF家族基因是否可作为CC的预后生物标志物以及TNF家族基因的分子机制仍不清楚。
从癌症基因组图谱（TCGA）和基因型-组织表达（GTEx）数据库中获取了总共306例CC样本和13例正常样本。我们鉴定了CC样本和正常样本之间差异表达的TNF家族基因，并对它们进行单变量Cox回归分析以选择预后性TNF家族基因。进行最小绝对收缩和选择算子（LASSO）回归及多变量Cox回归分析以筛选基因，从而建立TNF家族基因特征。进行基因集富集分析（GSEA）以研究TNF家族基因特征的生物学功能。最后，利用CC的甲基化和拷贝数变异数据来分析TNF家族基因的潜在分子机制。
在CC样本和正常样本之间共鉴定出26个差异表达的TNF家族基因。接下来，基于单变量Cox、LASSO和多变量Cox回归分析构建了一个TNF家族基因特征，包括CD27、EDA、TNF、TNFRSF12A、TNFRSF13C和TNFRSF9。TNF家族基因特征与年龄、病理分期M和N相关，并且能够独立于临床因素预测患者生存。此外，KEGG富集分析表明，TNF家族基因特征主要参与TGF-β信号通路，并且TNF家族基因特征可能影响免疫治疗反应。最后，我们证实CC中CD27、TNF、TNFRSF12A、TNFRSF13C和TNFRSF9的mRNA表达上调，而EDA的mRNA表达下调。CD27、EDA、TNF、TNFRSF12A、TNFRSF13C和TNFRSF9的mRNA表达可能受基因甲基化和拷贝数变异影响。
我们的研究首次证明，CD27、EDA、TNF、TNFRSF12A、TNFRSF13C和TNFRSF9可能作为CC的预后生物标志物，并且与CC的免疫治疗反应相关。
