Comprehensive Molecular Analyses of a TNF Family-Based Gene Signature as a Potentially Novel Prognostic Biomarker for Cervical Cancer

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: TCGA; TNF family genes; cervical cancer; immunotherapy response; prognosis.