A novel DNA methylation signature to improve survival prediction of progression-free survival for testicular germ cell tumors

Abstract

AbstractThis study aimed to develop a nomogram for predicting the progression-free survival (PFS) of testicular germ cell tumors (TGCT) patients based on DNA methylation signature and clinicopathological characteristics. The DNA methylation profiles, transcriptome data, and clinical information of TGCT patients were obtained from the Cancer Genome Atlas (TCGA) database. Univariate Cox, lasso Cox, and stepwise multivariate Cox regression were applied to identify a prognostic CpG sites-derived risk signature. Differential expression analysis, functional enrichment analysis, immunoinfiltration analysis, chemotherapy sensitivity analysis, and clinical feature correlation analysis were performed to elucidate the differences among risk groups. A prognostic nomogram integrating CpG sites-derived risk signature and clinicopathological features was further established and evaluated likewise. A risk score model based on 7 CpG sites was developed and found to exhibit significant differences among different survival, staging, radiotherapy, and chemotherapy subgroups. There were 1452 differentially expressed genes between the high- and low-risk groups, with 666 being higher expressed and 786 being lower expressed. Genes highly expressed were significantly enriched in immune-related biological processes and related to T-cell differentiation pathways; meanwhile, down-regulated genes were significantly enriched in extracellular matrix tissue organization-related biological processes and involved in multiple signaling pathways such as PI3K-AKT. As compared with the low-risk group, patients in the high-risk group had decreased lymphocyte infiltration (including T-cell and B-cell) and increased macrophage infiltration (M2 macrophages). They also showed decreased sensitivity to etoposide and bleomycin chemotherapy. Three clusters were obtained by consensus clustering analysis based on the 7 CpG sites and showed distinct prognostic features, and the risk scores in each cluster were significantly different. Multivariate Cox regression analysis found that the risk scores, age, chemotherapy, and staging were independent prognostic factors of PFS of TGCT, and the results were used to formulate a nomogram model that was validated to have a C-index of 0.812. Decision curve analysis showed that the nomogram model was superior to other strategies in the prediction of PFS of TGCT. In this study, we successfully established CpG sites-derived risk signature, which might serve as a useful tool in the prediction of PFS, immunoinfiltration, and chemotherapy sensitivity for TGCT patients.