Testicular germ cell tumors (TGCTs) are the most common cancer in young male adults (aged 15 to 40). Unlike most other cancer types, identification of molecular signatures in TGCT has rarely reported. In this study, we developed a novel integrative analysis framework to identify co-methylated and co-expresses genes [mRNAs and microRNAs (miRNAs)] modules in two TGCT subtypes: non-seminoma (NSE) and seminoma (SE). We first integrated DNA methylation and mRNA/miRNA expression data and then used a statistical method, CoMEx (Combined score of DNA Methylation and Expression), to assess differentially expressed and methylated (DEM) genes/miRNAs. Next, we identified co-methylation and co-expression modules by applying WGCNA (Weighted Gene Correlation Network Analysis) tool to these DEM genes/miRNAs. The module with the highest average Pearson's Correlation Coefficient (PCC) after considering all pair-wise molecules (genes/miRNAs) included 91 molecules. By integrating both transcription factor and miRNA regulations, we constructed subtype-specific regulatory networks for NSE and SE. We identified 4 hub miRNAs (miR-182-5p, miR-520b, miR-520c-3p, and miR-7-5p), 2 hub TFs (MYC and SP1) and 2 genes (RECK and TERT) in the NSE-specific regulatory network, and 2 hub miRNAs (miR-182-5p and miR-338-3p), 5 hub TFs (ETS1, HIF1A, HNF1A, MYC, and SP1) and 3 hub genes (CDH1, CXCR4, and SNAI1) in the SE-specific regulatory network. MiRNA (miR-182-5p) and two TFs (MYC and SP1) were common hubs of NSE and SE. We further examined pathways enriched in these subtype-specific networks. Our study provides a comprehensive view of the molecular signatures and co-regulation in two TGCT subtypes.
Epigenetics. 2020 Jul 02 [Epub ahead of print]
Saurav Mallik, Guimin Qin, Peilin Jia, Zhongming Zhao
Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston , Houston, TX 77030, USA.