Molecular signatures identified by integrating gene expression and methylation in non-seminoma and seminoma of testicular germ cell tumours

Testicular germ cell tumours (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-expressed 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 DNAMethylation andExpression), to assess differentially expressed and methylated (DEM) genes/miRNAs. Next, we identified co-methylation and co-expression modules by applying WGCNA (WeightedGeneCorrelationNetworkAnalysis) tool to these DEM genes/miRNAs. The module with the highest averagePearson'sCorrelationCoefficient (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 four hub miRNAs (miR-182-5p, miR-520b, miR-520c-3p, and miR-7-5p), two hub TFs (MYC and SP1), and two genes (RECKandTERT) in the NSE-specific regulatory network, and two hub miRNAs (miR-182-5p and miR-338-3p), five hub TFs (ETS1, HIF1A, HNF1A, MYC, and SP1), and three hub genes (CDH1, CXCR4, andSNAI1) 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.

Automated summary

A novel integrative analysis framework was developed to identify co-methylated and co-expressed genes in two subtypes of testicular germ cell tumours. Subtype-specific regulatory networks were constructed, revealing common hubs and pathways enriched in these networks, providing a comprehensive view of the molecular signatures and co-regulation in the two subtypes of TGCT.