Pre-diagnostic circulating RNAs networks identify testicular germ cell tumour susceptibility genes

Testicular germ cell tumour (TGCT) is a malignancy with known inherited risk factors, affecting young men. We have previously identified several hundred circulating RNAs that were differentially expressed in pre-diagnostic serum samples from TGCT cases when compared to healthy controls. In this study we performed network preservation analyses of pre-diagnostic serum mRNA and miRNA. Hub genes, enriched functional pathways, and regulatory feature prediction were identified for all TGCT, seminoma, and non-seminoma cases separately, compared to controls. We identified UBCA1, RCC1, FMR1, OSA3, and UBE2W as hub genes associated with TGCT. The genes OSA3 and UBE2W have previously been associated with testicular dysgenesis syndrome (TDS) disorders, including hypospadias. Previously described TGCT susceptibility genes TEX14, NARS2, and G3BP2 were identified as hub genes in both seminoma and non-seminoma networks. Furthermore, network module analysis showed prediction of transcription factors for oestrogen-related receptors. The overlap between network hub genes and TGCT susceptibility genes indicates a role in the progression from germ cell neoplasia in situ (GCNIS) to TGCT that should be further investigated.