Multi-omics highlights the impacts of cryptorchidism history on immune microenvironment variation in TGCT.

BACKGROUND

The unique altered biological processes in testicular germ cell tumor (TGCT) patients with cryptorchidism history require further investigation and the accumulation of tumor-related features in cryptorchidism remains unclear.

MATERIALS AND

METHODS

We analyzed transcriptome and DNA methylation (DNAme) data from normal, undescended testis (UDT), and TGCT samples. Clustering, pseudo temporal trajectory analysis, and functional annotation of differentially methylated probes (DMPs) and differentially expressed genes (DEGs) were performed. Protein-protein interaction (PPI) networks were constructed for DEGs affected by DMPs. Weighted gene co-expression network analysis (WGCNA) identified genes related to cryptorchidism history. Single-cell RNA sequencing (scRNA-seq) assessed hub gene expression differences at cellular level across tissues.

RESULTS

Transcriptome and DNAme analyses showed immune-related changes in TGCT samples, with increased immune infiltration and involvement of developmental pathways in cases with cryptorchidism history. WGCNA highlighted hub genes, with IFI16 and PLEKHG6 showing increased expression from normal to UDT and TGCT, whereas WDR60, LIPE, and F3 were predominantly expressed in normal tissues. ScRNA-seq analysis revealed the expression of hub genes primarily in spermatogenic and immune-related cell types. Public transcriptome from pediatric UDT samples demonstrated their similarities to tumor, with developmental and immune-related changes. Nevertheless, adult UDT samples exhibited fewer DNAme alterations than TGCT samples, with DNAme profiles resembling normal tissues and lacking tumor-related changes. The molecular pathways and characteristics of pediatric and adult UDT were distinct.

CONCLUSIONS

We revealed unique molecular pathways in TGCT samples with cryptorchidism history and identified tumor-related features in cryptorchidism accumulation. Cryptorchidism history significantly remodels the immune microenvironment of TGCT.