5026 Background: Cisplatin-based chemotherapy is highly effective in testicular germ cell tumors (GCTs); however, the presence of viable tumor after first-line chemotherapy is associated with chemoresistance and poor clinical outcome. The transcriptional programs distinguishing chemotherapy-naïve and post-chemotherapy viable GCTs remain incompletely characterized. Methods: Tumor samples from 50 GCT patients treated between 2010 and 2022 were analyzed, including 30 chemotherapy-naïve tumors and 20 post-chemotherapy viable GCTs resected from the retroperitoneum. Five normal testicular tissue samples served as controls. Formalin-fixed paraffin-embedded samples were profiled using the HTG EdgeSeq Oncology Biomarker Panel. Differential gene expression analysis was performed using DESeq2, adjusted for histology, with significance defined as adjusted p-value 1. Functional enrichment analysis was conducted to identify deregulated biological pathways. Results: Compared with normal testicular tissue, chemotherapy-naïve GCTs and post-chemotherapy viable GCTs exhibited 1,010 and 720 differentially expressed genes, respectively. Direct comparison between chemotherapy-naïve and post-chemotherapy tumors identified 424 differentially expressed genes. Post-chemotherapy viable GCTs demonstrated marked downregulation of genes associated with pluripotency and embryonal stem cell identity, including POU5F1 , UTF1 , DPPA4 , and PRDM14 . In contrast, post-chemotherapy tumors showed upregulation of immediate early stress response genes, inflammatory and cytokine signaling pathways, EGFR-related growth factor signaling, and metabolic stress adaptation. Conclusions: Post-chemotherapy viable GCTs are characterized by loss of pluripotent transcriptional programs and acquisition of stress-responsive, inflammatory, and adaptive signaling pathways. These transcriptional changes provide insight into the biology of chemotherapy resistance in GCTs and may have prognostic and therapeutic implications.
Mego et al. (Wed,) studied this question.