The identification of novel cancer susceptibility and prognostic biomarkers in RCC and other tumor types through “omic” technologies is a long-lasting objective of our group. We are currently focused on cisplatin resistance in testicular cancer, the most common tumor in young men, applying transcriptomic analyses to uncover pathways and microenvironment features predictive of response and able to guide therapy.
Testicular germ cell tumors (TGCTs) are the most common cancers in young men, accounting for the majority of testicular malignancies and typically occurring between ages 15 and 35. Although most patients respond well to cisplatin, a subset with advanced disease exhibits primary resistance or relapse and currently lacks effective treatments. Proposed mechanisms of cisplatin resistance include mutations in DNA repair genes, loss of pluripotency, and epigenetic remodeling, but reliable predictive biomarkers are lacking.
We aim to identify molecular hallmarks of cisplatin resistance through comprehensive transcriptomic analysis of intermediate- and poor-prognosis TGCT patients. Our analyses have revealed pathways associated with resistance and highlighted the tumor microenvironment as a key determinant of therapeutic response. These findings provide a foundation for developing predictive biomarkers and guiding future therapies for resistant TGCTs (Figure 1; unpublished results).
Figure 1. Unsupervised hierarchical clustering heatmap displaying gene expression data from testicular germ cell tumor (TGCT) samples. The dendrogram shows sample clustering based on expression similarity. The clustering reveals distinct molecular patterns associated with histological subtypes and suggests potential gene expression signatures that correlate with platinum-based chemotherapy response in TGCT patients. Cisplatin-resistant tumors showed upregulation of DNA repair and cell cycle pathways, while apoptosis and immune pathways were downregulated. Tumor microenvironment analysis revealed that cisplatin-sensitive cases had greater immune cell infiltration, enrichment antitumor signatures, higher expression of immune checkpoint molecules, and increased presence of cancer-associated fibroblasts. Clinical annotations are displayed above the heatmap: Sample_Pairs indicates paired samples, Tumor/Normal distinguishes malignant from normal tissue, Primary/MTX denotes primary tumors versus metastases, Seminoma/NonSeminoma indicates histological classification, Stromal and Immune represent estimated stromal and immune cell infiltration levels using computational deconvolution (ESTIMATE algorithm), and Sen/Res indicates cisplatin sensitivity status.