A minimal transcriptomic signature predicts intravascular tumor extension in renal cell carcinoma

Renal cell carcinoma (RCC) with venous tumor thrombus, termed renal intravascular tumor extension (RITE), is associated with aggressive behavior and poor clinical outcomes. Yet, its underlying molecular determinants remain incompletely defined. We analyzed RNA sequencing data from three independent RCC cohorts comprising 721 samples. Two cohorts included matched samples of index tumor, tumor thrombus, and normal adjacent kidney tissue. Analyses integrated dimensionality reduction, differential gene expression, interpretable machine learning, and gene ontology approaches. Principal component analysis revealed that only these two cohorts exhibited a coherent RITE-associated transcriptional structure. Their sequencing depth was sufficient to delineate 6,317 differentially expressed genes that distinguish RITE from non-RITE tumors. SHAP-based feature attribution across logistic regression, random forest, and XGBoost yielded a robust 29-gene consensus signature, which was further distilled into a compact 13-gene panel that preserved maximal classification performance. These genes converged on biological themes, including loss of distal epithelial identity, dysregulation of ion transport pathways, and consistent enrichment of mitochondrial processes such as oxidative phosphorylation. Together, these findings define a newly discovered and uniquely refined molecular signature of venous tumor extension in RCC and highlight mechanistically relevant pathways that may inform biomarker development and future translational strategies for predicting or mitigating RITE progression.