Metabolic reprogramming in chromophobe renal cell carcinoma: Transcriptomic insights into the transition from indolent to aggressive disease.

Abstract

530 Background: Chromophobe renal cell carcinoma (CHRCC) is an uncommon subtype that is usually indolent but becomes aggressive in later stages. The mechanisms driving this shift are unclear, though mitochondrial and metabolic alterations are implicated. Using TCGA transcriptomic data, the study examined stage-specific changes in oxidative phosphorylation, glycolysis, and glutamine metabolism genes to identify metabolic pathways associated with tumor progression. Methods: Transcriptomic data for chromophobe renal cell carcinoma (KICH) were obtained from The Cancer Genome Atlas (TCGA) and analyzed using TIMER 2.0 and GEPIA 2.0 platforms. Differential gene expression was assessed with a p value < 0.05 and |log₂FC| ≥ 1 as cut-off criteria. Results were cross-validated with the NCBI-GEO dataset GSE15641 (adjusted p < 0.05, |log₂FC| ≥ 1). Survival analysis was performed using GEPIA 2.0 (TCGA + GTEx) and the Human Protein Atlas to examine associations between metabolic gene expression and overall survival. Results: Transcriptomic analysis showed significant upregulation of oxidative phosphorylation genes IDH3A, OGDH, and SDHA (p < 0.05). No significant change in expression was observed for glycolysis-related genes (LDHA, SLC2A1) or for the glutaminolysis marker (ACLY). Cross-validation across TCGA, GTEx, and NCBI-GEO datasets confirmed these expression patterns. In survival analysis, high expression of LDHA and SLC2A1 (glycolysis) and ACLY (glutaminolysis) was associated with shorter overall survival, while IDH3A, OGDH, and SDHA (oxidative phosphorylation) showed variable or nonsignificant prognostic associations. Conclusions: This study highlights metabolic heterogeneity in chromophobe renal cell carcinoma. Transcriptomic profiling across independent datasets revealed that early-stage tumors predominantly express oxidative phosphorylation–related genes, whereas advanced disease shows a relative increase in glycolytic and glutaminolysis-associated gene expression. The association of LDHA, SLC2A1, and ACLY overexpression with poorer survival suggests that metabolic pathway shifts contribute to disease aggressiveness. These findings provide new insight into the metabolic evolution of chromophobe RCC and identify potential molecular targets for future therapeutic exploration.