Distinct metabolic and molecular programs define early- and late-onset sporadic clear cell renal carcinoma

Renal cell carcinoma (RCC) is a heterogeneous malignancy with increasing incidence in younger adults, however whether sporadic clear cell RCC diagnosed in younger patients represents a distinct metabolic and molecular phenotype remains poorly understood. A retrospective analysis was conducted on 1,979 patients with non-metastatic, sporadic ccRCC, stratified by age at diagnosis (≤ 45 years [early-onset, E-RCC] vs. >45 years [late-onset, L-RCC]). Clinical and pathological features were compared. Gene expression and pathway analyses were performed using TCGA-KIRC data. Metabolomic profiling, functional assays and immunohistochemistry were conducted on 30 tumor samples and primary cancer cell lines stratified into E-RCC and L-RCC. E-RCC patients exhibited lower tumor grade and stage, less lymph node involvement, and improved cancer-specific and recurrence-free survival compared to L-RCC. Multivariate analysis identified age, nuclear grade, tumor stage, nodal metastases, and tumor size as independent prognostic factors. Molecular analyses revealed that E-RCC had lower tumor mutational burden, reduced DNA methylation, and fewer mutations in PBRM1 and SETD2. Metabolomic profiling showed E-RCC favored glycolysis, tricarboxylic acid cycle activity, and oxidative phosphorylation, while L-RCC displayed increased pentose phosphate pathway activity and lipid accumulation. Functional assays demonstrated higher proliferation and migration in L-RCC cells, whereas E-RCC cells exhibited greater angiogenic potential. Distinct expression patterns of HIF1α and HIF2α were observed between groups, correlating with metabolic differences. Early- and late-onset sporadic ccRCC are distinct biological phenotypes with divergent clinical outcomes, molecular alterations, and metabolic programs. These findings provide a biological rationale for investigating age-associated metabolic vulnerabilities in ccRCC.