Younger and older clear cell kidney cancers follow distinct metabolic programs

Clear cell renal cell carcinoma diagnosed in adults aged 45 or younger appears to be a biologically distinct disease from the same cancer diagnosed later in life, according to a retrospective study published in Clinical and Experimental Medicine. The researchers analyzed 1,979 patients with non-metastatic, sporadic clear cell renal cell carcinoma, dividing them into an early-onset group diagnosed at age 45 or below and a late-onset group diagnosed above that age. The work combined clinical and pathological comparisons with gene expression analyses of TCGA-KIRC data, metabolomic profiling, functional assays and immunohistochemistry on 30 tumor samples and primary cancer cell lines.

On clinical outcomes, the early-onset group fared better. These patients had lower tumor grade and stage, less lymph node involvement, and improved cancer-specific and recurrence-free survival compared with the late-onset group. In multivariate analysis, age, nuclear grade, tumor stage, nodal metastases and tumor size emerged as independent prognostic factors. The study was retrospective, so the reported associations describe differences between groups rather than the effect of any intervention.

Molecular profiling revealed clear differences between the two age groups. Early-onset tumors had a lower tumor mutational burden, reduced DNA methylation, and fewer mutations in the chromatin-regulating genes PBRM1 and SETD2. Because the analysis drew on TCGA-KIRC data for gene expression and pathway work, the molecular findings reflect patterns observed in that cohort alongside the metabolomic and functional studies of the 30-sample set.

The most striking divergence appeared in metabolism. Early-onset tumors favored glycolysis, tricarboxylic acid cycle activity and oxidative phosphorylation, while late-onset tumors showed increased pentose phosphate pathway activity and lipid accumulation. Functional assays mirrored this split: late-onset cells displayed higher proliferation and migration, whereas early-onset cells showed greater angiogenic potential. The researchers also observed distinct expression patterns of the hypoxia-related factors HIF1α and HIF2α between the groups, and these patterns correlated with the metabolic differences.

The authors conclude that early- and late-onset sporadic clear cell renal cell carcinoma are distinct biological phenotypes with divergent clinical outcomes, molecular alterations and metabolic programs. They position these findings as a biological rationale for investigating age-associated metabolic vulnerabilities in clear cell renal cell carcinoma, noting that the cancer’s incidence is increasing in younger adults and that whether younger patients harbor a distinct metabolic and molecular phenotype had previously remained poorly understood. As the article is shared ahead of final editorial production, the published version is subject to further edits before the final Version of Record replaces it.

Subject of Research: Metabolic and molecular differences between early- and late-onset sporadic clear cell renal cell carcinoma

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

Article References: Lucarelli, G., Lasorsa, F., Milella, M., d’Amati, A., Ingravallo, G., Pandolfo, S. D., Caniglia, A., Trotti, I., Zito, F. A., Naglieri, E., Azzariti, A., Ribatti, D., Tamma, R., Ditonno, P., & Rutigliano, M. (2026). Distinct metabolic and molecular programs define early- and late-onset sporadic clear cell renal carcinoma. Clinical and Experimental Medicine. https://doi.org/10.1007/s10238-026-02374-2

Image Credits: AI Generated

DOI: 10.1007/s10238-026-02374-2

Keywords: clear cell renal cell carcinoma, early-onset cancer, metabolomics, TCGA-KIRC, PBRM1, SETD2, HIF1α, HIF2α, glycolysis, oxidative phosphorylation, tumor mutational burden, prognosis