Background: Age significantly influences the development and progression of clear cell renal cell carcinoma (ccRCC). While non-metastatic (M0) ccRCC is managed through surgery and surveillance, and metastatic (M1) ccRCC benefits from immune checkpoint inhibitors and anti-angiogenic therapies, long-term remission remains elusive. Predictive criteria for relapse tailored to different age groups are lacking, emphasizing the need for age-specific prognostic models. Objective and Methods: This study aimed to validate tumor aggressiveness markers in ccRCC, focusing on age as a determinant factor. Data from The Cancer Genome Atlas (TCGA) were analyzed to identify age-related gene expression differences, which were then validated using an independent cohort and ccRCC cell lines. Random Survival Forest models were employed to predict overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). Results: Of 110 age-differentiated genes identified, 31 were significantly correlated with OS and DFS. Key poor prognostic markers included CIAO1, EIF2B1, NARF, UBE2G2, and SART3. TMEM167B emerged as particularly promising, showing distinct expression patterns in ccRCC models and potential as a predictive biomarker for immune checkpoint inhibitor efficacy. Limitations include the need for larger independent cohort validation and deeper exploration of gene mechanisms. Conclusions: The study presents age-informed prognostic models that integrate gene expression profiles, offering a foundation for personalized treatment strategies. TMEM167B stands out as a novel candidate for improving age-specific ccRCC management. Advancing Practice: What does the study add? This study identifies age-dependent differentially expressed genes in clear cell renal cell carcinoma (ccRCC). We developed an age-specific prognostic gene signature for both non-metastatic and metastatic patients, which could aid in identifying individuals at higher risk of relapse. Patient Summary: Aggressiveness in ccRCC varies with age and gene expression. Tailored treatments based on these factors may enhance outcomes and minimize side effects, especially for elderly patients.

The authors have declared no competing interest.

This study was funded by the French ministry of research, the CNRS, The League against cancer, the French association for cancer research (ARC, labelled team and contract ARCAGEING2023020006332), the foundation for medical research (FRM).

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TCGA data base and publication of Beuselinck et al

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