Background and objectives Age influences the development and progression of clear cell renal cell carcinoma (ccRCC). Management of non-metastatic (M0) ccRCC involves surgery, adjuvant immune checkpoint inhibition (e.g., pembrolizumab) and surveillance. For metastatic (M1) ccRCC, treatment combines immune checkpoint inhibitors with anti-angiogenic therapies, achieving long-term remission in approximately 30% of patients. Despite these advancements, a definitive cure remains elusive for most individuals. Furthermore, predictive criteria for relapse that incorporate age-specific variations are lacking, highlighting the critical need for prognostic models to optimize outcomes across diverse age groups. This study aimed to validate tumor aggressiveness markers in ccRCC, focusing on age as a determinant factor.

Methods 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) and disease-free survival (DFS) post nephrectomy and progression-free survival upon tyrosine kinase inhibitors and immunotherapies.

Key findings and limitations Of 110 age-differentiated genes identified, 31 were significantly correlated with OS and DFS. Poor prognostic markers included CIAO1, EIF2B1, NARF, UBE2G2, and SART3, while TMEM167B emerged as a good prognostic marker, and a potential predictive biomarker for immunotherapy efficacy. Limitations include the need for larger independent cohort validation and deeper exploration of gene mechanisms.

Conclusions and clinical implications 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 explores age-dependent differentially expressed genes in clear cell renal cell carcinoma (ccRCC) and proposes a potential age-specific prognostic gene signature that could be applicable to both non-metastatic and metastatic patients. This signature may assist in identifying individuals at higher risk of relapse. Among the identified genes, TMEM167B is highlighted as a candidate associated with favorable prognosis and shows promise as a potential predictive biomarker for immunotherapy efficacy.

Patient Summary Aggressiveness in ccRCC varies with age and gene expression. Tailored treatments based on these factors may enhance outcomes and minimize side effects, particularly for patients over 75 years of age.

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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