Age-dependent gene alterations is associated with distinct immune profiles in renal cell carcinoma.

[BACKGROUND] The role of genetic alterations (GAs) in renal cell carcinoma (RCC) accumulating over time remains unclear. We examined GAs by age group and their associations with overall survival (OS), immune infiltration, and immune checkpoint inhibitor (ICI) response.

[METHODS] Next-generation sequencing data from 3,360 RCC patients in the AACR Project GENIE registry were analyzed. GAs with >5% frequency were stratified by age into <45, 45 to 75, and >75 years. Kaplan-Meier analysis assessed OS. Immune profiles and ICI responses were evaluated using TIMER2.0 and ROC Plotter. Co-occurrence and synthetic lethality (SL) analyses were also performed. P < 0.05 was considered significant.

[RESULTS] Among 3,360 patients, 53.8% had clear cell, 25.5% papillary, and 12.1% chromophobe RCC. Younger and older patients exhibited significantly higher MUC4 (13.9%), TP53 (9.6%), and VHL (48.4%), TTN (21.0%), and PBRM1 (27.8%) GAs, respectively (P < 0.001). Subtype analysis revealed that clear cell RCC largely drove these patterns. While chromophobe RCC in older patients showed significantly higher KMT2C, MST1, and MUC4 alterations, papillary tumors showed none. TP53, VHL, TTN, and PBRM1 alterations were associated with worse OS (P < 0.001). TP53, TTN, and PBRM1 also showed distinct immune profiles, although differences in ICI response were not demonstrable, presumably due to small sample size. Several novel SL pairs were identified.

[CONCLUSION] Age-related GAs in RCC are largely driven by clear cell and chromophobe subtypes. These alterations are associated with differences in survival and immune profiles but not with ICI response.