Deciphering mitotic catastrophe-associated transcriptomic patterns in renal cell carcinoma: prognostic significance...

Renal cell carcinoma (RCC) is a highly heterogeneous malignancy with complex molecular features. Mitotic catastrophe (MC), a key regulator of cell fate during aberrant mitosis, contributes to tumor progression and therapeutic response; however, its prognostic relevance in RCC remains unclear.

We integrated multi-omics, clinical, and imaging data from TCGA and multiple external cohorts. Prognostic mitotic catastrophe-related genes were identified to construct a mitotic catastrophe-related score (MCRS) using CoxBoost and random survival forest models. Associations with clinicopathologic features, immune contexture, and mutational profiles were analyzed. Single-cell RNA sequencing characterized Cyclin F (CCNF) expression and its association with immunotherapy-treated cohort outcomes, and these findings were further validated in vitro and in murine xenograft models.

The nine-gene MCRG signature stratified patients into high- and low-risk groups with strong prognostic performance (TCGA 1-, 3-, 5-year AUCs > 0.9). High MCRS correlated with advanced stage, adverse CT features, angiogenesis, inflammatory signaling, regulatory T-cell infiltration, and elevated LAG3/TIGIT expression. MTOR mutations were enriched in high-risk tumors. SurvSHAP(t) analysis identified CCNF as the top prognostic contributor. CCNF was upregulated in tumor tissues and enriched in proliferating cells and epithelial cells. High CCNF expression was associated with worse survival and inferior outcomes in immunotherapy-treated cohorts. Overexpression of CCNF promoted RCC cell proliferation, migration, invasion, and in vivo tumor growth, partly through mTOR pathway activation.

We established a robust MC-based prognostic model for RCC and identified CCNF as a key regulator of tumor progression and the immune microenvironment, characterized by increased Treg abundance and checkpoint expression. CCNF may represent a candidate biomarker and therapeutic target in RCC, although its relevance to outcomes in immunotherapy-treated cohorts requires further validation.