Association Between Proto-Oncogene N-RAS Transcript Level and Overall Survival in Node-Negative Muscle-Invasive Bladder Cancer

INTRODUCTION: Despite the unprecedented advancement in the treatment landscape of muscle-invasive bladder cancer (MIBC), prognostic biomarkers remain investigational. In bladder cancer, oncogenic rat sarcoma (RAS) mutations mostly occur in H-RAS or K-RAS, whereas N-RAS mutations are rare. Overexpression of N-RAS has been previously reported, although its clinical implications remain uncertain. This study aimed to investigate the prognostic implications of N-RAS expression in MIBC. PATIENTS AND METHODS: Batch-corrected normalized transcript counts of The Cancer Genome Atlas Bladder Cancer project (n = 411) were analyzed, where 218 patients had non-metastatic node-negative MIBC. Tumor N-RAS transcript level of individual patients was classified as "high" or "low" using the cohort median as a reference value, and survival analyses were performed according to this stratification. RESULTS: High N-RAS expression was associated with inferior 5-year overall survival in node-negative MIBC (pT2-4a pN0 M0/x) compared to the low N-RAS expression, with a hazard ratio (HR) 1.91 (95% CI, 1.17-3.11, P = .007), although N-RAS expression did not emerge as a significant factor associated with overall survival upon multivariable adjustment for other clinicopathologic variables. Significant overall survival benefit with cisplatin-based chemotherapy was present in the low N-RAS group with HR 0.28 (95% CI, 0.10-0.81, P = .019), but not in the high N-RAS group. The high N-RAS group was associated with higher CD274 (PD-L1) transcript levels compared to the low N-RAS group (median 62.6 vs. 9.2, P < .0001). CONCLUSION: This retrospective study demonstrates that N-RAS transcript levels may be prognostic for node-negative MIBC. Low N-RAS transcript levels may also be associated with an overall survival benefit with cisplatin-based chemotherapy.