Association between proto-oncogene N-RAS transcript level and overall survival in node-negative muscle-invasive bladder cancer

Introduction: Despite the unprecedented advancement in treatment landscape of muscleinvasive 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 implication remains 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 patient 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 (cT2-4a cN0 M0/x) compared to the low N-RAS expression with hazard ratio (HR) 1.91 (95% CI 1.17-3.11,p=0.007), although N-RAS expression did not emerge as a significant factor associated with overall survival upon multivariable adjustment for other clinicopathologic variables.Significant OS benefit with cisplatin-based chemotherapy was present in the low N-RAS group with HR 0.28 (95% CI 0.10-0.81,p=0.019), 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<0.0001).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 overall survival benefit with cisplatin-based chemotherapy.