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

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Introduction Despite the unprecedented advancement in 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 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. Micro-Abstract Muscle invasive bladder cancer (MIBC) treatment landscape is rapidly evolving. However, clinically reliable prognostic indicators are yet to be established. In this retrospective analysis of The Cancer Genome Atlas Bladder Cancer tumor RNA-Seq data, high N-RAS expression was associated with inferior 5-year overall survival compared to low expression, with a HR 1.91 (95% CI 1.17-3.11, p=0.007), in node-negative MIBC.

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