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.
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.
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).
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.
Clinical genitourinary cancer. 2026 Apr 01 [Epub ahead of print]
Donghyun Kim, Yasser Ged, Petros Grivas, Parminder Singh, Bilal Rahim, Yousef Zakharia
Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Internal Medicine, University of Iowa Health Care, Iowa City, IA. Electronic address: ., Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD., Division of Hematology Oncology, Department of Medicine, University of Washington, Seattle, WA; Clinical Research Division, Fred Hutch Cancer Center, Seattle, WA., Division of Hematology and Medical Oncology, Department of Internal Medicine, Mayo Clinic Comprehensive Cancer Center, Phoenix, AZ., Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Internal Medicine, University of Iowa Health Care, Iowa City, IA., Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Internal Medicine, University of Iowa Health Care, Iowa City, IA; Division of Hematology and Medical Oncology, Department of Internal Medicine, Mayo Clinic Comprehensive Cancer Center, Phoenix, AZ.