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

Abstract

820 Background: Prognostication of urothelial bladder carcinoma relies on clinicopathologic factors including histology, TNM stage and genomic profiles. The prognostic value of tumor subtyping based on gene expression signature clustering has been proposed, but their clinical value remains uncertain. Here, we retrospectively review node-negative muscle-invasive urothelial bladder carcinoma RNA-Seq data and demonstrate that “low” mRNA expression of proto-oncogene N-RAS is associated with significantly superior overall survival (OS). Methods: The Cancer Genome Atlas (TCGA) Pan-Cancer project batch-corrected primary tumor RNA-Seq expression profiles of 114 urothelial bladder carcinoma cases (pT2-4a pN0 M0, n=97; any pT pN1 M0, n=17) and their associated clinical data were retrieved from the cBioPortal. Cohort median was used as a reference to determine “high” vs. “low” transcript levels of N-RAS gene. Log-rank Kaplan-Meier was performed for survival analysis. Two-tailed Mann-Whitney test was performed for group comparison. Results: In node-negative disease group, “low” N-RAS expression (n=58) was associated with significantly superior 5-year OS compared to patients with “high” N-RAS expression (n=39) with hazard ratio (HR) for death at 0.41 (95% CI 0.19-0.86, p=0.007). N-RAS expression-associated differential OS was independent from age group (≥67 vs. <67), gender, T stage (T2 vs. T3-4a), cisplatin-based chemotherapy exposure or underlying TP53, RB1, FGFR3, RAS mutation. However, in patients with “low” N-RAS expression the 5-year OS of those who received cisplatin-based chemotherapy (n=5) was significantly superior compared to those who did not (n=53) with HR for death at 0.26 (95% CI 0.07-0.98, p=0.047). “High” N-RAS expression group was associated with higher CD274 (PD-L1) mRNA expression (x3.9 higher median value, p<0.0001) and larger portion of patients with ≥10 mut/Mb tumor mutational burden (40% vs. 23%) compared to “low” N-RAS expression group. In node-positive disease group, N-RAS expression-dependent differential OS was not present. Conclusions: In node-negative muscle-invasive urothelial bladder carcinoma, “low” N-RAS expression was associated with superior OS which was most pronounced in patients who received cisplatin-based chemotherapy. “High” N-RAS expression was associated with higher PD-L1 mRNA expression and tumor mutational burden. We speculate that N-RAS transcript level might be a novel biomarker for prognostication and treatment response as an adjunct to TNM stage. Further investigation is warranted.