Prognostic Significance of NOTCH1-ICD Expression in Renal Cell Carcinoma

Abstract

The NOTCH1 signaling pathway regulates proliferation, differentiation, and apoptosis, with its intracellular domain (NOTCH1-ICD) reflecting pathway activation. While NOTCH1 dysregulation has been linked to renal cell carcinoma (RCC), its prognostic significance across RCC subtypes remains unclear. In this study, we analyzed NOTCH1-ICD immunohistochemical expression in 101 RCC patients: 69 clear cell RCC (ccRCC), 15 papillary RCC (pRCC), and 17 chromophobe RCC (chRCC), and correlated results with clinicopathological features and survival. In ccRCC, high NOTCH1-ICD expression (>15% positive nuclei) identified a small subgroup of tumors with aggressive features and a trend toward poorer overall survival; however, in multivariate analysis, tumor grade emerged as the only independent prognostic factor (HR = 3.36, 95% CI: 1.07–10.49, p = 0.037), while NOTCH1 showed nonsignificant association with poorer survival (HR = 1.30, 95% CI: 0.87–1.93, p = 0.203). In contrast, chRCC and pRCC exhibited minimal NOTCH1-ICD expression, with no observable impact on survival. NOTCH1-ICD was also detected in tumor endothelial cells, suggesting potential vascular mimicry. These findings indicate that NOTCH1-ICD may reflect tumor aggressiveness in ccRCC and could have implications for targeted therapy, but its independent prognostic value requires validation in larger cohorts.