Stage-dependent prognostic impact of GATA3/FOXA1-defined luminal-like subtype in upper tract urothelial carcinoma

Abstract

Upper tract urothelial carcinoma (UTUC) exhibits poorly defined molecular heterogeneity and lacks reliable biomarkers for subtype classification. We investigated the prognostic impact of luminal-like UTUC defined by GATA3 and FOXA1 immunohistochemistry in 245 surgically resected UTUC cases. The cohort included 183 non-muscle-invasive (NMI) and 62 muscle-invasive (MI) tumors. The Kaplan-Meier and Cox analyses demonstrated that the luminal-like subtype had opposite prognostic implications depending on muscle invasiveness: poorer outcomes in NMI-UTUC but more favorable outcomes in MI-UTUC. To provide biological context, we additionally analyzed independent RNA-seq datasets stratified by GATA3 and FOXA1 expression. Luminal-like tumors showed consistent upregulation of cell growth and developmental pathways, whereas non-luminal-like tumors, particularly in MI cases, were enriched for immune-related signatures such as antigen presentation and T-cell recruitment. Exploratory biomarker screening also identified one luminal-like gene and three non-luminal-like genes with survival implications. Using a large cohort of patients with UTUC, we establish GATA3 and FOXA1 as robust surrogate IHC biomarkers for luminal-like UTUC. Their prognostic value is dependent on muscle invasiveness, with transcriptomic analyses providing complementary mechanistic insights.