Abstract
PurposeRecently discovered molecular classifications for urothelial bladder cancer appeared to be promising prognostic and predictive biomarkers. The present study was conducted to evaluate the prognostic impact of molecular subtypes assessed by two different methodologies (gene and protein expression), to compare these two approaches and to correlate molecular with histological subtypes in a consecutively collected, mono-institutional muscle-invasive bladder cancer (MIBC) cohort.Methods193 MIBC were pathologically re-evaluated and molecular subtypes were assessed on mRNA (NanoString technology, modified 21-gene-containing MDACC approach) and protein levels (immuno-histochemical [IHC] analysis of CK5, CK14, CD44, CK20, GATA3 and FOXA1). Descriptive statistical methods and uni-/multi-variable survival models were employed to analyze derived data.ResultsNeither gene expression nor protein-based subtyping showed significant associations with disease-specific (DSS) or recurrence-free survival (RFS). Agreement between mRNA (reference) and protein-based subtyping amounted 68.6% for basal, 76.1% for luminal and 50.0% for double-negative tumors. Histological subtypes associated with RFS in uni-variable (P = 0.03), but not in multivariable survival analyses. Tumors with variant histology predominantly showed luminal subtypes (gene expression subtyping: 36/55 cases, 65.5%; protein subtyping: 44/55 cases, 80.0%). Squamous differentiation significantly associated with basal subtypes (gene expression subtyping: 44/45 squamous cases, 97.8%; protein subtyping: 36/45 cases, 80.0%).ConclusionIn our consecutive cystectomy cohort, neither gene, protein expression-based subtyping, nor histological subtypes associated with DSS or RFS in multi-variably adjusted survival analyses. Application of a limited IHC subtyping marker panel showed high concordance of 83.9% with gene expression-based subtyping, thus underlining the utility for subtyping in pathological routine diagnostics. In addition, histological MIBC subtypes are strong indicators for intrinsic subtypes.
Highlights
Urothelial bladder cancer (UBC) is among the tenth-most common cancers worldwide, and is a prime example of carcinogen-derived cancer with smoking representing the main risk factor [1]
Modern high-throughput genomic technologies rapidly led to new insights in molecular heterogeneity of UBC, e.g., distinct luminal, basal and neuroendocrine molecular subtypes identified by transcriptional analyses
While earlier studies suggested an improved response to neoadjuvant chemotherapy (NAC) in basal carcinomas [11], more recent findings indicate that NAC response is rather dependent on immune infiltration than intrinsic differentiation [12]
Summary
Urothelial bladder cancer (UBC) is among the tenth-most common cancers worldwide, and is a prime example of carcinogen-derived cancer with smoking representing the main risk factor [1]. Several widely overlapping subtyping approaches with heterogeneous nomenclatures have been proposed mainly for MIBC [4,5,6,7,8,9], which were summarized into six consensus subtypes in 2020 coordinated by the Bladder Cancer Molecular Taxonomy Group (BCMTG) [10]. The discovery of these three major molecular phenotypes, luminal, basal and neuroendocrine-like tumors, represents a milestone in bladder cancer research. Smaller case series suggested that subtypes correlate with histological subtypes/variant histologies of MIBC [2, 5, 6, 8, 10, 13, 14], but systematic analysis in coherent cohorts is lacking
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
