Abstract
A number of urinary bladder urothelial carcinoma (UB UC) mRNA-based classification systems have been reported. It also has been observed that treatment response and prognosis are different for each molecular subtype. In this study, cytokeratin (CK)5/6 and CK20 immunohistochemistry (IHC) were performed, and IHC-based subgroup classification was applied. UB UC was classified into CK5/6 single-positive (SP), CK20 SP, double-positive (DP) and double-negative (DN) subgroups, and transcriptional analysis was performed. The results of gene ontology (GO) terms and functional analysis using differentially expressed genes indicate that, CK5/6 SP and DP subgroups were enriched in cell migration, immune activation, interleukin 6-Janus kinase-signal transducer and activator of transcription 3 (IL6-JAK-STAT3) signaling pathway and tumor necrosis factor-α signaling via the nuclear factor-κB (NF-κB) signaling pathway signature gene. In addition, compared with the other subgroups, the DN subgroup showed inhibited cell movement, cell migration, and cell activation. Furthermore, in survival analysis, the CK5/6 SP subgroup was significantly associated with poor progression-free survival (p = 0.008). The results of our study indicate that the CK5/6 positive subgroup exhibited high gene expression signature related to aggressive behavior and exhibited worse clinical outcome.
Highlights
Bladder cancer worldwide is the 10th most common form of malignant tumor and has the 14th highest cancer-associated mortality [1]
Several studies have been published that utilized next-generation sequencing (NGS) analysis to analyze and classify Urinary bladder urothelial carcinoma (UB UC) according to gene expression [3,4,5]
The ingenuity pathway analysis (IPA) results showed that some functions related to immune response and cell migration were activated in the CK5/6 SP and DP subgroups (Table 3)
Summary
Bladder cancer worldwide is the 10th most common form of malignant tumor and has the 14th highest cancer-associated mortality [1]. Bladder cancers showing positive KRT5/6, KRT14 expression and negative GATA3, FOXA1 expression were classified into a specific subtype, known as basal-squamous-like (BASQ) [6]. In a phase II clinical trial of IMvigor210, different treatment responses to the immune check point inhibitor atezolizumab and prognosis were reported among molecular subtypes in patients with locally advanced urothelial carcinoma. In phase II clinical trial of CheckMate 275 using nivolumab, another immune check point inhibitor, different treatment responses were reported among molecular subtypes in patients with advanced stage urothelial carcinoma [12,13,14,15]. In the mRNA-based subtype classification, high expression of KRT5 is classified as the basal type and high expression of KRT20 is classified as the luminal type [4,5,16,17]. We could expect great clinical utility if two IHC assays could predict the molecular genetic characteristics of a tumor
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