Abstract
Recently, muscle-invasive bladder cancer (MIBC) has been subclassified by gene expression profiling, with a substantial impact on therapy response and patient outcome. We tested whether these complex molecular subtypes of MIBC can be determined by mRNA detection of keratin 5 (KRT5) and keratin 20 (KRT20). Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) was applied to quantify gene expression of KRT5 and KRT20 using TaqMan®-based assays in 122 curatively treated MIBC patients (median age 68.0 years). Furthermore, in silico analysis of the MD Anderson Cancer Center (MDACC) cohort (GSE48277 + GSE47993) was performed. High expression of KRT5 and low expression of KRT20 were associated with significantly improved recurrence-free survival (RFS) and disease-specific survival disease specific survival (DSS: 5-year DSS for KRT5 high: 58%; 5-year DSS for KRT20 high: 29%). KRT5 and KRT20 were associated with rates of lymphovascular invasion and lymphonodal metastasis. The combination of KRT5 and KRT20 allowed identification of patients with a very poor prognosis (KRT20+/KRT5−, 5-year DSS 0%, p < 0.0001). In silico analysis of the independent MDACC cohorts revealed congruent results (5-year DSS for KRT20 low vs. high: 84% vs. 40%, p = 0.042). High KRT20-expressing tumors as well as KRT20+/KRT− tumors were significantly enriched with aggressive urothelial carcinoma variants (micropapillary, plasmacytoid, nested).
Highlights
Urothelial bladder cancer (UBC) is one of the 10 most common malignancies worldwide, with nearly 386,000 new cases and nearly 150,200 deaths per year [1]
The MD Anderson Cancer Center (MDACC) subtypes resembled those identified for breast cancer and showed typical mRNA expression profiles of basal and luminal markers, with keratin 5 (KRT5) expression being highly upregulated in basal and keratin 20 (KRT20) being upregulated in luminal tumors
High KRT5 mRNA expression identified a subgroup of nonluminal Non-muscle-invasive bladder cancer (NMIBC) that showed superior recurrence-free survival (RFS) and progression-free survival (PFS) despite being World Health Organization (WHO) grade 3 and stage pT1
Summary
Urothelial bladder cancer (UBC) is one of the 10 most common malignancies worldwide, with nearly 386,000 new cases and nearly 150,200 deaths per year [1]. Several groups have started to characterize UBC by gene expression profiling, as was previously done for breast cancer [6,7], which identified highly prognostic molecular signatures [5,8,9,10,11,12,13,14,15,16,17,18,19]. The MD Anderson Cancer Center (MDACC) subtypes resembled those identified for breast cancer and showed typical mRNA expression profiles of basal and luminal markers, with keratin 5 (KRT5) expression being highly upregulated in basal and keratin 20 (KRT20) being upregulated in luminal tumors. High KRT5 mRNA expression identified a subgroup of nonluminal NMIBC that showed superior recurrence-free survival (RFS) and progression-free survival (PFS) despite being World Health Organization (WHO) grade 3 and stage pT1. NMIBC with high KRT20 mRNA expression was accompanied by significantly increased rates of tumor progression
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